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"abstract": "High-dose chemotherapy with autologous stem-cell rescue (SCR) is a key component of high-risk neuroblastoma (HRNB) therapy. Carboplatin, etoposide, and melphalan (CEM) or busulfan and melphalan (Bu/Mel) are the most evaluated, effective high-dose chemotherapy for HRNB on the basis of results from major cooperative group studies. Toxicity profiles vary between these regimens, and practice variation exists regarding the preferred high-dose therapy (HDT). We sought to evaluate the safety of HDT and autologous SCR for HRNB in a resource-limited country (Egypt) compared with the resource-rich United States.\n\n\n\nWe performed a retrospective comparative review of single CEM-based HDT/SCR outcomes through day 100 for HRNB at the Fred Hutchinson Cancer Research Center (FH) in the United States (2005 to 2015) versus Bu/Mel-based HDT at El-Sheikh Zayed Specialized Hospital (SZ) in Egypt (2009 to 2015).\n\n\n\nForty-four patients at FH and 77 patients at SZ were reviewed. Pretransplant hepatic comorbidities were significantly higher at SZ (29 of 77 v nine of 44; P = .05), with 19 of 77 patients at SZ having hepatitis infection. Engraftment was delayed after SZ-Bu/Mel therapy compared with FH-CEM therapy for neutrophils (median 12 days v 10 days, respectively; P < .001) and platelets (median 20 days v 18 days, respectively; P < .001). Sinusoidal obstruction syndrome occurred later, after SZ-Bu/Mel therapy (median 19 days v 7 days; P = .033), and four of eight cases were fatal (six of eight patients had underlying hepatitis infection), whereas three of three cases after FH-CEM therapy were moderately severe. Resource utilization associated with the number of days with fever, antibiotic use, and the number of transfusions administered was significantly higher after FH-CEM therapy than after SZ-Bu/Mel therapy.\n\n\n\nUse of autologous stem-cell transplantation is feasible in the context of a resource-limited country.",
"affiliations": "Mahmoud M. Elzembely, Paul A. Carpenter, and K. Scott Baker, Fred Hutchinson Cancer Research Center; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, University of Washington; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, Seattle Children's Hospital, Seattle WA; Mahmoud M. Elzembely, Khaled F. Riad, and Heba A. Sayed, South Egypt Cancer Institute, Assiut University, Assiut; Alaa El-Haddad, El-Sheikh Zayed Specialized Hospital; Alaa El-Haddad, 57357 Children's Cancer Hospital; and Alaa El-Haddad, Cairo University, Cairo, Egypt.;Mahmoud M. Elzembely, Paul A. Carpenter, and K. Scott Baker, Fred Hutchinson Cancer Research Center; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, University of Washington; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, Seattle Children's Hospital, Seattle WA; Mahmoud M. Elzembely, Khaled F. Riad, and Heba A. Sayed, South Egypt Cancer Institute, Assiut University, Assiut; Alaa El-Haddad, El-Sheikh Zayed Specialized Hospital; Alaa El-Haddad, 57357 Children's Cancer Hospital; and Alaa El-Haddad, Cairo University, Cairo, Egypt.;Mahmoud M. Elzembely, Paul A. Carpenter, and K. Scott Baker, Fred Hutchinson Cancer Research Center; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, University of Washington; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, Seattle Children's Hospital, Seattle WA; Mahmoud M. Elzembely, Khaled F. Riad, and Heba A. Sayed, South Egypt Cancer Institute, Assiut University, Assiut; Alaa El-Haddad, El-Sheikh Zayed Specialized Hospital; Alaa El-Haddad, 57357 Children's Cancer Hospital; and Alaa El-Haddad, Cairo University, Cairo, Egypt.;Mahmoud M. Elzembely, Paul A. Carpenter, and K. Scott Baker, Fred Hutchinson Cancer Research Center; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, University of Washington; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, Seattle Children's Hospital, Seattle WA; Mahmoud M. Elzembely, Khaled F. Riad, and Heba A. Sayed, South Egypt Cancer Institute, Assiut University, Assiut; Alaa El-Haddad, El-Sheikh Zayed Specialized Hospital; Alaa El-Haddad, 57357 Children's Cancer Hospital; and Alaa El-Haddad, Cairo University, Cairo, Egypt.;Mahmoud M. Elzembely, Paul A. Carpenter, and K. Scott Baker, Fred Hutchinson Cancer Research Center; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, University of Washington; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, Seattle Children's Hospital, Seattle WA; Mahmoud M. Elzembely, Khaled F. Riad, and Heba A. Sayed, South Egypt Cancer Institute, Assiut University, Assiut; Alaa El-Haddad, El-Sheikh Zayed Specialized Hospital; Alaa El-Haddad, 57357 Children's Cancer Hospital; and Alaa El-Haddad, Cairo University, Cairo, Egypt.;Mahmoud M. Elzembely, Paul A. Carpenter, and K. Scott Baker, Fred Hutchinson Cancer Research Center; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, University of Washington; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, Seattle Children's Hospital, Seattle WA; Mahmoud M. Elzembely, Khaled F. Riad, and Heba A. Sayed, South Egypt Cancer Institute, Assiut University, Assiut; Alaa El-Haddad, El-Sheikh Zayed Specialized Hospital; Alaa El-Haddad, 57357 Children's Cancer Hospital; and Alaa El-Haddad, Cairo University, Cairo, Egypt.;Mahmoud M. Elzembely, Paul A. Carpenter, and K. Scott Baker, Fred Hutchinson Cancer Research Center; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, University of Washington; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, Seattle Children's Hospital, Seattle WA; Mahmoud M. Elzembely, Khaled F. Riad, and Heba A. Sayed, South Egypt Cancer Institute, Assiut University, Assiut; Alaa El-Haddad, El-Sheikh Zayed Specialized Hospital; Alaa El-Haddad, 57357 Children's Cancer Hospital; and Alaa El-Haddad, Cairo University, Cairo, Egypt.;Mahmoud M. Elzembely, Paul A. Carpenter, and K. Scott Baker, Fred Hutchinson Cancer Research Center; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, University of Washington; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, Seattle Children's Hospital, Seattle WA; Mahmoud M. Elzembely, Khaled F. Riad, and Heba A. Sayed, South Egypt Cancer Institute, Assiut University, Assiut; Alaa El-Haddad, El-Sheikh Zayed Specialized Hospital; Alaa El-Haddad, 57357 Children's Cancer Hospital; and Alaa El-Haddad, Cairo University, Cairo, Egypt.",
"authors": "Elzembely|Mahmoud M|MM|;Park|Julie R|JR|;Riad|Khaled F|KF|;Sayed|Heba A|HA|;Pinto|Navin|N|;Carpenter|Paul A|PA|;Baker|K Scott|KS|;El-Haddad|Alaa|A|",
"chemical_list": "D005047:Etoposide; D016190:Carboplatin; D002066:Busulfan; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": "10.1200/JGO.17.00118",
"fulltext": "\n==== Front\nJ Glob OncolJ Glob OncoljgojgoJGOJournal of Global Oncology2378-9506American Society of Clinical Oncology 170011810.1200/JGO.17.00118Original ReportsAcute Complications After High-Dose Chemotherapy and Stem-Cell Rescue in Pediatric Patients With High-Risk Neuroblastoma Treated in Countries With Different Resources Elzembely Mahmoud M. Park Julie R. Riad Khaled F. Sayed Heba A. Pinto Navin Carpenter Paul A. Baker K. Scott El-Haddad Alaa Mahmoud M. Elzembely, Paul A. Carpenter, and K. Scott Baker, Fred Hutchinson Cancer Research Center; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, University of Washington; Julie R. Park, Navin Pinto, Paul A. Carpenter, and K. Scott Baker, Seattle Children’s Hospital, Seattle WA; Mahmoud M. Elzembely, Khaled F. Riad, and Heba A. Sayed, South Egypt Cancer Institute, Assiut University, Assiut; Alaa El-Haddad, El-Sheikh Zayed Specialized Hospital; Alaa El-Haddad, 57357 Children’s Cancer Hospital; and Alaa El-Haddad, Cairo University, Cairo, Egypt.Corresponding author: K. Scott Baker, MD, MS, Pediatric Blood and Marrow Transplantation and Survivorship Programs, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, Mail Stop D5-280, Seattle, WA 98109; e-mail: ksbaker@fredhutch.org.2018 13 3 2018 4 JGO.17.00118© 2018 by American Society of Clinical Oncology2018American Society of Clinical OncologyCreative Commons Attribution Non-Commercial No Derivatives 4.0 License: https://creativecommons.org/licenses/by-nc-nd/4.0/Purpose\nHigh-dose chemotherapy with autologous stem-cell rescue (SCR) is a key component of high-risk neuroblastoma (HRNB) therapy. Carboplatin, etoposide, and melphalan (CEM) or busulfan and melphalan (Bu/Mel) are the most evaluated, effective high-dose chemotherapy for HRNB on the basis of results from major cooperative group studies. Toxicity profiles vary between these regimens, and practice variation exists regarding the preferred high-dose therapy (HDT). We sought to evaluate the safety of HDT and autologous SCR for HRNB in a resource-limited country (Egypt) compared with the resource-rich United States.\n\nPatients and Methods\nWe performed a retrospective comparative review of single CEM-based HDT/SCR outcomes through day 100 for HRNB at the Fred Hutchinson Cancer Research Center (FH) in the United States (2005 to 2015) versus Bu/Mel-based HDT at El-Sheikh Zayed Specialized Hospital (SZ) in Egypt (2009 to 2015).\n\nResults\nForty-four patients at FH and 77 patients at SZ were reviewed. Pretransplant hepatic comorbidities were significantly higher at SZ (29 of 77 v nine of 44; P = .05), with 19 of 77 patients at SZ having hepatitis infection. Engraftment was delayed after SZ-Bu/Mel therapy compared with FH-CEM therapy for neutrophils (median 12 days v 10 days, respectively; P < .001) and platelets (median 20 days v 18 days, respectively; P < .001). Sinusoidal obstruction syndrome occurred later, after SZ-Bu/Mel therapy (median 19 days v 7 days; P = .033), and four of eight cases were fatal (six of eight patients had underlying hepatitis infection), whereas three of three cases after FH-CEM therapy were moderately severe. Resource utilization associated with the number of days with fever, antibiotic use, and the number of transfusions administered was significantly higher after FH-CEM therapy than after SZ-Bu/Mel therapy.\n\nConclusion\nUse of autologous stem-cell transplantation is feasible in the context of a resource-limited country.\n\n SJS Export v1\n==== Body\nINTRODUCTION\nNeuroblastoma (NB) is the most common extra cranial solid tumor in children younger than age 14 years, representing 7% of all childhood cancer diagnoses in the United States (US) between 1999 and 2013,1 7.6% of childhood cancer diagnoses in Europe from 1998 to 2007,2 and 8% of childhood cancer diagnoses in Egypt between 2002 and 2010.3 High-risk NB (HRNB) represents nearly half of all newly diagnosed patients with NB.4 HRNB requires intensive multimodality treatment, and gradual improvements in overall survival have been achieved through the adoption of more intensive therapy and novel immunotherapeutic strategies.5 Several randomized clinical trials demonstrated that high-dose chemotherapy (HDC) with stem-cell rescue (SCR) improved event-free survival (EFS) of patients with HRNB relative to observation,6 low-dose chemotherapy,7 or dose-intensive chemotherapy.8 There is no international consensus on the best HDC regimen for consolidation treatment of HRNB. Total-body irradiation has been removed from HDC-SCR on the basis of data from the Children’s Oncology Group COG A3973 study, which demonstrated similar 5-year EFS after HDC-SCR with carboplatin, etoposide, and melphalan (CEM), followed by delayed primary site–involved field radiotherapy compared with EFS after the CCG 3891 regimen of total-body irradiation and lower-dose CEM.9 A retrospective analysis by the European Group for Blood and Marrow Transplantation of 2,741 patients with HRNB who received HDC-SCR in Europe from 1984 to 2006 demonstrated that busulfan and melphalan (Bu/Mel) therapy resulted in a significantly improved 5-year overall survival rate of 48% in first remission compared with other reported regimens.10 Hartman et al11 retrospectively reviewed 218 patients who underwent transplantation at Gustave Rousey Institute from 1980 through 1996 and demonstrated similarly that Bu/Mel was associated with better progression-free survival than other regimens. These data prompted a randomized controlled trial that was conducted by the NB group of the International Society of Pediatric Oncology (the HRNBL1/SIOPEN trial) that demonstrated superior survival for children with responsive HRNB who received Bu/Mel compared with CEM (3-year EFS: 49% v 33%; P < .001) and with less acute toxicity.12 As a result, Bu/Mel is the preferred consolidation chemotherapy regimen in Europe and some areas in the Middle East. Although Bu/Mel has been studied in pilot trials performed in North America, it has not been adopted as the standard North American consolidation regimen as a result of the discrepancy in outcomes for CEM noted in the HRNBL1/SIOPEN trial compared with those in the COG A3973 trial9 and the results of the recently completed randomized trial ANBL0532 that demonstrated a superior outcome after tandem transplantation consolidation compared with single transplantation.13\n\nThe purpose of our study was to compare acute complications, regimen-related toxicities, and 100-day survival between two regimens of HDC-SCR for the treatment of HRNB administered in two different centers within two countries with different economic status and different pretransplantation health problems.\n\nPATIENTS AND METHODS\nWe conducted a retrospective cohort study that compared patients with HRNB who were treated at either Fred Hutchinson Cancer Research Center (FH) in Seattle, WA, between 2005 and 2015 or El-Sheikh Zayed Specialized Hospital (SZ) in 6th of October, Egypt, between 2009 and 2015. SZ is the second largest hematopoietic cell transplantation (HCT) center in Egypt and performs the largest number of autologous transplantations in the country, with approximately 100 patients per year, of which 30 are pediatric patients who undergo autologous transplantation. FH is one of the largest bone marrow transplantation centers in the United States, with approximately 75 pediatric patients who undergo transplantation per year, approximately 10 of whom undergo autologous transplantation annually. Research was conducted after approval was obtained from the institutional review boards of both institutions. Eligible patients had HRNB classified by using the Children’s Oncology Group risk classification incorporating the international staging system,14 age, MYCN status, ploidy, and histology at diagnosis. Patients were included if they underwent a single HDC-SCR with Bu/Mel at SZ or with CEM at FH regardless of where they received induction therapy. Data for eligible individuals were collected from medical records and transplantation databases at each institution from the time of transplant admission until 100 days after stem-cell infusion (D+100). The following data were collected: demographics, disease status at the time of transplantation, pretransplant morbidity, HCT comorbidity index (HCT-CI),15 post-transplantation acute complications according to the Common Toxicity Criteria of Adverse Events (version 4.03),16 and D+100 mortality.\n\nHD Chemotherapy\nAt SZ, all patients received myeloablative conditioning with oral busulfan 5 mg/kg/d, divided into four oral doses—or 4 mg/kg/d if younger than age 10 years—on each of days −7, −6, −5, and −4, and intravenous melphalan 70 mg/m2/d on days −3 and −2. Therapeutic drug monitoring was not available, and busulfan levels were therefore not obtained. Anticonvulsant prophylaxis with phenytoin 6 mg/kg/d was administered on days −7 through −2. At FH, all patients received myeloablative conditioning with carboplatin 425 mg/m2 per dose—14.2 mg/kg for patients < 12 kg—on days −7, −6, −5, and −4 (dose modified according to pretransplant glomerular filtration rate and the Calvert formula)9; etoposide 338 mg/m2 per dose—11.3 mg/kg for patients < 12 kg—on days −7, −6, −5, and −4; and melphalan 70 mg/m2 per dose—2.3 mg/kg for patients < 12 kg—on days −7, −6, and −5.\n\nSupportive Care\nEligible patients at both institutions received granulocyte colony-stimulating factor (G-CSF)–mobilized peripheral blood stem cells with an infused cell dose of ≥ 2 × 106 CD34-positive cells per kilogram. At SZ, G-CSF 5 μg/kg/d was administered from day +6 post-transplantation until neutrophils > 1,000/mm3 for 3 consecutive days. At FH, G-CSF 5 μg/kg/d was administered starting 24 hours after transplantation until neutrophils > 2,000/mm3 for 3 consecutive days. At both centers, patients received transfusions with packed RBCs for hematocrit < 20% and platelet transfusion for a platelet count < 10,000/μL or in the presence of bleeding. Prophylactic ursodeoxycholic acid was used in both cohorts. Policies for the use of prophylactic antibiotics, antivirals, and antifungal were the same.\n\nEvaluation of Acute Toxicities\nToxicities were graded according to the Common Toxicity Criteria of Adverse Events (version 4.03).16 Sinusoidal obstruction syndrome (SOS) was defined according to modified Seattle17 or Baltimore criteria.18 Time to engraftment was defined as the first of 3 consecutive days of absolute neutrophil count > 500/μL and the first of 3 consecutive days of platelets ≥ 20,000/μL, at least 7 days from the last platelet transfusion. Transfusion support was quantified as the number of packed RBC and platelet transfusions received. Blood stream infection was defined as the isolation of bacteria not normally known to colonize the skin from at least one blood culture. Blood stream infections for bacteria that typically colonize the skin—coagulase-negative Staphylococcus, Propionibacterium, and Streptococcus viridians group—were defined as two consecutive positive blood cultures within 72 h, or one positive peripheral blood culture and one positive culture from an indwelling catheter within 72 h. All blood cultures were obtained in response to an infectious indication, usually fever.\n\nStatistical Analysis\nQuantitative data were expressed as medians, means, minimum, and maximum, and were compared by using Mann-Whitney U test. Qualitative data were expressed as numbers and percentages, and were compared by using χ2 test or Fischer’s exact test when appropriate. A significance level of .05 was used in all statistical tests.\n\nRESULTS\nPatient Characteristics\nAmong the 50 and 95 patients at FH and SZ, respectively, who were identified as having received HDC-SCR for upfront HRNB therapy during the study period, 44 individuals at FH received CEM and 77 patients at SZ received Bu/Mel and were eligible for review. Patients were excluded if they were conditioned with regimens other than CEM (n = 5), Bu/Mel (n = 0), and tandem transplantation (n = 1), or if records were unavailable (n = 12). Age at transplantation was significantly higher in the SZ-Bu/Mel group compared with the FH-CEM group (P = .002). Characteristics of patients at each center are listed in Table 1.\n\nTable 1 Patient Characteristics\n\nPretransplant Comorbidity\nHCT-CI scores were obtained for all patients and categorized into three groups: the first group with an HCT-CI score of 0, the second group with an HCT-CI score of 1 to 2, and the third group with and HCT-CI score of ≥ 3 (Table 1). There was no statistically significant difference in the distribution of HCT-CI scores between centers. We additionally categorized patients into HCT-CI scores 0 and ≥ 1 and observed no statistically significant difference in the proportion of patients with score ≥ 1 between the FH-CEM cohort (31.8%) and the SZ-Bu/Mel cohort (37.7%). Pretransplant hepatic comorbidity was significantly higher in the SZ-Bu/Mel cohort than in the FH-CEM cohort (88% v 47.4%, respectively; P = .05). In addition, pretransplant hepatitis was present only in the SZ-Bu/Mel cohort.\n\nAcute Complications of HDC-SCR\nMedian length for hospital stay in the FH-CEM cohort was 32 days, which was not significantly different compared with 36 days in the SZ-Bu/Mel cohort (P = .07). Details of acute complications are listed in Table 2.\n\nTable 2 Acute Complications of High-Dose Chemotherapy With Stem-Cell Rescue\n\nHematologic Toxicities\nMedian number of infused CD34-positive stem cells was significantly higher in the FH-CEM cohort compared with the SZ-Bu/Mel cohort (P ≤ .001). Median time for neutrophil engraftment was 12 days (range, nine to 48 days) for the SZ-Bu/Mel cohort and longer than the 10 days (range, eight to 39 days) observed for the FH-CEM cohort (P < .001; Fig 1). Median time to platelet engraftment was 20 days (range, 12 to 78 days) in the SZ-Bu/Mel cohort compared with 18 days (range, 10 to 50 days) in the FH-CEM cohort (P < .001). We used 3.9 CD34/kg as a cutoff value to compare the median time to neutrophil and platelet engraftments in both cohorts. We found that median times for neutrophil and platelet engraftments were significantly lower in patients who received an infused stem-cell dose of ≥ 3.9 × 106/kg compared with those who received a stem-cell dose of < 3.9 × 106/kg in FH-CEM and SZ-Bu/Mel cohorts, respectively (FH-CEM: P = .05 and .033, respectively; SZ-Bu/Mel: P = .03 and .045, respectively). Median number of RBC transfusions in the FH-CEM cohort was three (range, zero to 10 transfusions) compared with two (range, zero to 16 transfusions) in the SZ-Bu/Mel cohort (P = .033). Median number of platelet transfusions was also significantly higher in the FH-CEM cohort compared with the SZ-Bu/Mel cohort at six transfusions (range, one to 22 transfusions) versus one transfusion (range, zero to 17 transfusions), respectively (P ≤ .001).\n\nFig 1 Time to neutrophil and platelet engraftment. FH-CEM, carboplatin, etoposide, and melphalan at Fred Hutchinson Cancer Research Center; SZ-Bu/Mel, busulfan and melphalan at El-Sheikh Zayed Specialized Hospital.\n\nHepatic Toxicity\nThere were no statistically significant differences in hepatic dysfunction—elevated liver enzymes—and hyperbilirubinemia between both cohorts (Table 2). Three patients (6.8%) were diagnosed with SOS in the FH-CEM cohort, whereas eight patients (10.4%) were diagnosed with SOS in the SZ-Bu/Mel cohort. Median time to the onset to SOS was 19 days after SZ-Bu/Mel conditioning compared with 7 days after FH-CEM conditioning (P = .033; Fig 2). Details of the diagnostic criteria for SOS, underlying hepatitis infection, complications, and outcome are listed in Table 3. Using χ2 test, hepatitis infection was significantly related to the development of SOS (P < .001). All SOS cases from the FH-CEM cohort were of moderate severity, whereas in the SZ-Bu/Mel cohort, four cases (50%) were severe and four cases (50%) were moderately severe. Underlying liver infection was present in all four of the severe cases and in one-half of the cases of moderate severity in the SZ-Bu/Mel cohort\n\nFig 2 Time to onset of sinusoidal obstruction syndrome (SOS). FH-CEM, carboplatin, etoposide, and melphalan at Fred Hutchinson Cancer Research Center; SZ-Bu/Mel, busulfan and melphalan at El-Sheikh Zayed Specialized Hospital.\n\nTable 3 Characteristics of Patients With Sinusoidal Obstruction Syndrome\n\nNephrotoxicity\nThere were more patients with nephrotoxicity in the FH-CEM cohort than in the SZ-Bu/MEL cohort (P = .047), although two patients in the SZ-Bu/Mel group required dialysis as a result of hepatorenal syndrome as a complication of severe SOS.\n\nInfectious Complications\nFebrile neutropenia occurred commonly and was observed in 39 patients (88.6%) from the FH-CEM cohort and in 71 patients (92.2%) from the SZ-Bu/Mel cohort. The number of days with fever and days receiving antibiotics were significantly higher for the FH-CEM cohort compared with the SZ-Bu/Mel cohort (Table 2).\n\n100-Day Transplant-Related mortality\nFour patients who underwent transplantation after SZ-Bu/Mel died before day 100 (Fig 3). All had severe SOS, developed respiratory failure, and required mechanical ventilation. Two patients developed hepatorenal syndrome and required dialysis. There was no transplantation-related mortality in the FH-CEM cohort.\n\nFig 3 Kaplan-Meier curve of overall survival at 100 days between carboplatin, etoposide, and melphalan at Fred Hutchinson Cancer Research Center (FH-CEM) and busulfan and melphalan at El-Sheikh Zayed Specialized Hospital (SZ-Bu/Mel).\n\nDISCUSSION\nHDC-SCR plays a major role in the treatment strategy for HRNB, although there currently is no consensus about what comprises the best conditioning regimen. We explored the acute complications, regimen-related toxicities, and 100-day survival in two cohorts of patients with HRNB who were conditioned with either CEM or Bu/Mel. One cohort received HDC-SCR at a bone marrow transplantation (BMT) center located in Egypt, a developing lower middle-income country where the BMT program started in 1989,19 whereas the other cohort received HDC-SCR in the United States, a high-income country where the BMT program started in the early 1950s, with significantly larger numbers of transplantations having been performed.20 Egyptian patients with HRNB have been receiving the same Bu/Mel conditioning regimen used in Europe. Meanwhile, patients with HRNB in the United States, for the most part, have received CEM.\n\nThe prevailing public health problems in Egypt and the United States are different. Hepatitis is a major public health problem in Egypt, with intermediate endemicity for hepatitis B (2% to 5% hepatitis B surface antigen prevalence) and high endemicity for hepatitis C (17.5%).21-23 In this analysis, there were no significant differences in HCT-CI scores between FH-CEM and SZ-Bu/Mel cohorts; however, pretransplant hepatic comorbidities were significantly higher in the SZ-Bu/Mel cohort compared with the FH-CEM cohort. Of importance, there was a high incidence of hepatitis B and C infections in the SZ-Bu/Mel cohort—5.2% of patients were coinfected with both hepatitis B and C virus.\n\nSOS developed in fewer patients in the FH-CEM cohort than in the SZ-Bu/Mel cohort. Ladenstein et al12 reported similar findings in the HRNBL1/SIOPEN trial. As Bu depletes intracellular glutathione and alters melphalan metabolism, glutathione-depleted cells are predisposed to the hepatotoxic metabolites of high-dose Mel24,25 SOS developed earlier in the FH-CEM cohort compared with the SZ-Bu/Mel. Different studies that compared Bu/Mel and CEM reported similar results.12,26-28 Although the frequency of SOS was higher in other studies by Proust-Houdemont et al29 and the HRNBL1/SIOPEN trial12 compared with SZ-Bu/Mel, severe SOS developed more frequently in the SZ-Bu/Mel group. The higher frequency of infectious hepatitis in the SZ-Bu/Mel group might be a contributing factor in the development of severe SOS. Several studies have demonstrated that pretransplant hepatitis infection increased the severity of SOS in recipients of stem-cell transplantation.30-32 Potential differences in the method of Bu administration between different centers might also be relevant to the frequency of occurrence of severe SOS. In the SZ-Bu/Mel cohort, oral Bu was used without therapeutic drug monitoring, whereas oral Bu with therapeutic drug monitoring was used until 2006 in Proust-Houdemont et al and until 2007 in the HRNBL1/SIOPEN trial, when intravenous Bu was used. Oral bioavailability of Bu is unpredictable, with marked interpatient variability in the plasma concentration, especially in children.33 Veal et al34 compared the pharmacokinetics of oral and intravenous Bu in patients with HRNB who were treated in the HRNBL1/SIOPEN trial. They reported that oral Bu was significantly related to the development of grade 3 and 4 hepatic toxicity and SOS. This is likely a result of the effect of the first-pass metabolism that leads to higher Bu concentrations in liver-enhancing hepatic toxicity.\n\nThe practice and supportive care of HDC-SCR differ between Egypt and the United States, which may be responsible, in part, for the difference in the pattern of acute toxicity of HDC-SCR between the two centers. The earlier use of G-CSF in the FH-CEM cohort—starting 24 hours after infusion compared with 6 days after stem-cell infusion in the SZ-Bu/Mel cohort—might explain, in part, the longer median time for neutrophil engraftment in SZ-Bu/Mel patients compared with FH-CEM patients. Longer median time can also be explained by differences in the infused cell dose. Median infused cell dose in the FH-CEM cohort was significantly higher than that in the SZ-Bu/Mel cohort (P < .001). We found that the median times for neutrophil and platelet engraftments were significantly lower in patients who received an infused stem-cell dose of ≥ 3.9 × 106 cells/kg compared with those who received a stem-cell dose of < 3.9 × 106 cells/kg in FH-CEM and SZ-Bu/Mel cohorts. This finding was similar to that reported by Morgenstern et al.35 Desai et al26 compared the time to neutrophil and platelet engraftment between Bu/Mel and CEM for the treatment of patients with HRNB who received the same dose of infused CD34-positive cells per kilogram and found no significant difference in the time to neutrophil and platelet engraftments between both cohorts.\n\nNephrotoxicity was significantly more frequent after conditioning with FH-CEM compared with SZ-Bu/Mel. Several studies have reported similar results.12-29 This is likely correlated with the use of high-dose carboplatin. Carboplatin is a platinum derivative that is less toxic than cisplatin but still associated with a decrease in the glomerular filtration rate and hypomagnesaemia.36 There were two patients after SZ-Bu/Mel conditioning who required renal dialysis as a result of hepato-renal syndrome secondary to severe SOS.\n\nDespite the differences in economic status between Egypt and the United States, we found no significant difference in the frequency of blood stream infections between the two cohorts. This may suggest that the overall quality of supportive care provided to these vulnerable, high-risk patients in a lower middle-income country was equivalent to that in a high-income country.\n\nThere was a trend toward a higher, but insignificant, percentage of Gram-negative organisms in the SZ-Bu/Mel cohort compared with the FH-CEM cohort. This is in agreement with other reports that have noted the re-emergence of infections with Gram-negative organisms in Egypt.37\n\nOverall, resource utilization was greater in the FH-CEM cohort than in the SZ-Bu/Mel cohort, as evidenced by a significantly higher number of days with fever, antibiotic use, and number of packed RBC and platelet transfusions administered. Thus, SZ-Bu/Mel is more suitable to be used as HDC-SCR for the treatment of HRNB in lower middle-income Egypt.\n\nOur study is limited by its retrospective design that included two different centers with different practice guidelines and resources; however, these data demonstrate that, compared with a well-established program, such as that in the United States, the utilization of a highly technical intensive therapy, such as BMT, can be safely undertaken in a developing country. It also demonstrates the unique challenges that exist for a country with endemic hepatitis that lead to significantly higher risks of potentially fatal hepatic toxicity.\n\nIn conclusion, use of HDC-SCR is feasible in the context of a resource-limited country. Bu/Mel is preferred in Egypt because of fewer infections, lower resource utilization, and less nephrotoxicity, although its contribution to hepatic complications is still a major concern and requires consideration of earlier supportive and/or prophylactic interventions.\n\nSupported by a scholarship from the Ministry of High Education, Egypt (to M.M.E.).\n\nAUTHOR CONTRIBUTIONS\nConception and design: Julie R. Park, Khaled F. Riad, Heba A. Sayed, Navin Pinto, K. Scott Baker, Alaa El-Haddad, Mahmoud M. Elzembely\n\nProvision of study materials or patients: K. Scott Baker\n\nCollection and assembly of data: Mahmoud M. Elzembely, Alaa El-Haddad\n\nData analysis and interpretation: Mahmoud M. Elzembely, Julie R. Park, Navin Pinto, Paul A. Carpenter\n\nManuscript writing: All authors\n\nFinal approval of manuscript: All authors\n\nAccountable for all aspects of the work: All authors\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\nThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc.\n\nMahmoud M. Mohammed\nNo relationship to disclose\n\nJulie R. Park\nHonoraria: Bristol-Myers Squibb\n\nTravel, Accommodations, Expenses: Roche\n\nKhaled F. Riad\nNo relationship to disclose\n\nHeba A. Sayed\nNo relationship to disclose\n\nNavin Pinto\nNo relationship to disclose\n\nPaul A. Carpenter\nConsulting or Advisory Role: Mallinckrodt, Incyte\n\nResearch Funding: Mesoblast, Mallinckrodt\n\nTravel, Accommodations, Expenses: Pharmacyclics\n\nK. Scott Baker\nNo relationship to disclose\n\nAlaa El-Haddad\nNo relationship to disclose\n==== Refs\nREFERENCES\n1. US Centers for Disease Control and Prevention United States Cancer Statistics (USCS): 1999–2014 cancer incidence and mortality data https://nccd.cdc.gov/uscs/ \n2. Kaatsch P Epidemiology of childhood cancer Cancer Treat Rev 36 277 285 2010 20231056 \n3. US National Cancer Institute http://www.nci.cu.edu.eg/Portals/0/Documents/Biostatstics/NCI_registry 2002-2010.pdf \n4. Orkin SH Nathan DG Ginsburg D Neuroblastoma Nathan and Oski’s Hematology of Infancy and Childhood Elsevier Health Sciences Philadelphia, PA 2008 509 -540 \n5. Speleman F Park JR Henderson TO Neuroblastoma: A tough nut to crack Am Soc Clin Oncol Educ Book 35 e548 e557 2016 27249766 \n6. Pritchard J Cotterill S J Germond S M et al High dose melphalan in the treatment of advanced neuroblastoma: Results of a randomised trial (ENSG-1) by the European Neuroblastoma Study Group Pediatr Blood Cancer 44 348 357 2005 15546135 \n7. Berthold F Boos J Burdach S et al Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: A randomised controlled trial Lancet Oncol 6 649 658 2005 16129365 \n8. Matthay KK Reynolds CP Seeger RC et al Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: A Children’s Oncology Group study J Clin Oncol 27 1007 1013 2009 Erratum: J Clin Oncol 32:1862-1863, 2014 19171716 \n9. Kreissman SG. Seeger RC. Matthay KK. et al Purged versus non-purged peripheral blood stem-cell transplantation for high-risk neuroblastoma (COG A3973): A randomised phase 3 trial Lancet Oncol 14 999 1008 2013 23890779 \n10. Ladenstein R Pötschger U Hartman O et al 28 years of high-dose therapy and SCT for neuroblastoma in Europe: Lessons from more than 4000 procedures Bone Marrow Transplant 41 S118 S127 2008 suppl 2 18545256 \n11. Hartmann O Valteau-Couanet D Vassal G et al Prognostic factors in metastatic neuroblastoma in patients over 1 year of age treated with high-dose chemotherapy and stem cell transplantation: A multivariate analysis in 218 patients treated in a single institution Bone Marrow Transplant 23 789 795 1999 10231141 \n12. Ladenstein R Pötschger U Pearson ADJ et al Busulfan and melphalan versus carboplatin, etoposide, and melphalan as high-dose chemotherapy for high-risk neuroblastoma (HR-NBL1/SIOPEN): An international, randomised, multi-arm, open-label, phase 3 trial Lancet Oncol 18 500 514 2017 28259608 \n13. Park JR Kreissman SG London WB et al. A phase III randomized clinical trial (RCT) of tandem myeloablative autologous stem cell transplant (ASCT) using peripheral blood stem cell (PBSC) as consolidation therapy for high-risk neuroblastoma (HR-NB): A Children's Oncology Group (COG) study J Clin Oncol 34 2016 suppl; abstr LBA3 \n14. Irwin MS Park JR Neuroblastoma: Paradigm for precision medicine Pediatr Clin North Am 62 225 256 2015 25435121 \n15. Sorror ML How I assess comorbidities before hematopoietic cell transplantation Blood 121 2854 2863 2013 23355537 \n16. US National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_8.5x11.pdf \n17. McDonald GB Hinds MS Fisher LD et al Veno-occlusive disease of the liver and multiorgan failure after bone marrow transplantation: A cohort study of 355 patients Ann Intern Med 118 255 267 1993 8420443 \n18. Jones RJ Lee KS Beschorner WE et al Venoocclusive disease of the liver following bone marrow transplantation Transplantation 44 778 783 1987 3321587 \n19. Mahmoud H El-Haddad A Fahmy O et al Hematopoietic stem cell transplantation in Egypt Bone Marrow Transplant 42 S76 S80 2008 suppl 1 18724311 \n20. Thomas ED Lochte HL Jr Cannon JH et al Supralethal whole body irradiation and isologous marrow transplantation in man J Clin Invest 38 1709 1716 1959 13837954 \n21. Demography and Health Surveys Program Egypt health issues survey 2015 https://dhsprogram.com/pubs/pdf/FR313/FR313.pdf \n22. Paez Jimenez A El-Din NS El-Hoseiny M et al Community transmission of hepatitis B virus in Egypt: Results from a case-control study in Greater Cairo Int J Epidemiol 38 757 765 2009 19420088 \n23. Karoney MJ Siika AM Hepatitis C virus (HCV) infection in Africa: A review Pan Afr Med J 14 44 2013 23560127 \n24. Carreras E Rosiñol L Terol MJ et al Veno-occlusive disease of the liver after high-dose cytoreductive therapy with busulfan and melphalan for autologous blood stem cell transplantation in multiple myeloma patients Biol Blood Marrow Transplant 13 1448 1454 2007 18022574 \n25. Pai RK van Besien K Hart J et al Clinicopathologic features of late-onset veno-occlusive disease/sinusoidal obstruction syndrome after high dose intravenous busulfan and hematopoietic cell transplant Leuk Lymphoma 53 1552 1557 2012 22280517 \n26. Desai AV Heneghan MB Li Y et al Toxicities of busulfan/melphalan versus carboplatin/etoposide/melphalan for high-dose chemotherapy with stem cell rescue for high-risk neuroblastoma Bone Marrow Transplant 51 1204 1210 2016 27159174 \n27. Moffet JR Summers ED Allewelt HB et al A single center retrospective analysis of busulfan/melphalan conditioning compared to carboplatin/melphalan/etoposide in autologous transplant for high risk neuroblastoma Biol Blood Marrow Transplant 22 S129 2016 suppl; abstr 150 \n28. Desai AV Seif AE Li Y et al Resource utilization and toxicities after carboplatin/etoposide/melphalan and busulfan/melphalan for autologous stem cell rescue in high-risk neuroblastoma using a national administrative database Pediatr Blood Cancer 63 901 907 2016 26797923 \n29. Proust-Houdemont S Pasqualini C Blanchard P et al Busulfan-melphalan in high-risk neuroblastoma: The 30-year experience of a single institution Bone Marrow Transplant 51 1076 1081 2016 27042850 \n30. Strasser SI Myerson D Spurgeon CL et al Hepatitis C virus infection and bone marrow transplantation: A cohort study with 10-year follow-up Hepatology 29 1893 1899 1999 10347135 \n31. Lau GKK Liang R Chiu EKW et al Hepatic events after bone marrow transplantation in patients with hepatitis B infection: A case controlled study Bone Marrow Transplant 19 795 799 1997 9134171 \n32. El-Sayed MH El-Haddad A Fahmy OA et al Liver disease is a major cause of mortality following allogeneic bone-marrow transplantation Eur J Gastroenterol Hepatol 16 1347 1354 2004 15618844 \n33. Sobecks RM Rybicki L Yurch M et al Intravenous compared with oral busulfan as preparation for allogeneic hematopoietic progenitor cell transplantation for AML and MDS Bone Marrow Transplant 47 633 638 2012 21874055 \n34. Veal GJ Nguyen L Paci A et al Busulfan pharmacokinetics following intravenous and oral dosing regimens in children receiving high-dose myeloablative chemotherapy for high-risk neuroblastoma as part of the HR-NBL-1/SIOPEN trial Eur J Cancer 48 3063 3072 2012 22742881 \n35. Morgenstern DA Ash S Pötschger U et al Engraftment following busulfan/melphalan (BuMel) high dose chemotherapy for high risk neuroblastoma. A report from the HRNBL1/SIOPEN trial Advances in Neuroblastoma Research Congress Queensland, Australia June 19-24, 2016 \n36. Stefanowicz J Owczuk R Izycka-Swieszewska E et al Nephrotoxicity of platinum derivatives in children—A review of the literature Wspolczesna Onkol. 15 74 79 2011 \n37. El-Mahallawy H Samir I Abdel Fattah R et al Source, pattern and antibiotic resistance of blood stream infections in hematopoietic stem cell transplant recipients J Egypt Natl Canc Inst 26 73 77 2014 24841157\n\n",
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"issn_linking": "2378-9506",
"issue": "4()",
"journal": "Journal of global oncology",
"keywords": null,
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"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D064592:Autografts; D002066:Busulfan; D016190:Carboplatin; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004534:Egypt; D005047:Etoposide; D005260:Female; D006801:Humans; D008297:Male; D008558:Melphalan; D008875:Middle Aged; D009447:Neuroblastoma; D033581:Stem Cell Transplantation; D019172:Transplantation Conditioning",
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"pages": "1-12",
"pmc": null,
"pmid": "30241255",
"pubdate": "2018-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
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"title": "Acute Complications After High-Dose Chemotherapy and Stem-Cell Rescue in Pediatric Patients With High-Risk Neuroblastoma Treated in Countries With Different Resources.",
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"abstract": "OBJECTIVE\nAlthough severe cutaneous adverse drug reactions (SCARs) are rare, they are associated with high morbidity and mortality, and thus early diagnosis and treatment are critical for improving prognoses. However, few studies have reported the characteristics of SCARs in children. Thus, we aimed to evaluate the clinical characteristics, current management and prognosis of pediatric SCARs.\n\n\nMETHODS\nWe analyzed pediatric data in the Korean SCARs registry, which was built retrospectively in 2016 with SCAR cases treated in 34 tertiary referral university hospitals during 2010-2015. Using these cases, we descriptively analyzed detailed data regarding etiology, clinical and laboratory features, treatment strategies, and prognosis.\n\n\nRESULTS\nForty-seven pediatric SCAR cases from 15 tertiary referral hospitals were included. The median patient age was 10 (interquartile range, 3-15.5) years and 68.1% (n = 32) were males. The culprit drug was identified in 95.7% (n = 45) of the patients; antibiotics (44.7%) and antiepileptic drugs (19.1%) were the most common and second most common culprits, respectively. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) cases presented with the largest area of skin involvement without permanent sequelae. Stevens-Johnson syndrome (SJS) cases involved relatively small areas of skin but serious sequelae in two children. Of 4 patients with toxic epidermal necrolysis (TEN), 1 died. Of all patients assessed, 36 (76.6%) received systemic steroids and 21 (44.7%) received intravenous immunoglobulin (IVIG). Thirteen (27.7%) received both systemic steroids and IVIG. Cyclosporine was administered to only 1 patient along with a systemic steroid.\n\n\nCONCLUSIONS\nIn patients with pediatric SCARs, including those with DRESS, SJS and TEN, clinical presentations were variable. Thus, there was no clear continuous disease spectrum. Although the mortality rate was low (2.1%), clinical suspicion may be the best tool for proactive SCAR management.",
"affiliations": "Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.;Drug Safety Monitoring Center, Seoul National University Hospital, Seoul, Korea.;Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.;Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.;Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.;Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.;Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea.;Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea. dongins0@snu.ac.kr.",
"authors": "Oh|Hea Lin|HL|https://orcid.org/0000-0002-6583-8993;Kang|Dong Yoon|DY|https://orcid.org/0000-0003-4283-2633;Kang|Hye Ryun|HR|https://orcid.org/0000-0002-2317-4201;Kim|Sujeong|S|https://orcid.org/0000-0002-2494-9216;Koh|Young Il|YI|https://orcid.org/0000-0002-5100-9473;Kim|Sae Hoon|SH|https://orcid.org/0000-0002-2572-5302;Kim|Min Hye|MH|https://orcid.org/0000-0002-1775-3733;Suh|Dong In|DI|https://orcid.org/0000-0002-7817-8728;|||",
"chemical_list": null,
"country": "Korea (South)",
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"doi": "10.4168/aair.2019.11.2.241",
"fulltext": "\n==== Front\nAllergy Asthma Immunol ResAllergy Asthma Immunol ResAAIRAllergy, Asthma & Immunology Research2092-73552092-7363The Korean Academy of Asthma, Allergy and Clinical Immunology; The Korean Academy of Pediatric Allergy and Respiratory Disease 3066131610.4168/aair.2019.11.2.241Original ArticleSevere Cutaneous Adverse Reactions in Korean Pediatric Patients: A Study From the Korea SCAR Registry https://orcid.org/0000-0002-6583-8993Oh Hea Lin 1https://orcid.org/0000-0003-4283-2633Kang Dong Yoon 23https://orcid.org/0000-0002-2317-4201Kang Hye-Ryun 45https://orcid.org/0000-0002-2494-9216Kim Sujeong 6https://orcid.org/0000-0002-5100-9473Koh Young-Il 7https://orcid.org/0000-0002-2572-5302Kim Sae Hoon 8https://orcid.org/0000-0002-1775-3733Kim Min-Hye 9https://orcid.org/0000-0002-7817-8728Suh Dong In 1the Korean Severe Cutaneous Adverse Reactions Consortium 1 Department of Pediatrics, Seoul National University College of Medicine, Seoul, Korea.2 Drug Safety Monitoring Center, Seoul National University Hospital, Seoul, Korea.3 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.4 Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea.5 Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul, Korea.6 Department of Internal Medicine, School of Medicine, Kyungpook National University, Daegu, Korea.7 Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea.8 Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.9 Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, Korea.Correspondence to Dong In Suh, MD, PhD. Department of Pediatrics, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Tel: +82-2-2072-3625; Fax: +82-2-743-3455; dongins0@snu.ac.kr3 2019 07 1 2019 11 2 241 253 27 7 2018 08 11 2018 18 11 2018 Copyright © 2019 The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory Disease2019The Korean Academy of Asthma, Allergy and Clinical Immunology • The Korean Academy of Pediatric Allergy and Respiratory DiseaseThis is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\nAlthough severe cutaneous adverse drug reactions (SCARs) are rare, they are associated with high morbidity and mortality, and thus early diagnosis and treatment are critical for improving prognoses. However, few studies have reported the characteristics of SCARs in children. Thus, we aimed to evaluate the clinical characteristics, current management and prognosis of pediatric SCARs.\n\nMethods\nWe analyzed pediatric data in the Korean SCARs registry, which was built retrospectively in 2016 with SCAR cases treated in 34 tertiary referral university hospitals during 2010–2015. Using these cases, we descriptively analyzed detailed data regarding etiology, clinical and laboratory features, treatment strategies, and prognosis.\n\nResults\nForty-seven pediatric SCAR cases from 15 tertiary referral hospitals were included. The median patient age was 10 (interquartile range, 3-15.5) years and 68.1% (n = 32) were males. The culprit drug was identified in 95.7% (n = 45) of the patients; antibiotics (44.7%) and antiepileptic drugs (19.1%) were the most common and second most common culprits, respectively. Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) cases presented with the largest area of skin involvement without permanent sequelae. Stevens-Johnson syndrome (SJS) cases involved relatively small areas of skin but serious sequelae in two children. Of 4 patients with toxic epidermal necrolysis (TEN), 1 died. Of all patients assessed, 36 (76.6%) received systemic steroids and 21 (44.7%) received intravenous immunoglobulin (IVIG). Thirteen (27.7%) received both systemic steroids and IVIG. Cyclosporine was administered to only 1 patient along with a systemic steroid.\n\nConclusions\nIn patients with pediatric SCARs, including those with DRESS, SJS and TEN, clinical presentations were variable. Thus, there was no clear continuous disease spectrum. Although the mortality rate was low (2.1%), clinical suspicion may be the best tool for proactive SCAR management.\n\nDrug-related side effects and adverse reactionschildrenDrug eruptions\n==== Body\nINTRODUCTION\nCutaneous reactions constitute the most common type of adverse drug reactions in pediatric populations, with a prevalence of up to 36%.1 Despite the high prevalence of cutaneous adverse drug reactions, these reactions are mostly benign, cause only mild clinical symptoms, and subside with discontinuation of the suspected drug.2 However, 2.0%–6.7% of cutaneous reactions can develop into severe cutaneous adverse drug reactions (SCARs), which are potentially life-threatening.34\n\nConsidering serious morbidity and mortality associated with SCARs, their early diagnosis and treatment is crucial for achieving better prognoses. As clinical suspicion of SCARs is often based on a patient's clinical history, it is essential to determine the frequency and common symptoms of SCARs.\n\nMany previous studies have examined the clinical presentation and risk factors of SCARs in adults.56 However, few have reported these characteristics in a pediatric population, and even less in Korean children. This study aimed to retrospectively analyze the clinical characteristics, laboratory findings and clinical outcomes of pediatric SCAR cases using data from a large Korean clinical registry.\n\nMATERIALS AND METHODS\nPediatric data was collected from the Korean SCARs registry, which was built in 2016 using retrospective data from 34 tertiary referral hospitals in 2010-2015. To build the registry, researchers uploaded their institutions' potential cases and 2 allergy specialists validated each SCAR case. Researchers from 34 hospitals first filtered the individual case safety reports on adverse drug reactions, medical records on the diagnosis, and consultation records with allergists and dermatologists using the keywords of ‘Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS),’ ‘Stevens-Johnson syndrome (SJS),’ ‘toxic epidermal necrolysis (TEN),’ and ‘drug hypersensitivity.’ The medical records of the resulting filtered cases were then reviewed. All cases that meet the European Registry of SCARs (RegiSCAR) inclusion criteria were selected as the potential SCAR cases.78\n\nPotential cases of SJS/TEN were determined as hospitalized patients with widespread exanthema with 1% or more of skin detachment of epidermis, or with more than 1 blister and mucous membrane involvement. Potential cases of DRESS were defined as hospitalized patients with acute onset of exanthema with fever > 38°C, enlarged lymph nodes, involvement of at least 1 internal organ, and 1 or more of the following: eosinophilia > 10%, > 700/μL; atypical lymphocytes; lymphopenia < 4,000; lymphocytosis; or thrombopenia. Potential cases were excluded when symptoms and signs were suspicious of the following: pemphigus, erythema multiforme, bullous pemphigoid, staphylococcal scalded skin syndrome, mechanobullous eruption (heat, cold, friction, pressure), acute pustular psoriasis, Kawasaki's disease, toxic shock syndrome, graft-versus-host disease, vasculitis or epidermolysis bullosa.\n\nThe clinical data of potential cases were uploaded to the main data center with a standardized form that included data on the demographics, past medical history, culprit agents, clinical and laboratory findings, treatment, and clinical outcomes associated with each case. In addition, comorbid conditions were also investigated, including allergic diseases (asthma, rhinitis and atopic dermatitis), diabetes mellitus, renal and urologic diseases (acute cystitis, chronic renal failure, dialysis and kidney transplantation), hepatic diseases (hepatitis and cirrhosis), infectious diseases (human immunodeficiency virus [HIV] and other viral infection; pneumonia, bronchiolitis, rhinopharyngitis, otitis media, and tonsillitis), digestive diseases (gastroenteritis, acute cystitis), rheumatic diseases, immune deficiency, and malignancy.\n\nCausality assessment of SCARs to culprit drugs was conducted according to the World Health Organization-Uppsala Monitoring Center (WHO-UMC) criteria.9 The ‘probable’ relationship was suspected when a SCAR event presented a reasonable time relationship to drug intake, was unlikely attributed to disease or other drugs, and responded well to withdrawal. The ‘certain’ causality was suspected when there was relevant rechallenge information on the case with ‘probable’ causality.\n\nUploaded data of all potential cases were also reviewed by another allergy specialist in the main center, and the final SCAR cases were confirmed by both specialists of the regional hospital and the main center. Cases were registered only when both specialists agreed upon the SCAR diagnosis and the causality of ‘probable’ or ‘certain.’ Then, to evaluate the clinical characteristics of pediatric SCAR cases, we selected cases of individuals who were aged < 19 years.\n\nA final diagnoses of SJS was made when clinical records indicated the following: acute onset of mucous membrane involvement of at least 2 mucosal surfaces; skin symptoms, including maculae, target-like, bullae or erosion; a positive Nikolsky sign; and epidermal detachment of less than 10% of the total body surface area.10 A final diagnosis of TEN was made by the presence of the same lesions as in SJS, but with a confluence of blisters leading to a positive Nikolsky sign and the detachment of large epidermal sheets on more than 30% of the body surface area.10 Marginal cases between SJS and TEN were classified into SJS. A final diagnosis of DRESS was made based on the following items: characteristics of fever, enlarged lymph nodes, eosinophilia, atypical lymphocytes, skin involvement, organ involvement, duration for resolution and the exclusion of other potential causes. Since the scoring system for classifying DRESS of RegiSCAR811 and the diagnostic criteria of the Japanese consensus group1213 are similar but different, at least 2 allergy specialists discussed each potential case and moderated the DRESS diagnosis on a case-by-case basis.\n\nStatistical analyses were performed using SPSS 22.0 software for Windows (SPSS, Inc, Chicago, IL, USA). Descriptive statistics are provided and include the number and percentage for categorical variables and the median and interquartile range (IQR) for continuous variables. The protocol was approved by the Institutional Review Board of Seoul National University Hospital (No. 1804-115-939) and due to the retrospective nature of the study, the requirement for written informed consent was waived.\n\nRESULTS\nA total of 814 potential cases was listed. Thirty-three and 36 cases were excluded because of the onset time was out of 2010–2015 and doubtful diagnosis/causality, respectively. Among the 745 confirmed SCAR cases, a total of 47 occurred in subjects < 19 years (Figure).\n\nFigure Flow diagram of pediatric SCAR cases analyzed.\nSCAR, severe cutaneous adverse reaction.\n\nThe patient characteristics of the total 47 SCAR cases are shown in Table 1. The median patient age was 10 (IQR, 3-15.5) years and 68.1% (n = 32) were male. Of all cases, 14.9% (n = 7) were diagnosed with DRESS, 76.6% (n = 36) were diagnosed with SJS, and 8.5% (n = 4) were diagnosed with TEN. Nineteen patients (3, 14 and 2 patients with DRESS, SJS and TEN, respectively) had comorbid conditions: 15 patients had a concomitant infection, 2 had atopic dermatitis, 1 had hypertension, and 1 had SLE. Thirty-four (72.3%) patients were admitted to the hospital via the emergency department, 9 (19.1%) via an outpatient clinic, and the remaining 4 (8.5%) did not initially present with SCARs, but developed them during their admission. Only 1 patient had a history of previous SCAR.\n\nTable 1 Demographic characteristics of patients\nCharacteristic\tDRESS (n = 7)\tSJS (n = 36)\tTEN (n = 4)\tTotal (n = 47)\t\nAge (yr)\t15 (11.5–15.0)\t9.5 (2.8–16.0)\t5 (3.8–8.3)\t10 (3.0–15.5)\t\nMale sex\t3 (42.9)\t25 (69.4)\t4 (100)\t32 (68.1)\t\nComorbidity\t3 (42.9)\t14 (38.9)\t2 (50.0)\t19 (40.4)\t\n\tAtopic dermatitis\t2\t\t\t2\t\n\tHypertension\t\t\t1\t1\t\n\tSLE\t\t1\t\t1\t\n\tInfection\t\t\t\t\t\n\t\tURI\t\t3\t\t3\t\n\t\tAcute bronchitis\t\t1\t\t1\t\n\t\tBronchiolitis\t\t1\t\t1\t\n\t\tInfluenza\t\t6\t\t6\t\n\t\tChronic otitis media\t\t1\t\t1\t\n\t\tCervical lymphadenitis\t\t1\t\t1\t\n\t\tCholecystitis\t1\t\t\t1\t\n\t\tEnterobacter cloacae sepsis\t\t\t1\t1\t\nThe route of visit\t\t\t\t\t\n\tOutpatient clinic\t\t8 (22.2)\t1 (25.0)\t9 (19.1)\t\n\tEmergency clinic\t4 (57.1)\t27 (75)\t3 (75.0)\t34 (72.3)\t\n\tDuring admission\t3 (42.9)\t1 (2.8)\t\t4 (8.5)\t\nPast history of SCARs\t\t1 (2.8)\t\t1 (2.1)\t\nValues are presented as median (IQR) or number (%).\n\nDRESS, drug reaction with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; IQR, interquartile range; SLE, systemic lupus erythematosus; URI, upper respiratory tract infection; SCARs, severe cutaneous adverse reactions.\n\nEtiology\nThe culprit drugs were identified in 95.7% (n = 45) of the SCAR cases. The distribution of drug type, number and administration route across SCAR groups are listed in Table 2. Antibiotics were the most common (44.7%) culprit drugs, while antiepileptic drugs were the second most common (19.1%). Causative drugs for the remaining 4.3% (n = 2) of the patients could not be identified.\n\nTable 2 Kind, number and the route of suspected drugs as the etiology\nEtiology\tDRESS (n = 7)\tSJS (n = 36)\tTEN (n = 4)\tTotal (n = 47)\t\nAntibiotics\t3 (42.9)\t15 (41.7)\t3 (75.0)\t21 (44.7)\t\n\tPenicillin\t\t9\t2\t11\t\n\t\tAmoxicillin/clavulate\t\t7\t1\t8\t\n\t\tTMP/SMX\t\t2\t1\t3\t\n\tCephalosporine\t2\t3\t1\t6\t\n\tMacrolide\t\t2\t\t2\t\n\tDapsone\t1\t\t\t1\t\n\tDoxycycline\t\t1\t\t1\t\nAntiepileptics\t4 (57.1)\t5 (13.9)\t\t9 (19.1)\t\n\tPhenobarbital\t1\t1\t\t2\t\n\tCarbamazepine\t1\t2\t\t3\t\n\tLamotrigine\t2\t2\t\t4\t\nNSAIDS\t\t3 (8.3)\t\t3 (6.4)\t\nAcetaminophen\t\t6 (16.7)\t\t6 (12.8)\t\nOther drugs\t\t5 (13.9)\t1 (25.0)\t6 (12.8)\t\n\tDeflazacort\t\t1\t1\t2\t\n\tPotassium clavulanate\t\t1\t\t1\t\n\tGuaifenesin\t\t1\t\t1\t\n\tStreptokinase\t\t1\t\t1\t\n\tDacarbazine\t\t1\t\t1\t\nUnknown\t\t2\t\t2 (4.3)\t\nMedication numbers\t\t\t\t\t\n\t1\t4 (57.1)\t21 (58.3)\t2 (50.0)\t27 (57.4)\t\n\t≥2\t3 (42.9)\t15 (41.7)\t2 (50.0)\t20 (42.6)\t\nAdministration route\t\t\t\t\t\n\tOral\t5 (71.4)\t34 (94.4)\t4 (100)\t43 (91.5)\t\n\tIV\t1 (14.3)\t\t\t1 (2.1)\t\n\tUnknown route\t1 (14.3)\t2 (5.6)\t\t3 (6.4)\t\nValues are presented as number (%).\n\nDRESS, drug reaction with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; TMP/SMX, trimethoprim/sulfamethoxazole; NSAIDS, nonsteroidal anti-inflammatory drugs; IV, intravenous.\n\nIn patients with DRESS, antibiotics (42.9%) and antiepileptic drugs (57.1%) played a major role in disease etiology. The most common causative antibiotic was amoxicillin/clavulanate (38.1%); the second most common causative antibiotic was cephalosporin (28.6%). In patients with SJS, antibiotics (41.7%), antiepileptic drugs (18.9%) and antipyretics (25.0%) were found to be the 3 most common causative classes of drugs. Antibiotics (75%) and systemic steroids (25%) were suspected to cause all 4 cases of TEN.\n\nTwenty-seven (57.4%) patients were administered a single drug, while the other 20 (42.6%) received 1 suspected drug together with another medication unrelated with SCARs. Forty-three patients ingested the drug(s) orally, 1 was administered the medication intravenously, and there was no information on administration route available for the remaining 3 patients.\n\nClinical and laboratory features\nCase clinical and laboratory features are presented in Table 3. The most common type of skin disorder was rash (91.5%, n = 43). In patients with SJS or TEN, other skin symptoms such as appearance of the target sign (14.9%, n = 17), desquamation (21.3%, n = 10) and blister (48.9%, n = 23) were also observed. The Nikolsky sign was not observed in patients with DRESS but was observed in 5 patients (13.9%) with SJS and in all 4 patients with TEN. In the DRESS group, the median extent of skin involvement was 99% (IQR, 91%–100%), whereas in the SJS and TEN groups the median extent of skin involvement was 67.5% (IQR, 37.1%–100%) and 99.5% (IQR, 97.9%–100%), respectively.\n\nTable 3 Clinical and laboratory features of pediatric SCARs\nCharacteristic\tDRESS (n = 7)\tSJS (n = 36)\tTEN (n = 4)\t\nCutaneous lesion extent (%)\t99 (91.0–100)\t67.5 (37.1–100)\t99.5 (97.9–100)\t\nCutaneous findings\t\t\t\t\n\tRash\t5 (71.4)\t34 (94.4)\t4 (100)\t\n\tTarget sign\t\t5 (13.9)\t2 (50)\t\n\tDesquamation\t\t8 (22.2)\t2 (50)\t\n\tBlister\t\t20 (55.6)\t3 (75)\t\nNikolsky signs\t\t5 (13.9)\t4 (100)\t\nSkin detachment\t\t\t\t\n\tDay 1\t1 (14.3)\t6 (16.7)\t1 (25.0)\t\n\tDay 7\t\t5 (13.9)\t1 (25.0)\t\nTachycardia*\t\t\t\t\n\tDay 1\t\t6 (16.7)\t1 (25.0)\t\n\tDay 7\t\t\t2 (50.0)\t\nMucosa involvement\t1 (14.3)\t33 (91.7)\t4 (100)\t\n\tOral\t1\t23\t3\t\n\tLabial\t\t19\t4\t\n\tOcular\t\t12\t4\t\n\tGenital\t\t6\t2\t\n\tRespiratory\t\t4\t1\t\nLymphadenitis\t1 (14.3)\t1 (2.8)\t2 (50)\t\nFever\t6 (85.7)\t24 (66.7)\t3 (75)\t\nFever duration (day)\t5.0 (4.0–8.0)\t4.0 (2.0–6.0)\t13 (10–21.5)\t\nHematologic finding\t\t\t\t\n\tLeukocytosis†\t3 (42.9)\t2 (5.6)\t1 (25)\t\n\tLeukopenia‡\t2 (28.6)\t10 (27.8)\t2 (50)\t\n\tAtypical lymphocytosis§\t2 (28.6)\t2 (5.6)\t1 (25)\t\n\tEosinophilia∥\t3 (42.9)\t4 (11.1)\t3 (75)\t\n\tThrombocytopenia¶\t2 (28.6)\t7 (19.4)\t2 (50)\t\nLiver function abnormality**\t7 (100)\t13 (36.1)\t2 (50)\t\nRenal function abnormality††\t\t1 (2.8)\t1 (25)\t\nValues are presented as median (IQR) or number (%).\n\nSCARs, severe cutaneous adverse reactions; DRESS, drug reaction with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; IQR, interquartile range.\n\n*Tachycardia: heart rate > 160 beats/min in 0–2 years and heart rate > 120 beats/min in > 2 years; †Leukocytosis: white blood cell count > 20,000/μL; ‡Leukopenia: white blood cell count < 4,000/μL; §Atypical lymphocytosis: atypical lymphocyte ≥ 5%; ∥Eosinophilia: eosinophil > 4%; ¶Thrombocytopenia: platelet < 150,000/μL; **Abnormalities in liver function tests: serum level of alanine transaminase > 40 IU/L; ††Abnormalities in renal function tests: glomerular filtration rate < 100 mL/min/1.73 m2.\n\nIn the DRESS group, 1 patient (14.3%) experienced skin detachment. The detached skin area was 90% of the whole body on the first day of SCAR development and was fully recovered by the seventh day of SCAR development. In the SJS group, the median detached skin area was 3% (IQR, 1.5%–6.3%) on the first day of SCAR development; the median decreased to 2% (IQR, 0%–5%) on the seventh day. Six patients (16.7%) had skin detachment on the first day of SCAR development. In the SJS group, 3 were fully recovered and 2 developed skin detachment on the seventh day of SCAR development. In the TEN group, 1 patient (25.0%) had skin detachment. The detached skin area was 2% on the first day of SCAR development and progressed to 36% by the seventh day of SCAR development.\n\nIn addition, the mucosal epithelium was involved in 1 (14.3%) case of DRESS, 33 (91.7%) cases of SJS and all 4 cases of TEN. The most commonly involved mucosal site was the mouth (57.4%, n = 27), followed by the labia (48.9%, n = 23). Lymphadenitis was observed in 1 patient (14.3%) with DRESS, 1 patient (2.8%) with SJS, and in 2 patients (50%) with TEN. Finally, 6 patients (85.7%) with DRESS, 24 patients (66.7%) with SJS, and 3 (75%) patients with TEN experienced a fever. The median fever duration was 5 days (IQR, 4–8) in the DRESS group, 4 days (IQR, 2–6) in the SJS group, and 13 days (IQR, 10–21.5) in the TEN group.\n\nLaboratory abnormalities were found in 4 (57.1%) patients in the DRESS group, 17 (47.2%) patients in the SJS group, and in all patients in the TEN group. The most common laboratory abnormality was eosinophilia and leukocytosis in the DRESS group (42.9%, n = 3), leukopenia in the SJS group (27.8%, n = 10) and eosinophilia in the TEN group (75%, n = 3). On the other hand, liver enzyme abnormalities were noted in all patients in the DRESS group, 13 (36.1%) patients in the SJS group, and 2 (50%) patients in the TEN group. Renal function abnormalities were only noted in the SJS group and the TEN group (1 patient for each).\n\nTreatment\nThe medications used to treat pediatric SCARs are listed in Table 4. Of all the patients examined, 36 (76.6%) received systemic steroids and 21 (44.7%) received intravenous immunoglobulin (IVIG). Thirteen patients (27.7%) received both systemic steroids and IVIG. When patients were divided by treatment option according to type of SCAR, all patients with DRESS received systemic steroids and 3 (42.9%) received additional IVIG. In the SJS group, 25 (69.5%) patients received systemic steroids, 14 (38.9%) patients received IVIG, and 6 (16.7%) patients received both systemic steroids and IVIG. Only 1 patient (2.1%) in the SJS group received cyclosporine concomitantly with systemic steroids. All 4 patients with TEN received both systemic steroids and IVIG. The most common steroids used to treat SCARs were methylprednisolone (36.2%, n = 17) and prednisolone (25.5%, n = 12). Dexamethasone (10.6%, n = 5), hydrocortisone (2.1%, n = 1) and deflazacort (2.1%, n = 1) were also used. The median duration of steroid treatment was 31 days (IQR, 13–134) in the DRESS group, 2.5 days (IQR, 0.0–9.0) in the SJS group, and 6 days (IQR, 5–22) in the TEN group.\n\nTable 4 Medications to treat pediatric SCARs\nCharacteristic\tDRESS (n = 7)\tSJS (n = 36)\tTEN (n = 4)\tTotal (n = 47)\t\nSteroid use only\t4 (57.1)\t19 (52.8)\t\t23 (48.9)\t\n\tMethylprednisolone\t3\t10\t4\t17\t\n\tPrednisolone\t3\t9\t\t12\t\n\tDexamethasone\t1\t4\t\t5\t\n\tHydrocortisone\t\t1\t\t1\t\n\tDeflazacort\t1\t4\t\t5\t\nIVIG use only\t\t8 (22.2)\t\t8 (17.0)\t\nIVIG + Steroid\t3 (42.9)\t6 (16.7)\t4 (100)\t13 (27.7)\t\nCyclosporine\t\t1 (2.8)\t\t1 (2.1)\t\n\tTotal steroid use days\t31 (13–134)\t2.5 (0.0–9.0)\t6 (5–22)\t\t\nOther medication\t2 (28.6)\t14 (38.9)\t1 (25.0)\t17 (36.2)\t\n\tAntibiotics\t1\t3\t\t4\t\n\tAcyclovir\t\t1\t\t1\t\n\tMupirocin\t\t1\t\t1\t\n\tAntihistamine\t\t8\t\t8\t\n\tL-cartinine\t1\t\t\t1\t\n\tUDCA\t\t1\t\t1\t\n\tFentanyl\t\t\t1\t1\t\nValues are presented as number (%) or median (IQR).\n\nDRESS, drug reaction with eosinophilia and systemic symptoms; IQR, interquartile range; IVIG, Intravenous immunoglobulin; SCARs, severe cutaneous adverse reactions; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; UDCA, ursodeoxycholic acid.\n\nSeventeen patients (36.1%) required further treatment in addition to the treatments indicated above. One DRESS patient and 3 SJS patients required antibiotics for a concurrent infection. One patient with DRESS required L-carnitine, 8 patients with SJS required antihistamines, and 1 required acyclovir. The other patient with TEN required fentanyl for pain control.\n\nProgression and prognosis\nThe progression and prognosis of pediatric SCAR cases are shown in Table 5. The median latency between drug administration and symptom expression was 23.5 (IQR, 17.3–32.8) days in the DRESS group, 4.0 days (IQR, 1.0–13.0) in the SJS group and 6.5 days (IQR, 0.8–16.0) in the TEN group. The median duration of symptoms was 15.0 days (IQR, 9.5–19.0) in the DRESS group, 12.0 days (IQR, 8.0–15.0) in the SJS group and 32.5 days (IQR, 26.8–62.0) in the TEN group. The median duration of admission was 12.0 days (IQR, 9.5–16.5) in the DRESS group, 10.0 days (IQR, 6.8–12.3) in the SJS group and 30.5 days (IQR, 24.3–60.5) in the TEN group. One patient in the DRESS group, 1 patient in the SJS group, and 2 patients in the TEN group were transferred to the intensive care unit (ICU). In the DRESS and SJS groups, the patients spent 7 and 3 days in the ICU, respectively. The 2 patients in the TEN group spent 5.0 days and 14.0 days in the ICU. Three (6.4%) patients experienced permanent skin and/or skin appendage sequelae. One of the 4 patients with TEN died.\n\nTable 5 Progression and prognosis of the pediatric SCARs\nCharacteristic\tDRESS (n = 7)\tSJS (n = 36)\tTEN (n = 4)\tTotal (n = 47)\t\nLatency time (day)\t23.5 (17.3–32.8)\t4 (1–13)\t6.5 (0.8–16)\t7.5 (1.75–19.0)\t\nDuration of symptom (day)\t15 (9.5–19)\t12 (8–15)\t32.5 (26.8–62)\t13 (9.0–17.0)\t\nDuration of admission(day)\t12 (9.5–16.5)\t10 (6.8–12.3)\t30.5 (24.3–60.5)\t10 (7.0–15.0)\t\nICU care\t1 (14.3)\t1 (2.8)\t2 (50.0)\t4 (8.5)\t\nClinical outcome\t\t\t\t\t\n\tRecovery\t7 (100)\t33 (91.7)\t2 (50.0)\t42 (89.4)\t\n\tSequelae\t\t2 (5.6)\t1 (25.0)\t3 (6.4)\t\n\t\tSkin\t\t2\t\t2\t\n\t\tSkin/skin appendage\t\t\t1\t1\t\n\tDeath\t\t\t1 (25.0)\t1 (2.1)\t\nValues are presented as number (%) or median (IQR).\n\nSCARs, severe cutaneous adverse reactions; DRESS, drug reaction with eosinophilia and systemic symptoms; SJS, Stevens-Johnson syndrome; TEN, toxic epidermal necrolysis; ICU, intensive care unit; IQR, interquartile range.\n\nDISCUSSION\nThis study found that SJS comprised the majority of the total 47 pediatric SCAR cases, followed by DRESS and TEN. The majority of patients were male, antibiotics and antiepileptics were the most common culprit drugs, and respiratory infections were the most common comorbidities. The clinical presentations of DRESS, SJS and TEN varied remarkably, and thus their clinical characteristics could not be explained along a single continuous disease spectrum. In this study, systemic steroids were the most common treatment of choice, and the mortality rate from pediatric SCARs was 2.1%. This is the first study to describe the clinical characteristics, current treatment modalities and prognosis of pediatric SCAR cases in Korea.\n\nThe culprit drug for SCAR events in this study was identified in 95.7% of the total assessed cases, which is comparable to 93.1% in a large-scaled pediatric research.10 However, it is higher than that of adult cases where 30% of SJS/TEN cases presented no causative drug.14 Considering that SCAR can be induced by infections such as HIV, hepatitis virus, herpes virus and Mycoplasma pneumoniae,15 it can be possible that part of SCARs associated with infection may have been regarded as SCARs due to antibiotics or antipyretics in children.\n\nIn the present study, we found that commonly used drugs were often the cause of pediatric SCARs; this tendency was observed across all SCAR groups. Importantly, antibiotics and antipyretics are among the most commonly used drugs in children,16 and we found that beta-lactam and macrolide antibiotics were the most common SCAR culprits in the present study. Antiepileptics, which were also found to be associated with high rates of SCARs in this study, are not commonly used in children; however, when they have been prescribed, they are used chronically. Our findings are consistent with those of a previous study, which reported a tendency for children to be most frequently affected by commonly used drugs, while adults are affected most frequently by specific drugs such as allopurinol, neuroleptics or antihypertensives.17\n\nOne interesting finding of the present study was that 57.4% of the patients experienced pediatric SCARs from a single drug. This differs from that of a previous study which found that 92.6% of pediatric SCAR cases resulted from a single drug.6 Moreover, most cases of SCARs in the present study resulted from orally administered medications; only 1 was associated with intravenous drug administration. This finding also contrasts with that of a previous report, which found that SCARs tended to occur more frequently after non-oral drug administration.18 Furthermore, 2 patients (4.3%) developed SCARs while they took systemic steroid and, in 1 out of 4 cases of TEN, oral steroid was suspected, which was not expected in another large-scaled pediatric research.10 In the literature, the rate of steroid hypersensitivity reaction is as low as 0.1%0.3%,1920 but the incidence of SCAR due to systemic steroid was not known. In a case-control study conducted by the EuroSCAR group, exposure to systemic steroid around the time of manifestation was as high as 14.8% in the SJS/TEN group.21 In that study, however, 55% of subjects with steroid-associated SJS/TEN were already taking another concomitant medication that are classified as high-risk for SCARs. Therefore, it is true that the systemic steroid can cause SCARs, but the result needs to be cautiously interpreted.\n\nIt has been proposed that DRESS, SJS and TEN are not individual diseases but rather exist along a SCAR spectrum.22 However, our results showed that DRESS was associated with different clinical characteristics than SJS or TEN. In DRESS cases, the area of skin damage could be as high as 90%, but resolved spontaneously and completely in 7 days. However, in SJS and TEN cases the area of skin damage was much smaller, but the damage did not recover in 7 days and left unresolved skin or mucosal damage. Furthermore, the involvement of the mucosa, most commonly in oral, labial and ocular zones, was shown in the SJS and TEN groups, but not in the DRESS group as has previously been reported.10\n\nIn the present study, we found that SCARs were accompanied by various systemic symptoms. This has previously been reported,17 but is some discrepancy between our results and previous findings. For example, while lymphadenitis was previously reported to be a common symptom of DRESS,10 it more frequently occurred with SJS and TEN in the SCAR cases that we analyzed. The pathogenesis of SCARs is not fully understood. However, considering that SCAR is associated with the activation of CD8+ cytotoxic cells,2324 the presence of lymphadenitis may serve as a positive diagnostic indicator of suspected SCARs in children.\n\nOn the other hand, thrombocytopenia and eosinophilia were observed in many cases, though atypical lymphocytosis was not as common as leukocytosis or leucopenia. Recently, in addition to SCARs caused by drugs, it has been proposed that infections, such as those resulting from mycoplasma or viruses, might cause SCARs.1225 This suggests that pediatric SCARs are heterogeneous, with various etiologies based on patient background.\n\nAn additional source of variability and heterogeneity among pediatric SCARs found in the present study was the latency period between drug initiation and the time at which SCARs developed. We found that DRESS had a longer median time (23.5 days) between administration of the first causative drug dose and the onset of symptoms than did the SJS (4.0 days) or TEN (6.5 days) groups. Previous studies have reported similar findings, with an average latency period of 22 days in DRESS cases26 and a shorter time period for both TEN and SJS than for DRESS, with symptoms generally emerging within the first 7 days of exposure.272829 This longer latency time in DRESS than in TEN/SJS indicate that early signs and symptoms of DRESS (fever, lymphadenopathy, flu-like symptoms, sore throat or dysphagia, burning pain and pruritus) can easily be overlooked or misdiagnosed.26\n\nAS for prognoses, TEN was associated with a much higher ICU transfer rate (50%) and a much longer median admission period (30.5 days) than SJS. Patients with skin detachment of more than 30% carry an increased risk of different systemic complication, it is recommended to transfer subjects with severe SJS/TEN.2730 Furthermore, the TEN mortality rate was 25% (1 of 4 cases) compared to a total mortality rate of 2.1% among the 3 groups. This result is comparable to the mortality rate of 1%–-5% for SJS and 25%-–30% for TEN28 and it shows the need for an urgent and special care for subjects with TEN.\n\nTreatment for pediatric SCARs are primarily based on supportive care—that is, withdrawal of the culprit drug, close monitoring and supportive care.28 Other immune-modulating treatments, such as systemic corticosteroids, IVIG and cyclosporines, are commonly used in persistent cases.1 In this study, systemic corticosteroid treatment was most commonly adopted, followed by IVIG. Both systemic corticosteroids and IVIG were administered to 27.7% of the patients assessed. However, in spite of more recent data that finds a favorable outcome from cyclosporine on SCAR progression31 and mortality rates,2332 cyclosporine was introduced in only 1 case, which keeps parallel to the fact that no SJS/TEN cases adopted the cyclosporine treatment in the large pediatric study.10 Considering that conflicting results and the possible risk associated with systemic corticosteroids in SCARs cases,333435 further studies are warranted to verify the safety and the efficacy of cyclosporine as the primary option for SCAR treatment.\n\nThe present study has a few limitations. All patients in the present study were diagnosed with SCARs based on a clinical assessment and most did not undergo a skin biopsy and/or patch testing for suspected drug sensitivity. Given that we analyzed cases diagnosed at referral tertiary university hospitals, milder cases treated at regional centers, where spontaneous resolution was achieved by a simple discontinuation of the offending drug, were not included. Nevertheless, this study is valuable because it is the first to assess the Korean representative SCARs registry for pediatrics cases, as per the internationally-accepted RegiSCAR criteria.\n\nIn conclusion, a high proportion of Korean pediatric SCARs cases occurred in responses to antibiotic and antiepileptic drugs that are commonly or chronically administered orally. The latency period between drug administration and the development of SCARs varied, and nonspecific symptoms, which were indistinguishable from viral or other infections, often indicated the early stages of SCAR development. None of the early signs noted could predict SCARs development; additionally, the extent of resulting skin damage could not be used to predict the development of sequelae. Thus, clinical suspicion should remain the primary method of rapidly diagnosing SCARs and providing prompt treatment.\n\nACKNOWLEDGMENTS\nWe specially give thanks to all members of the Korean SCAR registry for their efforts to build up this database.\n\nDisclosure: There are no financial or other issues that might lead to conflict of interest.\n==== Refs\n1 Noguera-Morel L Hernández-Martín Á Torrelo A Cutaneous drug reactions in the pediatric population Pediatr Clin North Am 2014 61 403 426 24636653 \n2 Gomes ER Brockow K Kuyucu S Saretta F Mori F Blanca-Lopez N Drug hypersensitivity in children: report from the pediatric task force of the EAACI Drug Allergy Interest Group Allergy 2016 71 149 161 26416157 \n3 Teo YX Walsh SA Severe adverse drug reactions Clin Med (Lond) 2016 16 79 83 26833523 \n4 Hoetzenecker W Nägeli M Mehra ET Jensen AN Saulite I Schmid-Grendelmeier P Adverse cutaneous drug eruptions: current understanding Semin Immunopathol 2016 38 75 86 26553194 \n5 Chantaphakul H Sanon T Klaewsongkram J Clinical characteristics and treatment outcome of Stevens-Johnson syndrome and toxic epidermal necrolysis Exp Ther Med 2015 10 519 524 26622347 \n6 Blumenthal KG Wickner PG Lau JJ Zhou L Stevens-Johnson syndrome and toxic epidermal necrolysis: a cross-sectional analysis of patients in an integrated allergy repository of a large health care system J Allergy Clin Immunol Pract 2015 3 277 280.e1 25609329 \n7 Mockenhaupt M International registry of severe cutaneous adverse reactions (SCAR) to drugs and collection of biological sample, study protocol [Internet] RegiSCAR study group 2010 cited 2018 Nov 5 Available from: http://www.regiscar.org/pdf/regiscarprotocol100312.pdf \n8 Jung HY Park S Shin B Lee JH Lee SJ Lee MK Prevalence and clinical features of drug reactions with eosinophilia and systemic symptoms syndrome caused by antituberculosis drugs: a retrospective cohort study Allergy Asthma Immunol Res 2019 \n9 World Health Organization Uppsala Monitoring Centre The use of the WHO-UMC system for standardized case causality assessment [Internet] Uppsala The Uppsala Monitoring Centre 2005 cited 2018 Nov 5 Available from: http://www.who.int/medicines/areas/quality_safety/safety_efficacy/WHOcausality_assessment.pdf \n10 Dibek Misirlioglu E Guvenir H Bahceci S Haktanir Abul M Can D Usta Guc BE Severe cutaneous adverse drug reactions in pediatric patients: a multicenter study J Allergy Clin Immunol Pract 2017 5 757 763 28351788 \n11 Kardaun SH Sidoroff A Valeyrie-Allanore L Halevy S Davidovici BB Mockenhaupt M Variability in the clinical pattern of cutaneous side-effects of drugs with systemic symptoms: does a DRESS syndrome really exist? Br J Dermatol 2007 156 609 611 17300272 \n12 Shiohara T Iijima M Ikezawa Z Hashimoto K The diagnosis of a DRESS syndrome has been sufficiently established on the basis of typical clinical features and viral reactivations Br J Dermatol 2007 156 1083 1084 17381452 \n13 Park HW Kim SH Chang YS Kim SH Jee YK Lee AY The fas signaling pathway is a common genetic risk factor for severe cutaneous drug adverse reactions across diverse drugs Allergy Asthma Immunol Res 2018 10 555 561 30088374 \n14 Duong TA Valeyrie-Allanore L Wolkenstein P Chosidow O Severe cutaneous adverse reactions to drugs Lancet 2017 390 1996 2011 28476287 \n15 Fakoya AO Omenyi P Anthony P Anthony F Etti P Otohinoyi DA Stevens - Johnson syndrome and toxic epidermal necrolysis; extensive review of reports of drug-induced etiologies, and possible therapeutic modalities Open Access Maced J Med Sci 2018 6 730 738 29731949 \n16 Vernacchio L Kelly JP Kaufman DW Mitchell AA Medication use among children <12 years of age in the United States: results from the Slone Survey Pediatrics 2009 124 446 454 19651573 \n17 Wolf R Orion E Marcos B Matz H Life-threatening acute adverse cutaneous drug reactions Clin Dermatol 2005 23 171 181 15802211 \n18 Demoly P Adkinson NF Brockow K Castells M Chiriac AM Greenberger PA International Consensus on drug allergy Allergy 2014 69 420 437 24697291 \n19 Baeck M Marot L Nicolas JF Pilette C Tennstedt D Goossens A Allergic hypersensitivity to topical and systemic corticosteroids: a review Allergy 2009 64 978 994 19416135 \n20 Freymond N Catelain A Queille E Augey F Nicolas JF Allergic reaction to methylprednisolone Rev Med Interne 2003 24 698 700 14550525 \n21 Mockenhaupt M Viboud C Dunant A Naldi L Halevy S Bouwes Bavinck JN Stevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study J Invest Dermatol 2008 128 35 44 17805350 \n22 Wolf R Matz H Marcos B Orion E Drug rash with eosinophilia and systemic symptoms vs toxic epidermal necrolysis: the dilemma of classification Clin Dermatol 2005 23 311 314 15896547 \n23 Khalili B Bahna SL Pathogenesis and recent therapeutic trends in Stevens-Johnson syndrome and toxic epidermal necrolysis Ann Allergy Asthma Immunol 2006 97 272 280 17042130 \n24 Downey A Jackson C Harun N Cooper A Toxic epidermal necrolysis: review of pathogenesis and management J Am Acad Dermatol 2012 66 995 1003 22169256 \n25 Shiohara T Kano Y A complex interaction between drug allergy and viral infection Clin Rev Allergy Immunol 2007 33 124 133 18094951 \n26 Kardaun SH Sekula P Valeyrie-Allanore L Liss Y Chu CY Creamer D Drug reaction with eosinophilia and systemic symptoms (DRESS): an original multisystem adverse drug reaction. Results from the prospective RegiSCAR study Br J Dermatol 2013 169 1071 1080 23855313 \n27 Belver MT Michavila A Bobolea I Feito M Bellón T Quirce S Severe delayed skin reactions related to drugs in the paediatric age group: a review of the subject by way of three cases (Stevens-Johnson syndrome, toxic epidermal necrolysis and DRESS) Allergol Immunopathol (Madr) 2016 44 83 95 26089185 \n28 Harr T French LE Stevens-Johnson syndrome and toxic epidermal necrolysis Chem Immunol Allergy 2012 97 149 166 22613860 \n29 Peter JG Lehloenya R Dlamini S Risma K White KD Konvinse KC Severe delayed cutaneous and systemic reactions to drugs: a global perspective on the science and art of current practice J Allergy Clin Immunol Pract 2017 5 547 563 28483310 \n30 Mockenhaupt M The current understanding of Stevens-Johnson syndrome and toxic epidermal necrolysis Expert Rev Clin Immunol 2011 7 803 813 22014021 \n31 St John J Ratushny V Liu KJ Bach DQ Badri O Gracey LE Successful use of cyclosporin A for Stevens-Johnson syndrome and toxic epidermal necrolysis in three children Pediatr Dermatol 2017 34 540 546 28884910 \n32 Kirchhof MG Miliszewski MA Sikora S Papp A Dutz JP Retrospective review of Stevens-Johnson syndrome/toxic epidermal necrolysis treatment comparing intravenous immunoglobulin with cyclosporine J Am Acad Dermatol 2014 71 941 947 25087214 \n33 Zhu QY Ma L Luo XQ Huang HY Toxic epidermal necrolysis: performance of SCORTEN and the score-based comparison of the efficacy of corticosteroid therapy and intravenous immunoglobulin combined therapy in China J Burn Care Res 2012 33 e295 e308 22955159 \n34 Lee HY Dunant A Sekula P Mockenhaupt M Wolkenstein P Valeyrie-Allanore L The role of prior corticosteroid use on the clinical course of Stevens-Johnson syndrome and toxic epidermal necrolysis: a case-control analysis of patients selected from the multinational EuroSCAR and RegiSCAR studies Br J Dermatol 2012 167 555 562 22639874 \n35 Schneck J Fagot JP Sekula P Sassolas B Roujeau JC Mockenhaupt M Effects of treatments on the mortality of Stevens-Johnson syndrome and toxic epidermal necrolysis: a retrospective study on patients included in the prospective EuroSCAR Study J Am Acad Dermatol 2008 58 33 40 17919775\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2092-7355",
"issue": "11(2)",
"journal": "Allergy, asthma & immunology research",
"keywords": "Drug eruptions; Drug-related side effects and adverse reactions; children",
"medline_ta": "Allergy Asthma Immunol Res",
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"pages": "241-253",
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"pmid": "30661316",
"pubdate": "2019-03",
"publication_types": "D016428:Journal Article",
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"title": "Severe Cutaneous Adverse Reactions in Korean Pediatric Patients: A Study From the Korea SCAR Registry.",
"title_normalized": "severe cutaneous adverse reactions in korean pediatric patients a study from the korea scar registry"
} | [
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"literaturereference": "OH HL, KANG DY, KANG H, KIM S, KOH Y, KIM SH, ET AL. SEVERE CUTANEOUS ADVERSE REACTIONS IN KOREAN PEDIATRIC PATIENTS: A STUDY FROM THE KOREA SCAR REGISTRY. ALLERGY, ASTHMA AND IMMUNOLOGY RESEARCH 01-MAR-2019?11 (2):241-253.",
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{
"abstract": "Serious infections such as endocarditis due to extremely drug-resistance gram-negative bacteria are an increasing challenge. Here, we present successful adjunctive use of cefiderocol for a patient with persistently bacteremic healthcare-associated native aortic valve endocarditis due to an extended-spectrum beta-lactamase-positive Pseudomonas aeruginosa susceptible in vitro only to colistin, following failure of conventional therapeutic options.",
"affiliations": "Department of Infectious Diseases, Guy's Hospital, Kings College London, London, United Kingdom.;Shionogi Limited, Global Clinical Development Unit, London, United Kingdom.;Shionogi Limited, Global Clinical Development Unit, London, United Kingdom.;Intensive Care Unit, London Bridge Hospital, HCA International, London, United Kingdom.;Microbiology Department, HCA International, London, United Kingdom.;Pharmacy Department, London Bridge Hospital, HCA International, London, United Kingdom.;Intensive Care Unit, London Bridge Hospital, HCA International, London, United Kingdom.;Intensive Care Unit, London Bridge Hospital, HCA International, London, United Kingdom.;Intensive Care Unit, London Bridge Hospital, HCA International, London, United Kingdom.;Shionogi & Co., Ltd., Kitaku, Osaka, Japan.;Shionogi & Co., Ltd., Kitaku, Osaka, Japan.;Norwich Medical School, University of East Anglia, United Kingdom.;School of Medicine, Guy's Hospital, Kings College London, United Kingdom.",
"authors": "Edgeworth|Jonathan D|JD|;Merante|Domenico|D|;Patel|Sanjay|S|;Young|Christopher|C|;Jones|Paul|P|;Vithlani|Seema|S|;Wyncoll|Duncan|D|;Roberts|Peter|P|;Jones|Andrew|A|;Den Nagata|Tsutae|T|;Ariyasu|Mari|M|;Livermore|David M|DM|;Beale|Richard|R|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002511:Cephalosporins; C000612166:cefiderocol; D001618:beta-Lactamases; D003091:Colistin",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciy963",
"fulltext": "\n==== Front\nClin Infect DisClin. Infect. DiscidClinical Infectious Diseases: An Official Publication of the Infectious Diseases Society of America1058-48381537-6591Oxford University Press US 10.1093/cid/ciy963ciy963Brief ReportsCompassionate Use of Cefiderocol as Adjunctive Treatment of Native Aortic Valve Endocarditis Due to Extremely Drug-resistant Pseudomonas aeruginosa Edgeworth Jonathan D 1Merante Domenico 2Patel Sanjay 2Young Christopher 3Jones Paul 4Vithlani Seema 5Wyncoll Duncan 3Roberts Peter 3Jones Andrew 3Den Nagata Tsutae 6Ariyasu Mari 6Livermore David M 78Beale Richard 91 Department of Infectious Diseases, Guy’s Hospital, Kings College London, London, United Kingdom2 Shionogi Limited, Global Clinical Development Unit, London, United Kingdom3 Intensive Care Unit, London Bridge Hospital, HCA International, London, United Kingdom4 Microbiology Department, HCA International, London, United Kingdom5 Pharmacy Department, London Bridge Hospital, HCA International, London, United Kingdom6 Shionogi & Co., Ltd., Kitaku, Osaka, Japan7 Norwich Medical School, University of East Anglia, United Kingdom8 Antimicrobial Resistance & Healthcare Associated Infections Reference Unit, Public Health England, Colindale, London9 School of Medicine, Guy’s Hospital, Kings College London, United KingdomCorrespondence: J. D. Edgeworth, Department of Infectious Diseases, 5th Floor, North Wing, St Thomas’ Hospital, Westminster Bridge Road, London, SE1 7EH (Jonathan.Edgeworth@gstt.nhs.uk).01 6 2019 12 11 2018 12 11 2018 68 11 1932 1934 10 9 2018 08 11 2018 © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.2018This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.Abstract\nSerious infections such as endocarditis due to extremely drug-resistance gram-negative bacteria are an increasing challenge. Here, we present successful adjunctive use of cefiderocol for a patient with persistently bacteremic healthcare-associated native aortic valve endocarditis due to an extended-spectrum beta-lactamase–positive Pseudomonas aeruginosa susceptible in vitro only to colistin, following failure of conventional therapeutic options.\n\ncefiderocolendocarditisPseudomonas aeruginosadrug resistancemicrobialUK government\n==== Body\nCefiderocol is a novel parenteral siderophore cephalosporin currently being developed to treat serious infections, including those due to carbapenem-resistant gram-negative strains [1–3]. Cefiderocol has a unique mechanism of cell entry via bacterial iron transport channels. This allows it to enter gram-negative bacteria efficiently, even when accumulation of other agents is reduced due to porin channel loss and increased expression of efflux pumps. Cefiderocol has good stability to all classes of beta-lactamases, including serine- or metallo-carbapenemases that hydrolyze most or all other beta-lactam antibiotics. This combination of properties allows potent antibacterial activity against a wide variety of Enterobacteriaceae and nonfermenting gram-negative bacteria including Pseudomonas aeruginosa, Acinetobacter baumannii, and Stenotrophomonas maltophilia, even when these have a potent combination of beta-lactamases. Activity is poor against gram-positive bacteria and anaerobic bacteria [1, 3].\n\nCefiderocol has been assessed in early-phase clinical trials for safety, tolerability, and pharmacodynamic behavior [4, 5]. Cefiderocol was shown to be safe and effective for the treatment of complicated urinary tract infection in a recently completed phase 2 study (APEKS-cUTI study) involving 452 randomized patients [6]; it is now being evaluated in phase 3 studies (CREDIBLE-CR and APEKS-NP). Shionogi, the developers of cefiderocol, will consider unsolicited requests for compassionate use and were approached to assist with treatment in the following case.\n\nA 78-year-old woman was admitted from an intensive care unit in Kuwait to London Bridge Hospital on 30 October 2017 for specialist urological and respiratory management. She had been in hospital in Kuwait for 3 months following complications of hydronephrosis secondary to a spontaneous ureteric hematoma. She had a past medical history of aortic stenosis, ischemic heart disease, and cerebral infarction and was in remission from breast cancer.\n\nOn arrival in London, she was ventilated and received intermittent hemofiltration without hemodynamic support or antimicrobials. Admission blood cultures grew extremely drug-resistant (XDR) P. aeruginosa susceptible to gentamicin, amikacin, and colistin (minimum inhibitory concentration [MIC] <3 mg/L) but resistant to all beta-lactams and quinolones. There was no in vitro synergy between antipseudomonal agents and fosfomycin or rifampicin. The isolate lacked carbapenemase genes, and resistance to these agents was inferred to reflect loss of porin (OprD). A bla(Vietnam ESBL) gene was found by polymerase chain reaction (PCR) assay and was considered to account for resistance to penicillins and cephalosporins, including ceftazidime/avibactam and ceftolozane/tazobactam. The patient also had rectal colonization with OXA-48 Klebsiella pneumoniae and OXA-23/OXA-51 A. baumannii. She was commenced empirically on colistin (9 megaunits (MU) loading dose followed by 3 MU 3 times per day, subsequently changed to 4.5 MU 2 times per day) together with intermittent gentamicin based on serum levels. A transthoracic echocardiogram showed a thickened aortic valve but no obvious regurgitation or vegetation. Representative clinical and microbiological features from her admission are presented in Figure 1.\n\nFigure 1. Clinical, microbiological, and antimicrobial treatment course. Abbreviations: BC, blood culture positive (+) Pseudomonas aeruginosa or negative (−); ECHO, transthoracic echocardiogram.\n\nShe became clinically septic following insertion of percutaneous nephrostomies and started high-flow continuous veno-venous hemofiltration (estimated creatinine clearance 40–50 mL/minute). Blood cultures again grew P. aeruginosa on days 3, 7, and 10. Gentamicin was stopped after the third dose on day 5 and replaced with meropenem 2 g 2 times per day, although MICs of the drug for all the P. aeruginosa isolates were >32 mg/L. Sepsis resolved on day 14, with a negative blood culture and C-reactive protein (CRP) falling from 212 to 41; this improvement prompted cessation of antibiotic therapy. Sepsis returned within a few days, however, and the CRP rose to 267 mg/L, with day 22 and 27 blood cultures again growing P. aeruginosa, leading to recommencement of colistin and gentamicin. CRP continued to rise to 327 mg/L, and a day 27 P. aeruginosa isolate was reported as intermediately resistant to gentamicin, so gentamicin was again switched to meropenem. A second transthoracic echocardiogram showed possible vegetation on a tricuspid aortic valve with mild to moderate regurgitation.\n\nBlood cultures were negative on days 38, 49, and 52, and the patient initially improved clinically while undergoing assessment for aortic valve surgery. However, during that time, there was a significant neurological deterioration with a computed tomography scan showing multifocal infarcts consistent with embolization; blood cultures again became positive (days 56, 62, and 68). A decision was made to source additional active antibiotics to control bacteremia prior to valve surgery.\n\nADJUNCTIVE TREATMENT WITH CEFIDEROCOL\nAccordingly, a formal request was made to Shionogi on day 73 for compassionate use of cefiderocol. The request was granted, and the drug was obtained after appropriate governance approvals. Disk diffusion testing performed on day 3 and day 68 isolates gave zones of 17.4 and 21.3 mm, respectively, against a prospective 18-mm breakpoint for a 30-μg disk. Cefiderocol was administered from day 83 while continuing meropenem and colistin, and aortic valve replacement was performed on day 85. Intensivists decided on a cefiderocol dose of 2 g administered over 3 hours 3 times a day for the first 2 days then 2 g twice daily, based on a combination of renal function, septic state, complexity of the infection, and laboratory susceptibility testing. Blood culture taken before the first cefiderocol dose remained positive, but a blood culture taken after the sixth dose, on the day before surgery, was negative after 5 days of culture. The valve appeared heavily infected and disrupted at surgery and was positive for P. aeruginosa by PCR. Nevertheless, no gram-negative bacteria were seen on microscopy, and no growth was obtained, including on enrichment culture. Meropenem was stopped a week after surgery, but the cefiderocol/colistin combination was continued for an additional 3 weeks. The neutrophil count fell during the last 4 days of antibiotic treatment to a low of 0.2 109/L on the planned last day of antibiotics, then returned to the normal range within a few days after stopping antibiotics. Neutropenia was reported in the serious adverse event report form, with either colistin or cefiderocol being considered the most likely potential causes. Multiple blood cultures after surgery and after stopping antibiotics were negative up to day 275 while the patient received convalescent care with slow neurological recovery leading to transfer back to Kuwait.\n\nDISCUSSION\nInfective endocarditis due to P. aeruginosa is rare, except among intravenous drug users, accounting for <0.5% of all endocarditis cases [7]. A recent literature review of 27 cases over 20 years reported 75% as healthcare associated, of which half required surgery and a third relapsed after apparent adequate treatment [8]. Pseudomonas aeruginosa endocarditis is usually treated with combination therapy, such as meropenem or ceftazidime plus an aminoglycoside [7], but these regimens are compromised against XDR strains, as in this case. Colistin is usually used as backbone therapy for XDR gram-negative bacterial infections, often with meropenem. However, in this case, a combination of these agents achieved only temporary blood culture sterility, with no other identified available options. Antibiotic dosing was at the high end of the recommended range, and a trough colistin serum level was measured at 6.3 mg/mL (target 2–4 mg/mL) 2 weeks prior to surgery, so it was considered that adequate doses were used.\n\nThe cause of the endocarditis was not identified but was probably present prior to transfer from Kuwait. Pseudomonas aeruginosa was not grown from any other cultures, including samples from the urinary tract. There were no predisposing factors such as a prosthetic valve or the presence of pacing wires, as reported in other studies [9]. Although P. aeruginosa endocarditis can be treated with antibiotics alone, the failure to achieve sterility in this case combined with evolving valvular destruction meant surgery was essential for any prospect of cure. However, this was delayed in part due to embolization and was considered unlikely to succeed with persistently positive blood cultures on antibiotic therapy. The addition of cefiderocol led to blood culture sterility within 2 days, allowing potentially curative surgery to proceed. It is not possible to ascribe the relative contribution of surgery vs cefiderocol, but the rapid blood and valve sterility after starting cefiderocol suggest that this cephalosporin made a significant contribution. This report adds to the evidence from ongoing randomized studies that cefiderocol holds promise of being a useful new agent for treating XDR gram-negative bacteria, including when no other options exist.\n\nFrom a microbiological perspective, it is striking that for P. aeruginosa, where there is easy mutational resistance to carbapenems, an extended-spectrum beta-lactamase (ESBL) gave the broadest spectrum of resistance. Also striking, and typical of VEB ESBLs in P. aeruginosa, is the fact that resistance included ceftolozane/tazobactam and ceftazidime/avibactam [10]. Although VEB enzymes are uncommon in the United Kingdom (and the United States), the number of producer is increasing, often via imports from the Middle East and Eastern Europe [10], where these enzymes appear to be more prevalent.\n\nCONCLUSIONS\nThe emergence of multiresistant and extremely resistant gram-negative pathogens presents a global health challenge and underscores the urgent need for new antibiotics [11, 12]. Cefiderocol is being developed to address this need, targeting Enterobacteriaceae, P. aeruginosa, A. baumannii, and S. maltophilia [1, 2].\n\nThis case report documents a patient with XDR P. aeruginosa who was successfully managed with the addition of cefiderocol to control bacteremia and to allow aortic valve replacement. Compassionate use of cefiderocol was opted for this patient because there were no other available therapeutic options and because conventional agents were failing to control persistent bacteremia. An episode of transient acute neutropenia occurred during the last few days of treatment with both cefiderocol and colistin, highlighting the importance of continued pharmacovigilance during extended courses of antibiotics.\n\nNotes\n\nAcknowledgments. We are grateful to Rachel Pike and Daniele Meunier at Public Health England (PHE) for susceptibility testing and molecular characterization of the isolates. We are also grateful to Hamish Rankin at Shionogi Limited London UK for the clinical operations activities that led to the provision of cefiderocol.\n\n\nFinancial support. PHE is funded by the UK government.\n\n\nPotential conflicts of interest. J. D. E. served on advisory boards for Pfizer and Merck. D. W. reports personal fees from Merck, Pfizer, Johnson & Johnson, and Fisher & Paykel. D. M. L. has served on advisory boards or ad-hoc consultancy for Accelerate, Achaogen, Adenium, Allecra, Basilea, BioVersys, Centauri, Integra Holdings, Meiji, Melinta, Nordic Pharma, Pfizer, F Hoffmann-la-Roche, Shionogi, Taxis, T.A.Z., Tetraphase, the Medicines Company, VenatoRx, Wockhardt, and Zambon; has received personal fees for paid lectures from Astellas, AstraZeneca, bioMérieux, Beckmann Coulter, Cardiome/Correvio, Cepheid, Merck, Pfizer, and Nordic; has received research funding from Melinta, Merck, Paratek, Roche, and VenatoRx outside the submitted work; has performed contract research for Merck, Melinta, Pfizer, and Wockhardt; and has relevant shareholdings with Dechra, GlaxoSmithKline, Merck, Perkin Elmer, and Pfizer amounting to <10% of portfolio value. D. M. L.’s affiliation, PHE, is funded by the UK government and has undertaken contract research on cefiderocol for Shionogi. D. M., S. P., T. D. N, and M. A. are employees of Shionogi Ltd. All other authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n==== Refs\nReferences\n1. \nHackel MA , Tsuji M , Yamano Y , Echols R , Karlowsky JA , Sahm DF \nIn vitro activity of the siderophore cephalosporin, cefiderocol, against a recent collection of clinically relevant gram-negative bacilli from North America and Europe, including carbapenem-nonsusceptible isolates (SIDERO-WT-2014 Study) . Antimicrob Agents Chemother 2017 ; 61 . doi:10.1128/AAC.00093-17 .\n2. \nKohira N , West J , Ito A , et al \nIn vitro antimicrobial activity of a siderophore cephalosporin, S-649266, against Enterobacteriaceae clinical isolates, including carbapenem-resistant strains . Antimicrob Agents Chemother 2016 ; 60 :729 –34 .26574013 \n3. \nChoi JJ , McCarthy MW \nCefiderocol: a novel siderophore cephalosporin . Expert Opin Investig Drugs 2018 ; 27 :193 –7 .\n4. \nKatsube T , Echols R , Arjona Ferreira JC , Krenz HK , Berg JK , Galloway C \nCefiderocol, a siderophore cephalosporin for gram-negative bacterial infections: pharmacokinetics and safety in subjects with renal impairment . J Clin Pharmacol 2017 ; 57 :584 –91 .27874971 \n5. \nKatsube T , Wajima T , Ishibashi T , Arjona Ferreira JC , Echols R \nPharmacokinetic/pharmacodynamic modeling and simulation of cefiderocol, a parenteral siderophore cephalosporin, for dose adjustment based on renal function . Antimicrob Agents Chemother 2017 ; 61 . doi:10.1128/AAC.01381-16 \n6. Portsmouth S, van Veenhuyzen D, Echols R, et al. Cefiderocol versus imipenem-cilastatin for the treatment of complicated urinary tract infectious caused by Gram-negative uropathogens: a phase 2, randomised, double-blind, non-inferiority trial. Lancet Infect Dis 2018; doi:10.1016/S1473-3099(18)30554-1\n7. \nHagiya H , Tanaka T , Takimoto K , et al \nNon-nosocomial healthcare-associated left-sided Pseudomonas aeruginosa endocarditis: a case report and literature review . BMC Infect Dis 2016 ; 16 :431 .27543116 \n8. \nLin TI , Huang YF , Liu PY , et al \n\nPseudomonas aeruginosa infective endocarditis in patients who do not use intravenous drugs: analysis of risk factors and treatment outcomes . J Microbiol Immunol Infect 2016 ; 49 :516 –22 .25442867 \n9. \nLoubet P , Lescure FX , Lepage L , et al \nEndocarditis due to gram-negative bacilli at a French teaching hospital over a 6-year period: clinical characteristics and outcome . Infect Dis (Lond) 2015 ; 47 :889 –95 .26260729 \n10. \nGreenwood B , Meunier D , Hopkins KL , et al \n\nPseudomonas aeruginosa sequence type 357 with VEB extended-spectrum β-lactamases in the UK: relatedness and resistance . Int J Antimicrob Agents 2018 ; 52 :301 –2 .29580931 \n11. \nLivermore DM \nCurrent epidemiology and growing resistance of gram-negative pathogens . Korean J Intern Med 2012 ; 27 :128 –42 .22707882 \n12. \nLi XZ , Plésiat P , Nikaido H \nThe challenge of efflux-mediated antibiotic resistance in gram-negative bacteria . Clin Microbiol Rev 2015 ; 28 :337 –418 .25788514\n\n",
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"abstract": "Fluoxetine is a selective serotonin reuptake inhibitor (SSRI) commonly used in the treatment of depression. While most intoxications with SSRI's have favorable outcomes and do not require interventions other than strict observation of vital signs and heart rhythm, clinicians should be aware of the life-threatening complications that may occur.\nA 61-year-old woman presented to the emergency department after an intentional multiple drug overdose. Upon examination, she was somnolent with stable respiration and hemodynamics. Electrocardiography showed a prolonged QTc interval of 503 ms. The patient was admitted to the ICU for cardiopulmonary monitoring. During admission, the patient remained stable and showed improved neurologic function over time. After 22 h, a second ECG showed normalization of the QTc interval to 458 ms. However, 36 to 40 h after admission, our patient developed recurrent episodes of Torsades de Pointes (TdP) with loss of cardiac output, leading to cardiopulmonary resuscitation. Spontaneous circulation was restored after intravenous administration of magnesium sulphate. Retrospective serum analysis revealed fluoxetine concentrations of 2700 mcg/l.\nMost intoxications with selective serotonin reuptake inhibitors (SSRI) have favorable outcomes and do not require medical interventions other than strict cardiopulmonary observation. However, higher doses have been associated with QTc interval prolongation, TdP, serotonin syndrome, and death. This case illustrates that life-threatening complications may occur late in the course of hospital admission. Even though overdoses with SSRI's generally result in few fatalities, clinicians should be aware of the life-threatening clinical manifestations that may occur. Despite being an imperfect predictor of imminent TdP, continuous monitoring of cardiac rhythm is strongly recommended when either cardiac or non-cardiac symptoms are present.",
"affiliations": "1Intensive Care Unit, Deventer Hospital, Nico Bolkesteinlaan 75, Deventer, 7416 SE The Netherlands.;2Department of Clinical Pharmacy, Deventer Hospital, Nico Bolkesteinlaan 75, Deventer, 7416 SE The Netherlands.;1Intensive Care Unit, Deventer Hospital, Nico Bolkesteinlaan 75, Deventer, 7416 SE The Netherlands.",
"authors": "Groot|Jan Albert Nicolaas|JAN|;Ten Bokum|Leonore|L|;van den Oever|Hubertus Laurentius Antonius|HLA|",
"chemical_list": null,
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"fulltext": "\n==== Front\nJ Intensive CareJ Intensive CareJournal of Intensive Care2052-0492BioMed Central London 32910.1186/s40560-018-0329-1Case ReportLate presentation of Torsades de Pointes related to fluoxetine following a multiple drug overdose Groot Jan Albert Nicolaas n.groot@dz.nl 1ten Bokum Leonore l.tenbokum@dz.nl 2van den Oever Hubertus Laurentius Antonius h.vandenoever@dz.nl 11 0000 0004 0396 5908grid.413649.dIntensive Care Unit, Deventer Hospital, Nico Bolkesteinlaan 75, Deventer, 7416 SE The Netherlands 2 0000 0004 0396 5908grid.413649.dDepartment of Clinical Pharmacy, Deventer Hospital, Nico Bolkesteinlaan 75, Deventer, 7416 SE The Netherlands 10 9 2018 10 9 2018 2018 6 5918 4 2018 27 8 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nFluoxetine is a selective serotonin reuptake inhibitor (SSRI) commonly used in the treatment of depression. While most intoxications with SSRI’s have favorable outcomes and do not require interventions other than strict observation of vital signs and heart rhythm, clinicians should be aware of the life-threatening complications that may occur.\n\nCase presentation\nA 61-year-old woman presented to the emergency department after an intentional multiple drug overdose. Upon examination, she was somnolent with stable respiration and hemodynamics. Electrocardiography showed a prolonged QTc interval of 503 ms. The patient was admitted to the ICU for cardiopulmonary monitoring. During admission, the patient remained stable and showed improved neurologic function over time. After 22 h, a second ECG showed normalization of the QTc interval to 458 ms. However, 36 to 40 h after admission, our patient developed recurrent episodes of Torsades de Pointes (TdP) with loss of cardiac output, leading to cardiopulmonary resuscitation. Spontaneous circulation was restored after intravenous administration of magnesium sulphate. Retrospective serum analysis revealed fluoxetine concentrations of 2700 mcg/l.\n\nConclusion\nMost intoxications with selective serotonin reuptake inhibitors (SSRI) have favorable outcomes and do not require medical interventions other than strict cardiopulmonary observation. However, higher doses have been associated with QTc interval prolongation, TdP, serotonin syndrome, and death. This case illustrates that life-threatening complications may occur late in the course of hospital admission. Even though overdoses with SSRI’s generally result in few fatalities, clinicians should be aware of the life-threatening clinical manifestations that may occur. Despite being an imperfect predictor of imminent TdP, continuous monitoring of cardiac rhythm is strongly recommended when either cardiac or non-cardiac symptoms are present.\n\nKeywords\nFluoxetineRisperidoneDepressionOverdoseQTc prolongationTorsades de Pointesissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nIn 1966, French cardiologist François Dessertenne described a distinct polymorphic ventricular tachycardia in patients with QTc prolongation that exhibits specific characteristics on the electrocardiogram [1]. Torsades de Pointes (“twisting of the points”) is characterized by rapid, irregular QRS complexes “twisting” around the isoelectric baseline. Depending on the cause, TdP may either spontaneously revert back into sinus rhythm or degenerate into other life-threatening dysrhythmias. When nonsustained, it frequently reoccurs if the underlying cause is not treated adequately. Moreover, TdP may evolve into sustained ventricular fibrillation leading to hemodynamic compromise and eventually death. In this report, we describe an unsuspected case of TdP in a patient recovering from a multiple drug overdose.\n\nCase presentation\nA 61-year-old woman with a past medical history of type II diabetes, breast cancer, and major depression presented to the emergency department after an intentional overdose with fluoxetine (139 tablets of 20 mg), risperidone (6 tablets of 1 mg), bromazepam (90 tablets of 3 mg), zolpidem (40 tablets of 10 mg), naproxen (20 tablets of 500 mg), and clemastine (5 tablets of 1 mg). Quantities were determined by counting the remaining pills in the blister packaging. Upon arrival, the patient was somnolent but able to open her eyes on request (E3M6V5). Vital signs showed a blood pressure of 146/57 mmHg, a regular heart rate of 55/min with strong peripheral pulsations, a respiratory rate of 16/min, oxygen saturation levels varying between 95 and 100% at room air, and a body temperature of 36.2 °C. Her husband suggested that the pills must have been ingested 3 to 8 h prior to hospital admission. Electrocardiography (ECG) showed a sinus rhythm of 61 beats per minute with a prolonged corrected QT interval (QTc) of 503 ms as shown in Fig. 1. During admission, all ECGs were performed using a GE MAC 5500 HD electrocardiograph. The tangent method was used in order to define the end of the T-wave in the lead with the longest QT interval. All measured QTc intervals were corrected for cardiac frequency using Bazett’s formula [2].Fig. 1 Initial electrocardiogram showing a sinus rhythm with a prolonged QTc interval of 503 ms. The tangent method was used in order to define the end of the T-wave\n\n\n\nInitial laboratory findings showed a microcytic anemia (Hb 5.4 mmol/l, MCV 77 fl) with low serum ferritin (6 μg/l), along with a mild leukocytosis of 11.2/nl. Serum electrolytes, as well as liver and kidney function, were normal (Na+ 135 mmol/l, K+ 4.3 mmol/l, creatinine 89 μmol/l, corrected calcium 2.37 mmol/l, PO43− 1.41 mmol/l, magnesium 0.83 mmol/l). Arterial blood gas analysis showed a base excess of − 4.9 mmol/l (pH 7.37, pCO2 4.6 kPa, pO2 12.1 kPa, HCO3− 20 mmol/l). A chest X-ray displayed no aspiration pneumonia nor other cardiopulmonary anomalies. The patient was admitted to the ICU for observation, where she received intravenous fluids along with 40 mg of pantoprazole for the prevention of peptic ulcer disease due to the substantial ingestion of naproxen. This was administered only once due to the risk of further QTc interval prolongation. Initially, our patient remained hemodynamically stable and showed improved neurological function. Twenty-two hours after hospital admission, a second ECG showed normalization of the QTc interval to 458 ms, suggesting peak serum levels of the ingested drugs had passed. After psychiatric evaluation had taken place, our patient had fallen to the floor in search of the restroom. On examination, both her muscle strength and coordination were slightly disturbed. Due to the overall severity of the intoxication and the persistence of neurological symptoms, it was decided to observe the patient for one more night at the ICU. Flumazenil was not administered since the patient was fully conscious and already in a monitored environment and due to the risk of adverse effects, especially with chronic benzodiazepine use [3].\n\nThat night, 36 h after admission, our patient developed recurrent short episodes of Torsades de Pointes (TdP) with intermittent loss of cardiac output, as shown in Fig. 2. Two grams of magnesium sulphate was administered intravenously, after which sinus rhythm was restored. Four hours later, she had complete loss of circulation, after which cardiopulmonary resuscitation was initiated according to protocol. A 150-J biphasic shock was delivered using an automated external defibrillator (Zoll R-Series ALS). ECG findings consistent with TdP were again observed. Spontaneous circulation was restored after intravenous administration of magnesium sulphate. Our patient was awake and immediately able to maintain a patent airway following the incident. Serum levels of fluoxetine and risperidone and their metabolites were measured in retrospect, as shown in Table 1 and Fig. 3a, b. Laboratory findings at the time of the incident showed a mild hypocalcaemia of 2.10 mmol/l with a hypermagnesaemia of 1.72 mmol/l/, most likely caused due to the prior administration of magnesium sulphate. No other electrolyte abnormalities were identified (Na+ 137 mmol/l, K+ 3.8 mmol/l, PO43− 1.24 mmol/l). Subsequent ECGs showed progressive prolongation of the QTc interval up to 565 ms, as shown in Fig. 4. The patient remained hemodynamically stable for the remainder of the night on continuous infusion of magnesium sulphate (1 g/h). The following day, echocardiography was performed in order to exclude structural cardiac defects, which showed normal heart dimensions as well as a normal left and right ventricular function.Fig. 2 Telemetry records showing Torsades de Pointes\n\nTable 1 Serum drug concentration levels of (nor)fluoxetoine and (9-OH)risperidone during hospital admission\n\nHours after hospital admission\tFluoxetine (ref 100–450 mcg/l)\tNorfluoxetine (ref 50–350 mcg/l)\tSum (ref 15–500 mcg/l)\tRisperidone (ref 4–30 mcg/l)\t9-OH-risperidone (ref 12–60 mcg/l)\tSum (ref 20–60 mcg/l)\t\nT = 0\t2700\t397\t3097\t33\t4\t37\t\nT + 1.33\t2300\t370\t2670\t36\t3\t39\t\nT + 16.3\t1550\t310\t1860\t13\t6\t19\t\nT + 36.9\t1650\t281\t1931\t7\t5\t12\t\nT + 70.0\t1120\t263\t1383\t2\t4\t6\t\nT + 88.5\t990\t300\t1290\tNA\tNA\tNA\t\nFig. 3 a Showing serum drug serum levels of fluoxetine(black triangles), norfluoxetine (black circles), and the combined serum concentrations of both fluoxetine and norfluoxetine (black squares). b Showing drug serum levels of risperidone (black triangles), 9-OH-risperidone (black circles), and the combined concentrations of both risperidone and 9-OH-risperidone (black squares). The yellow striped line indicates the onset of TdP\n\nFig. 4 Showing the course of QTc interval duration during hospital admission\n\n\n\nDiscussion\nQT interval prolongation can either be congenital or, more commonly, drug-induced [4]. Apart from genetic predispositions, several risk factors have shown to increase a patient’s likelihood of developing TdP. Examples include electrolyte abnormalities, hypothermia, bradycardia, (congenital) heart disease, and the female sex [5]. When QT prolongation is present, immediate withdrawal of agents that may contribute to QT interval prolongation as well as prompt correction of underlying electrolyte disturbances is indicated. TdP leading to hemodynamic instability is primarily treated by electrical cardioversion. However, in stable patients with recurrent self-terminating episodes of TdP, administration of intravenous magnesium sulphate is the therapy of choice [6, 7].\n\nCongenital long QT syndrome (LQTS) is a condition which affects cardiac repolarization due to specific genetic alterations, leading to an increased risk of developing arrhythmias leading to syncope and possibly cardiac arrest [8]. In contrast to congenital long QT syndrome, drug-induced QT prolongation involves blocking of the delayed rectifier potassium current (IKr) by disrupting hERG potassium channels, thereby extending the repolarization phase of the myocardial cells resulting in QT prolongation [4].\n\nDrug-induced QTc prolongation along with the occurrence of TdP is associated with a wide range of drugs including class III repolarization-delaying antiarrhythmics, antipsychotics, and antimicrobial agents [4]. Previous to admission, our patient had ingested substantial amounts of fluoxetine and risperidone as well as zolpidem and clemastine. Although reports exist that suggest an association between zolpidem, clemastine, and QT prolongation, those reports are limited in number. Both zolpidem and clemastine do not appear on the 2018 AZCERT list of accepted QT prolongators [9–11]. Therefore, in this report, we focused on the QT-prolonging properties of fluoxetine and risperidone.\n\nFluoxetine is a selective serotonin reuptake inhibitor used in the treatment of major depression. It reaches its Tmax 6–8 h after administration and is metabolized mainly by CYP2D6 into its pharmacologically active metabolite norfluoxetine [12]. Both fluoxetine and norfluoxetine have shown to be potent inhibitors of CYP2D6 [13]. Fluoxetine has a half-life of 4–6 days, while its metabolite norfluoxetine has a half-life varying from 4 to 16 days. Risperidone is an atypical antipsychotic with strong anti-dopaminergic (D2) and anti-serotonergic (5Ht2) activity [14]. Tmax is reached 1–2 h after administration and is also metabolized by CYP2D6 into the active 9-hydroxyrisperidone. When compared to fluoxetine, both risperidone and 9-OH-risperidone have relatively short half-lives of 3 and 24 h respectively. Theoretically, (nor)fluoxetine-mediated CYP2D6 inhibition can result in higher than expected risperidone serum levels, causing adverse effects.\n\nWe hypothesized that the sudden clinical deterioration might have been caused by the accumulation of either fluoxetine, risperidone, or their respective metabolites, resulting in an increased susceptibly for additional risk factors as stated above. In order to test this hypothesis, serum levels of fluoxetine, norfluoxetine, risperidone, and 9-OH-risperidone were determined retrospectively using previously drawn blood samples (Fig. 3a, b). Furthermore, QTc interval durations were obtained from all electrocardiographs made during hospital admission and plotted as displayed in Fig. 4. Plasma serum levels of fluoxetine reached high concentrations of up to 2700 mcg/l, which declined gradually over time. Neither risperidone nor 9-OH-risperidone reached toxic serum concentrations. Both fluoxetine and risperidone serum levels peaked during the first hours of hospital admission. However, at that point, our patient showed no signs of cardiac impairment besides a prolonged QTc interval of 503 ms. On subsequent days, increasing QTc intervals up until 565 ms were measured 54 h after admission. During this time, we found no evidence for an accumulation of either (nor)fluoxetine or (9-OH)risperidone, suggesting factors other than fluoxetine and risperidone drug concentrations caused the onset of TdP in our patient.\n\nDespite being a key element in the development of TdP, QTc prolongation alone is considered insufficient to cause TdP [15]. Additional risk factors such as electrolyte abnormalities, hypothermia, (extreme) bradycardia, heart disease, and the female sex are believed to be contributing factors in the development of TdP. Unfortunately, except for the female sex and a mild hypocalcaemia, no additional risk factors were identified in our patient. Although hypocalcemia has been associated with QTc prolongation, the number of cases is limited and characterized by significantly lower serum calcium concentrations, making it an unlikely cause of TdP in our patient [16, 17]. Proton pump inhibitors (PPIs) have also shown to result in QT prolongation secondary due to the development of hypomagnesaemia [18]. However, serum magnesium concentrations in our patient were repeatedly measured to be within normal range. As a result, we considered the prior administration of pantoprazole an improbable cause of recurrent TdP. Sixteen hours after developing TdP, electrocardiography showed further QTC prolongation from 506 to 518 ms. Two hours later, the QTc interval reached its peak of 565 ms. Therefore, the prolonged QTc interval could not have been secondary to the ventricular arrythmia that had occurred 18 h earlier. It is possible that just before the onset of TdP, the QTc interval was prolonged even more than 506 ms. Unfortunately, during that period, no additional ECGs were performed. While possible, it is unlikely that our patient is genetically predisposed to LQTS, since ECGs from previous admissions showed normal QTc intervals. Moreover, family history was negative for LQTS and sudden cardiac arrest. It therefore seems evident that our patient developed QTc interval prolongation due to a substantial overdose of fluoxetine. Unfortunately, we were unable to identify any contributing risk factor(s) besides a mild hypocalcaemia and female sex. Moreover, it still remains unclear why the initial decline in QTc interval duration and the improvement of clinical symptoms were followed by QTc prolongation and the development of cardiac arrhythmias. This further highlights why extensive heart rhythm control and intermittent electrocardiography as well as monitoring of serum electrolytes should be considered mandatory in caring for a patient suffering from an overdose resulting in QTc prolongation.\n\nConclusion\nWe described a case of intentional drug overdose with fluoxetine resulting in QT prolongation and the development of TdP. While most overdoses with selective serotonin reuptake inhibitors have favorable outcomes and do not require medical interventions other than cardiopulmonary observation, clinicians should be aware of the potentially life-threatening complications that may occur. High-dose intoxications have been associated with QT prolongation, TdP, and eventually, death. This case illustrates that both measurement of serum drug concentrations and monitoring of the QT interval are imperfect indicators of imminent cardiac dysrhythmias. Increasing evidence shows that additional risk factors such as electrolyte disturbances are required to trigger TdP. Even though serum drug monitoring is considered unessential in caring for patients suffering from multiple drug overdoses, it may provide insight in estimating toxicity levels when pharmacokinetic and pharmacodynamic drug interactions are suspected. Extensive heart rhythm control, intermittent electrocardiography, and monitoring serum electrolytes are strongly recommended as long as any cardiac or non-cardiac symptoms are still present.\n\nAbbreviations\nCYP2D6Cytochrome P450 family 2 subfamily D member 6\n\nECGElectrocardiogram\n\nHbHemoglobin\n\nICUIntensive care unit\n\nLQTSLong QT syndrome\n\nMCVMean corpuscular volume\n\nSSRISelective serotonin reuptake inhibitor\n\nTdPTorsades de Pointes\n\nAvailability of data and materials\nThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nAll authors contributed equally to the writing of the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nConsent form available upon request.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Dessertenne F La tachycardie ventriculaire à deux foyers opposés variables Arch Mal Coeur Vaiss 1966 59 263 4956181 \n2. Postema PG Wilde AAM The measurement of the QT interval Curr Cardiol Rev 2014 10 3 287 294 10.2174/1573403X10666140514103612 24827793 \n3. Weinbroum AA Flaishon R Sorkine P Szold O Rudick V A risk-benefit assessment of flumazenil in the management of benzodiazepine overdose Drug Saf 1997 17 3 181 196 10.2165/00002018-199717030-00004 9306053 \n4. Yap YG Camm AJ Drug induced QT prolongation and torsades de pointes Heart 2003 89 11 1363 1372 10.1136/heart.89.11.1363 14594906 \n5. Drew BJ Ackerman MJ Funk M Gibler WB Kligfield P Menon V Philippides GJ Roden DM Zareba W Prevention of torsade de pointes in hospital settings: a scientific statement from the American Heart Association and the American College of Cardiology Foundation Circulation 2010 121 8 1047 1060 10.1161/CIRCULATIONAHA.109.192704 20142454 \n6. Tzivoni D Banai S Schuger C Benhorin J Keren A Gottlieb S Stern S Treatment of torsade de pointes with magnesium sulfate Circulation 1988 77 2 392 397 10.1161/01.CIR.77.2.392 3338130 \n7. Gupta A Lawrence AT Krishnan K Kavinsky CJ Trohman RG Current concepts in the mechanisms and management of drug-induced QT prolongation and torsade de pointes Am Heart J 2007 153 6 891 899 10.1016/j.ahj.2007.01.040 17540188 \n8. Crotti L Celano G Dagradi F Schwartz PJ Congenital long QT syndrome Orphanet J Rare Dis 2008 3 1 18 10.1186/1750-1172-3-18 18606002 \n9. Jehle J Ficker E Wan X Deschenes I Kisselbach J Wiedmann F Staudacher I Schmidt C Schweizer PA Becker R Katus HA Mechanisms of zolpidem-induced long QT syndrome: acute inhibition of recombinant hERG K+ channels and action potential prolongation in human cardiomyocytes derived from induced pluripotent stem cells Br J Pharmacol 2013 168 5 1215 1229 10.1111/bph.12002 23061993 \n10. Ridley JM Milnes JT Hancox JC Witchel HJ Clemastine, a conventional antihistamine, is a high potency inhibitor of the HERG K+ channel J Mol Cell Cardiol 2006 40 1 107 118 10.1016/j.yjmcc.2005.09.017 16288909 \n11. Woosley, RL, Heise, CW and Romero, KA, QTdrugs list, AZCERT, Inc. 1822 Innovation Park Dr., Oro Valley. www.Crediblemeds.org, Accession Date 5 June 2018.\n12. Altamura AC Moro AR Percudani M Clinical pharmacokinetics of fluoxetine Clin Pharmacokinet 1994 26 3 201 214 10.2165/00003088-199426030-00004 8194283 \n13. Jeppesen U Gram LF Vistisen K Loft S Poulsen HE Brøsen K Dose-dependent inhibition of CYP1A2, CYP2C19 and CYP2D6 by citalopram, fluoxetine, fluvoxamine and paroxetine Eur J Clin Pharmacol 1996 51 1 73 78 10.1007/s002280050163 8880055 \n14. Janssen PA Niemegeers CJ Awouters F Schellekens KH Megens AA Meert TF Pharmacology of risperidone (R 64 766), a new antipsychotic with serotonin-S2 and dopamine-D2 antagonistic properties J Pharmacol Exp Ther 1988 244 2 685 693 2450200 \n15. Schwartz PJ Woosley RL Predicting the unpredictable: drug-induced QT prolongation and torsades de pointes J Am Coll Cardiol 2016 67 13 1639 1650 10.1016/j.jacc.2015.12.063 27150690 \n16. Daya SK Gowda RM Khan IA Ciprofloxacin- and hypocalcemia-induced torsade de pointes triggered by hemodialysis Am J Ther 2004 11 1 77 79 10.1097/00045391-200401000-00014 14704599 \n17. Akiyama T Batchelder J Worsman J Moses HW Jedlinski M Hypocalcemic torsades de pointes J Electrocardiol 1989 22 1 89 92 10.1016/0022-0736(89)90026-5 2921582 \n18. Hoorn EJ van der Hoek J Rob A Kuipers EJ Bolwerk C Zietse R A case series of proton pump inhibitor-induced hypomagnesemia Am J Kidney Dis 2010 56 1 112 116 10.1053/j.ajkd.2009.11.019 20189276\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2052-0492",
"issue": "6()",
"journal": "Journal of intensive care",
"keywords": "Depression; Fluoxetine; Overdose; QTc prolongation; Risperidone; Torsades de Pointes",
"medline_ta": "J Intensive Care",
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"pmid": "30214811",
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"references": "8880055;18606002;2450200;3338130;14594906;4956181;20142454;8194283;16288909;2921582;27150690;20189276;9306053;24827793;17540188;14704599;23061993",
"title": "Late presentation of Torsades de Pointes related to fluoxetine following a multiple drug overdose.",
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] |
{
"abstract": "OBJECTIVE\nThe adverse prognosis of CD20 expression in adults with de novo precursor B-lineage acute lymphoblastic leukemia (ALL) prompted incorporation of monoclonal antibody therapy with rituximab into the intensive chemotherapy regimen hyper-CVAD (fractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone). Other modifications (irrespective of CD20 expression) included early anthracycline intensification, alterations in number of risk-adapted intrathecal chemotherapy treatments for CNS prophylaxis, additional early and late intensifications, and extension of maintenance phase chemotherapy by 6 months.\n\n\nMETHODS\nTwo hundred eighty-two adolescents and adults with de novo Philadelphia chromosome (Ph)-negative precursor B-lineage ALL were treated with standard or modified hyper-CVAD regimens. The latter incorporated standard-dose rituximab if CD20 expression > or = 20%.\n\n\nRESULTS\nThe complete remission (CR) rate was 95% with 3-year rates of CR duration (CRD) and survival (OS) of 60% and 50%, respectively. In the younger (age < 60 years) CD20-positive subset, rates of CRD and OS were superior with the modified hyper-CVAD and rituximab regimens compared with standard hyper-CVAD (70% v 38%; P < .001% and 75% v 47%, P = .003). In contrast, rates of CRD and OS for CD20-negative counterparts treated with modified versus standard hyper-CVAD regimens were similar (72% v 68%, P = not significant [NS] and 64% v 65%, P = NS, respectively). Older patients with CD20-positive ALL did not benefit from rituximab-based chemoimmunotherapy (rates of CRD 45% v 50%, P = NS and OS 28% v 32%, P = NS, respectively), related in part to deaths in CR.\n\n\nCONCLUSIONS\nThe incorporation of rituximab into the hyper-CVAD regimen appears to improve outcome for younger patients with CD20-positive Ph-negative precursor B-lineage ALL.",
"affiliations": "University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA. debthomas@mdanderson.org",
"authors": "Thomas|Deborah A|DA|;O'Brien|Susan|S|;Faderl|Stefan|S|;Garcia-Manero|Guillermo|G|;Ferrajoli|Alessandra|A|;Wierda|William|W|;Ravandi|Farhad|F|;Verstovsek|Srdan|S|;Jorgensen|Jeffrey L|JL|;Bueso-Ramos|Carlos|C|;Andreeff|Michael|M|;Pierce|Sherry|S|;Garris|Rebecca|R|;Keating|Michael J|MJ|;Cortes|Jorge|J|;Kantarjian|Hagop M|HM|",
"chemical_list": "D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D007155:Immunologic Factors; D000069283:Rituximab; D014750:Vincristine; D003907:Dexamethasone; D004317:Doxorubicin; D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.2009.26.9456",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "28(24)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D003907:Dexamethasone; D004317:Doxorubicin; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D010677:Philadelphia Chromosome; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma; D011379:Prognosis; D012074:Remission Induction; D000069283:Rituximab; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "3880-9",
"pmc": null,
"pmid": "20660823",
"pubdate": "2010-08-20",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "15178574;16145068;10214862;18780832;18853418;5910392;16502413;15538405;2189958;17283164;14551133;9166833;19335277;15955901;11807147;18024662;20466853;16896151;11508930;9519775;12522009;10653870;3491184;18316581;17209054;15767648;9708202;18703706;19773266;20572037;18411418;19825447;11144922;15481055;19846809",
"title": "Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia.",
"title_normalized": "chemoimmunotherapy with a modified hyper cvad and rituximab regimen improves outcome in de novo philadelphia chromosome negative precursor b lineage acute lymphoblastic leukemia"
} | [
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"literaturereference": "THOMAS DA, O^BRIEN S, FADERL S, GARCIA-MANERO G, FERRAJOLI A, WIERDA W, ET AL. CHEMOIMMUNOTHERAPY WITH A MODIFIED HYPER-CVAD AND RITUXIMAB REGIMEN IMPROVES OUTCOME IN DE NOVO PHILADELPHIA CHROMOSOME-NEGATIVE PRECURSOR B-LINEAGE ACUTE LYMPHOBLASTIC LEUKEMIA. JOURNAL OF CLINICAL ONCOLOGY 20-AUG-2010;28(24):3880-3889.",
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] |
{
"abstract": "There are relatively few studies that have looked at the longer-term developmental effects of intra-uterine topiramate exposure. The purpose of this report is to describe preliminary findings of the developmental outcomes of a group of nine children of preschool age (3-6 years, 11 months), exposed in utero to topiramate (TX) monotherapy, as compared to a control group of 18 children. The groups were compared on developmental measures of visual, fine and gross motor function as well as measures of behavior and cognitive functions. Results showed that the TX group performed significantly worse than the control group for almost all measures, with the most clearly delineated differences in the area of cognitive functioning. While the study group is small, and only preliminary conclusions may be inferred, it appears that TX exposure may have subtle effects on the development of children in a range of areas including motor function, cognition, and behavior.",
"affiliations": "School of Occupational Therapy, Hebrew University Hadassah Medical School, Jerusalem, Israel.",
"authors": "Rihtman|Tanya|T|;Parush|Shula|S|;Ornoy|Asher|A|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose",
"country": "United States",
"delete": false,
"doi": "10.1016/j.reprotox.2012.05.038",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0890-6238",
"issue": "34(3)",
"journal": "Reproductive toxicology (Elmsford, N.Y.)",
"keywords": null,
"medline_ta": "Reprod Toxicol",
"mesh_terms": "D000927:Anticonvulsants; D002652:Child Behavior; D002657:Child Development; D002675:Child, Preschool; D003071:Cognition; D005260:Female; D005632:Fructose; D006801:Humans; D007361:Intelligence Tests; D008297:Male; D008431:Maternal-Fetal Exchange; D009048:Motor Skills; D011247:Pregnancy; D011297:Prenatal Exposure Delayed Effects; D011795:Surveys and Questionnaires; D000077236:Topiramate",
"nlm_unique_id": "8803591",
"other_id": null,
"pages": "308-11",
"pmc": null,
"pmid": "22659273",
"pubdate": "2012-11",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Preliminary findings of the developmental effects of in utero exposure to topiramate.",
"title_normalized": "preliminary findings of the developmental effects of in utero exposure to topiramate"
} | [
{
"companynumb": "IL-CIPLA LTD.-2014IL02211",
"fulfillexpeditecriteria": "1",
"occurcountry": "IL",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TOPIRAMATE"
},
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"medicinalproduct": "TOPIRAMATE."
}
],
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{
"reactionmeddrapt": "Congenital nystagmus",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TANYA RIHTMAN, SHULA PARUSH, ASHER ORNOY. PRELIMINARY FINDINGS OF THE DEVELOPMENTAL EFFECTS OF IN UTERO EXPOSURE TO TOPIRAMATE. REPRODUCTIVE TOXICOLOGY. 2012;34:308-311",
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"qualification": "3",
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},
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"receivedate": "20141127",
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},
"reporttype": "1",
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 1,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150529"
}
] |
{
"abstract": "Measurement of serum acetaminophen-protein adducts (APAP-CYS) has been suggested to support or refute a diagnosis of acetaminophen (APAP)-induced hepatotoxicity when ingestion histories are unreliable or unavailable and when circulating APAP concentrations are low or undetectable. Non-APAP overdose patients commonly have used APAP products in non-toxic quantities and, thus, will have measurable APAP-CYS concentrations, even when hepatic injury results from other causes, such as ischemic hepatitis. The relationship between alanine aminotransferase (ALT) activity and APAP-CYS concentration might assist in distinguishing between toxic and non-toxic APAP doses in patients suspected of drug overdose.\n\n\n\nWe measured serial levels of serum APAP-CYS and ALT activities in 500 overdose patients in whom APAP toxicity was suspected on inpatient admission, but who were then classified at time of discharge and before results of APAP-CYS concentrations were available into three groups: 1) definite APAP group; 2) definitely not APAP group; and 3) indeterminate group. Subjects in the definite and definitely not APAP groups were selected in whom a plasma ALT activity was measured within ± 4 h of a serum APAP-CYS concentration. Regressions with correlation coefficients between APAP-CYS and ALT were calculated for repeat measures in the 335 subjects (908 blood samples) in the definite APAP group and 79 subjects (231 samples) in the definitely not APAP group, with an emphasis on APAP-CYS concentrations and calculation of 95% prediction intervals when ALT was ≥ 1000 IU/L.\n\n\n\nA strong correlation was found between APAP-CYS and ALT in the definite APAP group over all ALT activities (r = 0.93, p < 0.001; N = 335), and when ALT was > 1000 IU/L (r = 0.82, p < 0.001, N = 144). In the 79 definitely not APAP subjects, no significant correlation was found when ALT exceeded 1000 IU/L (r = 0.04; p = 0.84, N = 32). All subjects in the definitely not APAP group displayed APAP-CYS concentrations < 3 μM. In definitely not APAP subjects, the great majority of APAP-CYS levels were below the 95% prediction interval for APAP-CYS concentrations in definite APAP group subjects when ALT was ≥ 1000 IU/L. However, some definitely not APAP group subjects who had ingested non-toxic doses of APAP displayed APAP-CYS concentrations as high as 2.8 μM in the face of ALT elevation from ischemic hepatitis.\n\n\n\nThe interpretation of serum APAP-CYS concentrations must always be made in light of detailed clinical information and the population being tested, especially because of some overlap in APAP-CYS levels in subjects with and without APAP toxicity.",
"affiliations": "Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA. steven.curry@bannerhealth.com.;Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA.;Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA.;Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA.;Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA.;Center for Human Toxicology, University of Utah, Salt Lake City, UT, USA.;Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA.;Center for Toxicology, Pharmacology, Education and Research, University of Arizona College of Medicine-Phoenix, Phoenix, AZ, USA.;Department of Medical Toxicology, Banner-University Medical Center Phoenix, Phoenix, AZ, USA.",
"authors": "Curry|Steven C|SC|;Padilla-Jones|Angela|A|;Ruha|Anne-Michelle|AM|;O'Connor|Ayrn D|AD|;Kang|A Min|AM|;Wilkins|Diana G|DG|;Jaeschke|Hartmut|H|;Wilhelms|Kelly|K|;Gerkin|Richard D|RD|;|||",
"chemical_list": "D001798:Blood Proteins; D000082:Acetaminophen; D000410:Alanine Transaminase",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-019-00705-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-9039",
"issue": "15(3)",
"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": "Acetaminophen; Acetaminophen-protein adducts; Alanine aminotransferase; Hepatotoxicity; Overdose",
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000082:Acetaminophen; D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000410:Alanine Transaminase; D001798:Blood Proteins; D062787:Drug Overdose; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D055815:Young Adult",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "143-155",
"pmc": null,
"pmid": "30980348",
"pubdate": "2019-07",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "21401949;24836926;27479586;27429052;22378043;29233977;18923390;27641661;24597531;23571099;23979652;21319200;19439490;11790213;25239633;25288219;21274877;25092309;20305573;25681644",
"title": "The Relationship Between Circulating Acetaminophen-Protein Adduct Concentrations and Alanine Aminotransferase Activities in Patients With and Without Acetaminophen Overdose and Toxicity.",
"title_normalized": "the relationship between circulating acetaminophen protein adduct concentrations and alanine aminotransferase activities in patients with and without acetaminophen overdose and toxicity"
} | [
{
"companynumb": "US-JNJFOC-20190730380",
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"patient": {
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
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"drugdosageform": "UNKNOWN",
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"medicinalproduct": "PARACETAMOL"
}
],
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"reaction": [
{
"reactionmeddrapt": "Drug-induced liver injury",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute hepatic failure",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Renal tubular necrosis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Hepatic encephalopathy",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product administration error",
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"reactionoutcome": "6"
}
],
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},
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"literaturereference": "CURRY S, PADILLA-JONES A, RUHA A, O^CONNOR A, KANG A, WILKINS D, JAESCHKE H, WILHELMS K, GERKIN R. THE RELATIONSHIP BETWEEN CIRCULATING ACETAMINOPHEN-PROTEIN ADDUCT CONCENTRATIONS AND ALANINE AMINOTRANSFERASE ACTIVITIES IN PATIENTS WITH AND WITHOUT ACETAMINOPHEN OVERDOSE AND TOXICITY. JOURNAL OF MEDICAL TOXICOLOGY. 2019 JUL 15?15 (3):143-155.",
"literaturereference_normalized": "the relationship between circulating acetaminophen protein adduct concentrations and alanine aminotransferase activities in patients with and without acetaminophen overdose and toxicity",
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},
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20191004"
},
{
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{
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},
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"medicinalproduct": "OXYCODONE"
},
{
"actiondrug": "5",
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"activesubstancename": "ACETAMINOPHEN"
},
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"medicinalproduct": "ACETAMINOPHEN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NALOXONE"
},
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"medicinalproduct": "NALOXONE"
},
{
"actiondrug": "5",
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"activesubstancename": "TRAMADOL"
},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TRAMADOL."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Rhabdomyolysis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Liver injury",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cerebrovascular accident",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Renal tubular necrosis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Ischaemic cerebral infarction",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
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"literaturereference": "CURRY SC, JONES AP, RUHA AM, O CONNOR AD, KANG AM, WILKINS DG ET AL. THE RELATIONSHIP BETWEEN CIRCULATING ACETAMINOPHEN?PROTEIN ADDUCT CONCENTRATIONS AND ALANINE AMINOTRANSFERASE ACTIVITIES IN PATIENTS WITH AND WITHOUT ACETAMINOPHEN OVERDOSE AND TOXICITY. J MED TOXICOL. 2019?MAR 15:143?155",
"literaturereference_normalized": "the relationship between circulating acetaminophen protein adduct concentrations and alanine aminotransferase activities in patients with and without acetaminophen overdose and toxicity",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210224",
"receivedate": "20210224",
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},
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"safetyreportversion": 1,
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210420"
},
{
"companynumb": "US-SUN PHARMACEUTICAL INDUSTRIES LTD-2021R1-281209",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": "3",
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"drugauthorizationnumb": "76200",
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"drugcharacterization": "1",
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"drugdosagetext": "UNK",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "ACETAMINOPHEN."
}
],
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"reaction": [
{
"reactionmeddrapt": "Renal failure",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Myocardial infarction",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiogenic shock",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Ischaemic hepatitis",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumonia bacterial",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "CURRY SC, JONES AP, RUHA AM, O CONNOR AD, KANG AM, WILKINS DG ET AL. THE RELATIONSHIP BETWEEN CIRCULATING ACETAMINOPHEN?PROTEIN ADDUCT CONCENTRATIONS AND ALANINE AMINOTRANSFERASE ACTIVITIES IN PATIENTS WITH AND WITHOUT ACETAMINOPHEN OVERDOSE AND TOXICITY. J MED TOXICOL. 2019?MAR 15:143?155",
"literaturereference_normalized": "the relationship between circulating acetaminophen protein adduct concentrations and alanine aminotransferase activities in patients with and without acetaminophen overdose and toxicity",
"qualification": "3",
"reportercountry": "US"
},
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},
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},
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"seriousnesscongenitalanomali": null,
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"seriousnesshospitalization": 1,
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"seriousnessother": 1,
"transmissiondate": "20210420"
},
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXYCODONE HYDROCHLORIDE"
},
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"medicinalproduct": "OXYCODONE HYDROCHLORIDE."
},
{
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"activesubstancename": "CYCLOBENZAPRINE"
},
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"medicinalproduct": "CYCLOBENZAPRINE."
}
],
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"patientsex": "2",
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"reaction": [
{
"reactionmeddrapt": "Rhabdomyolysis",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Respiratory depression",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Renal tubular necrosis",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiomyopathy",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Ischaemic hepatitis",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "CURRY SC, PADILLA-JONES A, RUHA A, O^CONNOR AD, KANG AM, WILKINS DG ET AL. THE RELATIONSHIP BETWEEN CIRCULATING ACETAMINOPHEN-PROTEIN ADDUCT CONCENTRATIONS AND ALANINE AMINOTRANSFERASE ACTIVITIES IN PATIENTS WITH AND WITHOUT ACETAMINOPHEN OVERDOSE AND TOXICITY. JOURNAL OF MEDICAL TOXICOLOGY - OFFICIAL JOURNAL OF THE AMERICAN COLLEGE OF MEDICAL TOXICOLOGY 15: 143-155, NO. 3, JUL 2019. URL: HTTP://DOI.ORG/10.1007/S13181-019-00705-2",
"literaturereference_normalized": "the relationship between circulating acetaminophen protein adduct concentrations and alanine aminotransferase activities in patients with and without acetaminophen overdose and toxicity",
"qualification": "3",
"reportercountry": "US"
},
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"receiptdate": "20200615",
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"receiver": {
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},
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"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200714"
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"abstract": "The purpose of this retrospective study was to analyze data in patients with stage IB-IIB uterine cervical cancer who were treated with concurrent chemoradiotherapy (CCRT) with high dose cisplatin and fluorouracil as postoperative adjuvant therapy. Between February 2003 and November 2011, 76 patients with FIGO stage IB-IIB cervical cancer were analyzed. Seventy patients were treated with postoperative CCRT and 6 patients were treated with radiation therapy alone. Data related to overall survival (OS), disease-free survival (DFS), toxicity, and failure pattern were analyzed. The median patient age was 45 years (range, 20-80 years). The median follow-up duration was 63 months (range, 10-125 months). Fifty-eight patients (76.3%) had a squamous cell histologic type, 55 patients (72.4%) had lymphovascular invasion, 31 patients (40.8%) had parametrial invasion, and 28 patients (36.8%) had lymph node metastases. Five-year OS and DFS were 96% and 92%, respectively. Five-year DFS in stage IB1 patients was significantly higher than in stage IB2-IIB patients (p = 0.022). Nineteen patients (25%) had grade 3 or 4 neutropenia, 13 patients (17.1%) had grade 3 anemia, and 2 patients (2.6%) had grade 3 thrombocytopenia, but none of these patients died from the disease. Three patients experienced chronic toxicity: one had bladder perforation, one had hydronephrosis, and one experienced ileus. CCRT as postoperative adjuvant therapy resulted in good survival and outcome without severe toxicity.",
"affiliations": "Department of Radiology, Nagoya University Graduate School of Medicine, Aichi, Japan.;Department of Radiology, Nagoya University Graduate School of Medicine, Aichi, Japan.;Department of Radiology, Nagoya University Graduate School of Medicine, Aichi, Japan.;Center for Advanced Medicine and Clinical Research, Nagoya University Graduate School of Medicine, Aichi, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Shouwa-ku, Nagoya, Aichi, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Shouwa-ku, Nagoya, Aichi, Japan.;Department of Radiology, Nagoya University Graduate School of Medicine, Aichi, Japan.;Department of Radiology, Nagoya University Graduate School of Medicine, Aichi, Japan.;Department of Radiology, Nagoya University Graduate School of Medicine, Aichi, Japan.;Department of Radiology, Nagoya University Graduate School of Medicine, Aichi, Japan.;Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Shouwa-ku, Nagoya, Aichi, Japan.;Department of Radiology, Nagoya University Graduate School of Medicine, Aichi, Japan.",
"authors": "Miyauchi|Rise|R|;Itoh|Yoshiyuki|Y|;Kawamura|Mariko|M|;Hirakawa|Akihiro|A|;Shibata|Kiyosumi|K|;Kajiyama|Hiroaki|H|;Nakahara|Rie|R|;Kubota|Seiji|S|;Ito|Junji|J|;Okada|Tohru|T|;Kikkawa|Fumitaka|F|;Naganawa|Shinji|S|",
"chemical_list": "D002945:Cisplatin; D005472:Fluorouracil",
"country": "Japan",
"delete": false,
"doi": "10.18999/nagjms.79.2.211",
"fulltext": "\n==== Front\nNagoya J Med SciNagoya J Med SciNagoya Journal of Medical Science0027-76222186-3326Nagoya University 2862625610.18999/nagjms.79.2.211Original PaperPostoperative chemoradiation therapy using high dose cisplatin and fluorouracil for high- and intermediate-risk uterine cervical cancer Miyauchi Rise 1Itoh Yoshiyuki 1Kawamura Mariko 1Hirakawa Akihiro 2Shibata Kiyosumi 3Kajiyama Hiroaki 3Nakahara Rie 1Kubota Seiji 1Ito Junji 1Okada Tohru 1Kikkawa Fumitaka 3Naganawa Shinji 1\n1 Department of Radiology, Nagoya University Graduate School of Medicine, Aichi, Japan\n2 Center for Advanced Medicine and Clinical Research, Nagoya University Graduate School of Medicine, Aichi, Japan\n3 Department of Obstetrics and Gynecology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Shouwa-ku, Nagoya, Aichi, JapanCorresponding author: Mariko Kawamura, MD\n\nDepartment of Radiology, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan\n\nTel: +81-52-744-2328, fax: +81-52-744-2335, E-mail: mkawamura@med.nagoya-u.ac.jp\n\n5 2017 79 2 211 220 1 2 2017 4 4 2017 This is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (http://creativecommons.org/licenses/by-nc-nd/4.0/).ABSTRACT\nThe purpose of this retrospective study was to analyze data in patients with stage IB–IIB uterine cervical cancer who were treated with concurrent chemoradiotherapy (CCRT) with high dose cisplatin and fluorouracil as postoperative adjuvant therapy. Between February 2003 and November 2011, 76 patients with FIGO stage IB–IIB cervical cancer were analyzed. Seventy patients were treated with postoperative CCRT and 6 patients were treated with radiation therapy alone. Data related to overall survival (OS), disease-free survival (DFS), toxicity, and failure pattern were analyzed. The median patient age was 45 years (range, 20–80 years). The median follow-up duration was 63 months (range, 10–125 months). Fifty-eight patients (76.3%) had a squamous cell histologic type, 55 patients (72.4%) had lymphovascular invasion, 31 patients (40.8%) had parametrial invasion, and 28 patients (36.8%) had lymph node metastases. Five-year OS and DFS were 96% and 92%, respectively. Five-year DFS in stage IB1 patients was significantly higher than in stage IB2–IIB patients (p = 0.022). Nineteen patients (25%) had grade 3 or 4 neutropenia, 13 patients (17.1%) had grade 3 anemia, and 2 patients (2.6%) had grade 3 thrombocytopenia, but none of these patients died from the disease. Three patients experienced chronic toxicity: one had bladder perforation, one had hydronephrosis, and one experienced ileus. CCRT as postoperative adjuvant therapy resulted in good survival and outcome without severe toxicity.\n\nKey Words\nUterine cervical cancerHysterectomyConcurrent chemoradiotherapyCisplatin5-FU.\n==== Body\nINTRODUCTION\nCervical cancer is the most common gynecologic malignancy in the world.1) In Japan, an estimated 10,908 new cases of invasive cervical cancer were diagnosed in 2012, and there were 2,902 cancer-related mortalities in 2014.2)\n\nIt has been well documented that patients with early-stage cervical cancer have survival rates of approximately 90%, whether treated with radical hysterectomy or radiation therapy alone. However, in 15% to 20% of patients with early-stage disease, the disease has either spread to the lymph nodes, there is involvement of the parametrium, or there are positive surgical margins at the time of radical hysterectomy. When one or more of these factors is found, the 5-year survival rate drops to 50% to 70%.3)\n\nThe majority of patients with early-stage cervical cancer who undergo surgical treatment with radical hysterectomy will receive postoperative adjuvant therapy based on the analysis of surgical-pathological risk factors. Recurrence risk factors for cervical cancer after surgery include pelvic lymph node metastasis, parametrial invasion, tumor size, deep stromal invasion, lymphovascular space invasion, histological types, and degree of differentiation.4-6) In general, patients with positive pelvic nodes, parametrial invasion, or a positive surgical margin are classified as high risk. Patients with large tumors, deep stromal invasion, or lymphovascular space involvement to ≥2 are classified as intermediate risk.6-8)\n\nCurrently, concurrent chemoradiotherapy (CCRT) is recommended for high-risk patients and radiation therapy alone for intermediate-risk patients. The Gynecologic Oncology Group Study 92 (GOG 92) showed that pelvic radiotherapy (RT) after surgery significantly reduces the risk of recurrence and prolongs disease-free survival (DFS) in patients with Stage IB cervical cancer with ≥2 of the following features: deep stromal invasion, lymphovascular space involvement, and tumor diameter ≥4 cm.9,10) A Southwest Oncology Group (SWOG) phase III study (8797) showed that the addition of cisplatin/fluorouracil-based chemotherapy (CT) to postoperative RT in high-risk patients improved the survival rate.11) CCRT is now approved as standard therapy for cervical cancer. Some studies have shown that, in high-risk patients with early cervical cancer, prognosis after surgery is improved by the addition of CT to pelvic RT over radiation treatment alone.12, 13) At our institution, CCRT after surgery is provided to patients of intermediate or high risk in accordance with the Japan Society of Gynecologic Oncology guidelines 2011 for the treatment of uterine cervical cancer.\n\nThe purpose of this retrospective study was to investigate the effect of treatment among patients with early cervical cancer who were treated with CCRT after radical hysterectomy in terms of overall survival (OS), DFS, and treatment complications. We also examined various prognostic risk factors, including tumor size, deep stromal invasion, lymphovascular space involvement, positive pelvic nodes, parametrial invasion, and positive surgical margins.\n\nMETHODS AND MATERIALS\nThis study was approved by the Institutional Review Board of the Nagoya University Hospital, and all patients provided written informed consent.\n\nPatients\nFrom February 2003 to November 2011, 80 consecutive patients with FIGO stage IB1–IIB cervical cancer who received chemoradiotherapy or radiation alone after radical hysterectomy and pelvic lymphadenectomy at the Nagoya University Hospital were selected from patient medical records. Four patients were excluded from this analysis because of histopathological small cell carcinoma. No patients underwent CT and/or RT before operation.\n\nRT plus concurrent CT after surgery was performed in patients with at least one of the following risk factors: pelvic lymph node metastasis, parametrial invasion, large tumor size, deep stromal invasion, lymphovascular space invasion, or positive surgical margins. The decision to perform post-operative treatment was determined by the cancer board at our hospital.\n\nRadiotherapy\nAdjuvant RT was started 4–6 weeks postoperatively. Patients underwent external beam RT to the whole pelvis. Pelvic RT was performed using 10 MV x-rays delivered from a linear accelerator with a four-field box technique. The superior border of the radiation field was the top of the fifth lumbar vertebra, and the inferior border was the inferior margin of the pelvic bone. External irradiation was delivered to the whole pelvis at 1.8 Gy per fraction once daily, 5 fractions a week over 5–6 weeks.\n\nAccording to the policy at our institution, para-aortic lymph node irradiation was performed in patients under 35 years old who had one positive lymph node region in the pelvis, and patients over 35 years old who had >2 positive lymph node regions in the pelvis. To reduce side effects, para-aortic lymph node irradiation was performed after pelvic irradiation was completed. External irradiation was delivered to the para-aortic lymph node at 2 Gy per fraction once daily, 5 fractions a week, and the total radiation dose was 46 Gy in 23 fractions.\n\nChemotherapy\nCT was generally administered concurrently with RT and repeated for 3 cycles. Each cycle of CT consisted of cisplatin at a dose of 70 mg/m2 on Day 1 and 5-fluorouracil (5-FU) at a dose of 700 mg/m2 per day given as a continuous infusion over 96 h on Days 1–4. The second cycle of CT began on day 22. The third cycle of CT commenced after completion of RT on Day 43.\n\nFollow-up and evaluation\nThe patients were followed up in an outpatient clinic every month in the first year, every 2 months in the second year, every 3 months in the third year, every 4 months in the fourth year, every 6 months in the fifth year, and annually thereafter for 10 years after treatment. After the completion of treatment, patients underwent clinical surveillance such as a clinical history, physical examination, laboratory examinations, Papanicolaou smear, and radiographic studies.\n\nStatistical analysis\nStatistical analysis was performed using SAS software (SAS Institute Inc., Cary, NC, USA). Survival curves were computed using the Kaplan-Meier method and comparison of survival rate was performed by log-rank test. Multivariate analysis was performed by Cox regression analysis to assess prognostic factors in predicting DFS. Univariate and multivariate analysis were performed for DFS. P values of <0.05 were considered statistically significant.\n\nComplications\nToxicity was defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 4.0.\n\nRESULTS\nSeventy-six patients were postoperatively treated with CCRT or RT alone. Of these, 47 patients belonged to the high-risk group (a positive lymph node or parametrial invasion), and 29 patients belonged to the intermediate-risk group (a large tumor, deep stromal invasion, or lymphovascular space involvement). The characteristics of the patients pre- and post-treatment are shown in Table 1 and Table 2. The median patient age was 45 years (range, 20–80 years). Fifty-eight patients (76.3%) had a squamous cell histologic type, 55 (72.4%) had lymphovascular invasion, 31 (40.8%) had parametrial invasion, and 28 (36.8%) had lymph node metastases. Fourteen patients (18.4%) had a maximum tumor diameter > 4 cm.\n\nTable 1 Patient characteristics pre-treatment\n\n\tn\t(%)\t\nNumber of patients\t76\t\t\nMean age (range)\t45 years (20–80)\t\t\nPerformance status\t\t\t\n0\t52\t68.4\t\n1\t24\t31.6\t\nFIGO Stage\t\t\t\nT stage\t\t\t\nIB1\t56\t73.7\t\nIB2\t9\t11.8\t\nIIA\t8\t10.5\t\nIIB\t3\t3.9\t\nTumor size (cm)\t\t\t\n≤4\t62\t81.6\t\n>4\t14\t18.4\t\nHistology\t\t\t\nSquamous cell carcinoma\t58\t76.3\t\nAdenosquamous carcinoma\t8\t10.5\t\nAdenocarcinoma\t5\t6.6\t\nMucinous adenocarcinoma\t5\t6.6\t\nPretreatment Hemoglobin (g/dL)\t\t\t\n<11\t37\t48.7\t\n>11\t39\t51.3\t\nTable 2 Surgical, pathology, and postoperative treatment characteristics\n\n\tn\t(%)\t\nType of surgery\t\t\t\nRadical hysterectomy\t75\t98.7\t\nModified radical hysterectomy\t1\t1.3\t\nPositive lymph nodes\t\t\t\n0\t48\t63.2\t\n1\t14\t18.4\t\n2\t5\t6.5\t\n≥ 3\t9\t11.8\t\nParametrial invasion\t\t\t\nNo\t45\t59.2\t\nYes\t31\t40.8\t\nLymphovascular invasion\t\t\t\nNo\t21\t27.6\t\nYes\t55\t72.4\t\nDeep stromal invasion\t\t\t\nNo\t70\t92.1\t\nYes\t6\t7.9\t\nMargin status\t\t\t\nNegative\t73\t96.1\t\nPositive\t3\t3.9\t\nChemotherapya)\t\t\t\nYes\t70\t92.1\t\nNo\t6\t7.9\t\nCycles of chemotherapy\t\t\t\n0\t6\t7.9\t\n1\t2\t2.6\t\n2\t12\t15.8\t\n3\t56\t73.7\t\nExtent of radiotherapy\t\t\t\nWhole pelvic and para-aortic\t17\t22.3\t\nWhole pelvic only\t57\t75.0\t\nWhole pelvic and local boost\t1\t1.3\t\nWhole pelvic and brachytherapy\t1\t1.3\t\na) Cisplatin + 5-fluorouracil regimen\n\nIn postoperative treatment, 56 patients received 3 cycles of cisplatin (70 mg/m2 on Day 1) and 5-FU (700 mg/m2 on Days 1–4). Thirteen of these patients were not able to complete all 3 cycles (Table 2). Six patients received radiotherapy alone because of underlying diseases, such as renal impairment. The median dose of external irradiation to the whole pelvis was 45 Gy (range 41.4–50.4 Gy), and the median dose of irradiation to the para-aortic lymph node was 46 Gy (range 40–46 Gy). Two patients received intracavitary brachytherapy of 15 Gy in 3 fractions below the vaginal mucosa after external beam radiotherapy. One patient had a positive surgical margin and the other patient was treated with radiation therapy alone after surgery because of renal impairment.\n\nRecurrence and Survival Analysis\nThe median follow-up was 63 months (range 10–125 months). Recurrence occurred in 9 patients (11.8%). Table 3 shows recurrence by histologic type in each group. In the high-risk group, 3 patients (6.4%) developed pelvic recurrence and 4 patients (8.5%) developed distant metastases. Of the patients who developed pelvic recurrence, 1 case was in the pelvic lymph node region and 2 cases were stump recurrence. Among the patients who developed distant metastasis, 1 case was metastasis to the lung, 2 cases were para-aortic lymph node metastasis, and 1 case was mediastinal lymph node metastasis. In the intermediate-risk group, distant metastases were observed in 2 patients (8.7%), both to the lungs. Of the 17 patients who received radiation to the para-aortic region according to our policy, there were no cases of recurrence in the para-aortic region. However, of the remaining 30 patients in the high-risk group who did not receive radiation to the para-aortic region, 2 patients (6.7%) showed recurrence in this region.\n\nTable 3 Patterns of failure by histologic type\n\nRecurrence site\tPelvis (%)\tDistant (%)\tTotal (%)\t\nHigh-risk group (n =47)\t3 (6.4)\t4 (8.5)\t7 (14.9)\t\nSCC (n = 35)\t2 (5.7)\t3 (8.6)\t5 (14.3)\t\nNon-SCC (n = 12)\t1 (8.3)\t1 (8.3)\t2 (16.7)\t\nIntermediate-risk group (n = 29)\t0 (0)\t2 (6.9)\t2 (6.9)\t\nSCC (n = 23)\t0 (0)\t2 (8.7)\t2 (8.7)\t\nNon-SCC (n = 6)\t0 (0)\t0 (0)\t0 (0)\t\nSCC: squamous cell carcinoma\n\nThe 5-year OS and DFS of the patients were 96% and 92%, respectively. Five-year OS and DFS were 97% and 97% in the intermediate-risk group, respectively (n = 29), and 96% and 89% in the high-risk group, respectively (n = 47) (p = 0.71 for OS, p = 0.054 for DFS). Five-year DFS in patients with stage IB1 tumors was 95% in the intermediate-risk group (n = 22) and 100% in the high-risk group (n = 34) (p = 0.14) Five-year DFS in patients with stage IB2–IIB tumors was 100% in the intermediate-risk group (n = 7) and 62% in the high-risk group (n = 13) (p = 0.08). Five-year DFS in patients with stage IB1 tumors was significantly higher than in patients with stage IB2–IIB tumors (p = 0.022) (Table 4).\n\nTable 4 Five-year overall and disease-free survival according to stage and risk group\n\n\tIB1 vs. IB2–IIB\tIM vs. HR\n(all stages)\tIM vs. HR in IB1\tIM vs. HR in IB2–IIB\t\n5-OS (%)\t98 vs. 90\t97 vs. 96\t–\t–\t\np-value\t0.33\t0.71\t–\t–\t\n5-DFS (%)\t98 vs. 75\t97 vs. 89\t95 vs. 100\t100 vs. 62\t\np-value\t0.022a)\t0.54\t0.14\t0.08\t\nIM: Intermediate-risk group, HR: High-risk group, 5-OS: 5-year overall survival, 5-DFS: 5-year disease-free survival\n\na) A p-value of 0.022 is statistically significant.\n\nClinical and pathologic risk factors for predicting DFS were evaluated by univariate and multivariate analysis. In the univariate analysis, T-stage (p = 0.017), tumor size (p = 0.032), and margin status (p = 0.007) were significant risk factors for DFS (Table 5). However, in the multivariate analysis, T-stage (p = 0.019) was the only significant risk factor for DFS (Table 5).\n\nTable 5 Univariate and multivariate analysis of factors associated with disease-free survival\n\nVariable\t\tUnivariate\nP-valuea)\tMultivariate\nP-valueb)\t\n\t\tDFS\tDFS\t\nAge\t≥45 vs. <45\t0.78\t–\t\nStage\tIB2–IIB vs. IB1\t0.017\t0.019\t\nTumor size\t>4 cm vs. ≤4 cm\t0.032\t0.45\t\nHb\t≥11 g/dL vs.<11 g/dL\t0.15\t–\t\nCycles of chemotherapy\t>3 vs. ≤3\t0.59\t–\t\nPeriod to RT start\t≥30 days vs. <30 days\t0.94\t–\t\nIrradiation to PAN\t(yes vs. no)\t0.43\t–\t\nParametrial invasion\t(yes vs. no)\t0.97\t–\t\nLymphovascular invasion\t(yes vs. no)\t0.30\t–\t\nDeep stromal invasion\t(yes vs. no)\t0.75\t\t\nMargin status\t(yes vs. no)\t0.007\t0.27\t\nHistology\tnon-SCC vs. SCC\t0.74\t–\t\nLymph nodes in pelvis\t(yes vs. no)\t0.13\t–\t\nDFS: disease-free survival, Hb: Hemoglobin, RT: radiotherapy, PAN: para-aortic lymph node, SCC: squamous cell carcinoma.\n\na) As determined by log-rank test.\n\nb) As determined by backward selection for Cox proportional hazards model.\n\nComplications\nEvaluation of adverse events was performed using the CTCAE ver. 4.0. Treatment related-death was not observed in all patients. Acute and late toxicities are summarized in Table 6.\n\nTable 6 Acute and chronic toxicitya) of postoperative concurrent chemoradiotherapy\n\nAcute toxicity\tGrade 3 (%)\tGrade 4 (%)\t\nDiarrhea\t2 (2.6)\t0\t\nHematologic\t\t\t\nNeutropenia\t17 (22.4)\t2 (2.6)\t\nAnemia\t13 (17.1)\t0\t\nThrombocytopenia\t3 (3.9)\t0\t\n\t\t\t\nChronic toxicity\t\t\t\nBladder perforation\t1 (1.3)\t0\t\nHydronephrosis\t1 (1.3)\t0\t\nIleus\t1 (1.3)\t0\t\na) Defined as grade ≥3, CTCAE ver. 4.0.\n\nAcute toxicities of grades 3 or 4, neutropenia, anemia, thrombocytopenia, and diarrhea were observed, with hematological toxicities being the most frequently observed. Seventeen patients (22.4%) showed grade 3 neutropenia, and 2 patients (2.6%) showed grade 4 neutropenia. Thirteen patients (17.1%) showed grade 3 anemia, 3 patients (3.9%) developed grade 3 thrombocytopenia, and 2 patients (2.6%) developed grade 3 diarrhea. Eighteen patients had G3–4 adverse events of the bowel system (5 patients (28.8%) receiving chemoradiation plus para-aortic radiation vs. 13 patients (72.2%) receiving pelvic chemoradiation alone, p = 0.053). Eighteen patients had G3–4 hematological complications (7 patients (38.8%) who received chemoradiation plus para-aortic radiation vs. 11 patients (61.1%) who received pelvic chemoradiation alone, p = 0.054).\n\nThere were no grade 4 late toxicities in any of the patients. Grade 3 bladder perforation occurred in 1 patient (1.3%) and grade 3 hydronephrosis occurred in 1 patient (1.3%). Grade 3 ileus occurred in 1 patient (1.3%).\n\nDISCUSSION\nIn this study, the 5-year OS at all stages was very high; therefore, there were no significant differences by stage. However, the difference in 5-year DFS between stage IB1 and stage IB2–IIB was statistically significant (p = 0.022). In the univariate analysis, T-stage (p = 0.017), tumor size (p = 0.032), and margin status (p = 0.007) were significant risk factors for DFS (Table 5). However, in the multivariate analysis, T-stage (p = 0.019) was the only significant risk factor for DFS (Table 5).\n\nWe can point to several factors for the high survival rates seen in this study. First, the number of patients with lymph node metastasis was lower than previously reported, with the rate of node negative status being 63.2%. Additionally, the rate of ≥2 positive nodes was 14.4%, compared to a rate of 44% in SWOG (8797).11) Second, triweekly CT consisting of cisplatin and 5-FU was more effective than weekly cisplatin-only CT,14, 15) although we applied CCRT as modified by the procedure of Peters et al.11) (cisplatin was administered every 3 weeks at a dose of 70 mg/m2 by 2-hour intravenous infusion during RT). CT consisted of bolus infusion of cisplatin (70 mg/m2) and a 96-hour infusion of 5-FU at 1000 mg/(m2∙day) every 3 weeks for 4 cycles. It has been reported that chemoradiotherapy after cervical cancer surgery reduces the risk of recurrence and extends DFS for patients with high risk. Additionally, it has been reported that the outcome of chemoradiotherapy after surgery was better than with radiation alone.16-19) Third, para-aortic lymph node irradiation was performed in patients with positive lymph nodes in the pelvis. In our study, there was no recurrence in the para-aortic lymph nodes in patients who received preventive irradiation of the para-aortic lymph node area. Analysis of the sites of recurrence showed that patients who received CCRT tended to show distant metastasis and para-aortic lymph node metastasis rather than intrapelvic recurrence. Another strategy may be required to prevent distant metastasis and recurrence outside of the irradiated areas. Effective systemic CT and preventive irradiation of the para-aortic lymph node area might be considered for reducing distant metastasis.\n\nAlthough it has been reported that the incidence of complications over 10 years is elevated in patients receiving para-aortic lymph node irradiation,20) there has not been an increase in adverse events in our study population. With postoperative chemoradiation, an increase in adverse events is a concern.21, 22) Since adverse events in our study were within the acceptable range, it can be determined that chemoradiation is relatively safe, although it may be better to have a reduced dose of 5-FU (700 mg/m2).\n\nPrevious reports have shown that severe gastrointestinal toxicity was more common than we observed, despite use of the same regimen. The treatment regimen was carried out to 4 courses in that study,23) whereas patients received only 3 courses of CT in our study. This may be one of the reasons that gastrointestinal toxicity was more severe. A reduction in adverse events is expected with the use of intensity-modulated radiotherapy (IMRT) as the irradiation method.24, 25) Adverse events can also be expected in a dose-dependent manner when using IMRT. IMRT was the choice of post-operative irradiation in this study.\n\nOur study has several limitations. First, the number of cases analyzed in this study was small. Second, this is a retrospective study thus lack a control group. Third, although the median follow-up was 63 months, a much longer follow-up is needed for the evaluation of late adverse complications.\n\nIn conclusion, CCRT using high dose cisplatin and 5-FU as the postoperative adjuvant therapy for uterine cervical cancer resulted in good survival outcome without severe toxicity.\n\nCONFLICTS OF INTEREST\nThe authors declare that they have no competing interests.\n==== Refs\nREFERENCES\n1) Cancer mortality in Japan (1958–2014) Center for cancer control and information services, National Cancer Center, Japan. http://ganjoho.jp/reg_stat/statistics/dl/index.html#mortality. Accessed 27 Aug 2016.\n2) Ebina Y, Yaegashi N, Katabuchi H, Nagase S, Udagawa Y, Hachisuga T, et al. Japan Society of Gynecologic Oncology guidelines 2011 for the treatment of uterine cervical cancer. Int J Clin Oncol, 2015; 20: 240–248.\n3) Delgado G, Bundy B, Zaino R, Sevin BU, Creasman WT, Major F. Prospective surgical-pathological study of disease-free interval in patients with stage IB squamous cell carcinoma of the cervix: a Gynecologic Oncology Group study. Gynecol Oncol, 1990; 38: 352–357.\n4) Chernofsky MR, Felix JC, Muderspach LI, Morrow CP, Ye W, Groshen SG, et al. Influence of quantity of lymph vascular space invasion on time to recurrence in women with early-stage squamous cancer of the cervix. Gynecol Oncol, 2006; 100: 288–293.\n5) Marchiolé P, Buénerd A, Benchaib M, Nezhat K, Dargent D, Mathevet P. Clinical significance of lymphovascular space involvement and lymph node micrometastases in early-stage cervical cancer: a retrospective case-control surgico-pathological study. Gynecol Oncol, 2005; 97: 727–732.\n6) Atahan IL, Onal C, Ozyar E, Yiliz F, Selek U, Kose F. Long-term outcome and prognostic factors in patients with cervical carcinoma: a retrospective study. Int J Gynecol Cancer, 2007; 17: 833–842.\n7) Samlal RA, van der Velden J, Schilthuis MS, González González D, Ten Kate FJ, Hart AA, et al. Identification of high-risk groups among node-positive patients with stage IB and IIA cervical carcinoma. Gynecol Oncol, 1997; 64: 463–467.\n8) Fuller AF Jr, Elliott N, Kosloff C, Hoskins WJ, Lewis JL Jr. Determinants of increased risk for recurrence in patients undergoing radical hysterectomy for stage IB and IIA carcinoma of the cervix. Gynecol Oncol, 1989; 33: 34–39.\n9) Sedlis A, Bundy BN, Rotman MZ, Lentz SS, Muderspach LI, Zaino RJ. A randomized trial of pelvic radiation therapy versus no further therapy in selected patients with stage IB carcinoma of the cervix after radical hysterectomy and pelvic lymphadenectomy: A Gynecologic Oncology Group Study. Gynecol Oncol, 1999; 73: 177–183.\n10) Rotman M, Sedlis A, Piedmonte MR, Bundy B, Lentz SS, Muderspach LI, et al. A phase III randomized trial of postoperative pelvic irradiation in Stage IB cervical carcinoma with poor prognostic features: follow-up of a gynecologic oncology group study. Int J Radiat Oncol Biol Phys, 2006; 65: 169–176.\n11) Peters WAIII, Liu PY, Barrett RJ II, Stock RJ, Monk BJ, Berek JS, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol, 2000; 18: 1606–1613.\n12) Liu MT, Hsu JC, Liu WS, Wang AY, Huang WT, Chang TH, et al. Prognostic factors affecting the outcome of early cervical cancer treated with radical hysterectomy and post-operative adjuvant therapy. Eur J Cancer Care, 2008; 17: 174–181.\n13) Monk BJ, Wang J, Im S, Stock RJ, Peters WA III, et al. Gynecologic Oncology Group; Southwest Oncology Group; Radiation Therapy Oncology Group. Rethinking the use of radiation and chemotherapy after radical hysterectomy: a clinical-pathologic analysis of a Gynecologic Oncology Group/Southwest Oncology Group/Radiation Therapy Oncology Group trial. Gynecologic Oncology Group; Southwest Oncology Group; Radiation Therapy Oncology Group. Gynecol Oncol, 2005; 96: 721–728.\n14) Torres MA, Jhingran A, Thames HD Jr, Levenback CF, Bodurka DC, Ramondetta LM, et al. Comparison of treatment tolerance and outcomes in patients with cervical cancer treated with concurrent chemoradiotherapy in a prospective randomized trial or with standard treatment. Int J Radiat Oncol Biol Phys, 2008; 70: 118–125.\n15) Ryu SY, Lee WM, Kim K, Park SI, Kim BJ, Kim MH, et al. Randomized clinical trial of weekly vs. triweekly cisplatin-based chemotherapy concurrent with radiotherapy in the treatment of locally advanced cervical cancer. Int J Radiat Oncol Biol Phys, 2011; 81: e577–e581.\n16) Okazawa M, Mabuchi S, Isohashi F, Suzuki O, Yoshioka Y, Sasano T, et al. Impact of the addition of concurrent chemotherapy to pelvic radiotherapy in surgically treated stage IB1-IIB cervical cancer patients with intermediate-risk or high-risk factors: a 13-year experience. Int J Gynecol Cancer, 2013; 23: 567–575.\n17) Lee TY, Jeung YJ, Lee CJ, Kim HY, Kim SH, Kim WG. Promising treatment results of adjuvant chemotherapy following radical hysterectomy for intermediate risk stage 1B cervical cancer. Obstet Gynecol Sci, 2013; 56: 15–21.\n18) Song S, Song C, Kim HJ, Wu HG, Kim JH, Park NH, et al. 20 year experience of postoperative radiotherapy in IB-IIA cervical cancer patients with intermediate risk factors: impact of treatment period and concurrent chemotherapy. Gynecol Oncol, 2012; 124: 63–67.\n19) Takeshita S, Kita T, Motoike Y, Umezawa K, Sugisaki S, Matsumoto S, et al. Postoperative concurrent chemoradiotherapy for the high-risk uterine cervical cancer. J Obstet Gynaecol Res, 2010; 36: 1009–1014.\n20) Rotman M, Pajak TF, Choi K, Clery M, Marcial V, Grigsby PW, et al. Prophylactic extended-field irradiation of para-aortic lymph nodes in stages IIB and bulky IB and IIA cervical carcinomas. Ten-year treatment results of RTOG 79-20. JAMA, 1995; 274: 387–393.\n21) Kim HJ, Ha SW, Wu HG. Treatment outcomes and prognostic factors in uterine cervical cancer patients treated with postoperative extended field radiation therapy. J Gynecol Oncol, 2009; 20: 227–231.\n22) Yoon HI, Cha J, Keum KC, Lee HY, Nam EJ, Kim SW, et al. Treatment outcomes of extended-field radiation therapy and the effect of concurrent chemotherapy on uterine cervical cancer with para-aortic lymph node metastasis. Radiat Oncol, 2015; 10: 18.\n23) Takekuma M, Kasamatsu Y, Kado N, Kuji S, Tanaka A, Takahashi N, et al. Reconsideration of postoperative concurrent chemoradiotherapy with fluorouracil and cisplatin for uterine cervical cancer. J Obstet Gynaecol Res, 2015; 41: 1638–1643.\n24) Isohashi F, Mabuchi S, Yoshioka Y, Seo Y, Suzuki O, Tamari K, et al. Intensity-modulated radiation therapy versus three-dimensional conformal radiation therapy with concurrent nedaplatin-based chemotherapy after radical hysterectomy for uterine cervical cancer: comparison of outcomes, complications, and dose-volume histogram parameters. Radiat Oncol, 2015; 10: 180.\n25) Yang B, Zhu L, Cheng H, Li Q, Zhang Y, Zhao Y. Dosimetric comparison of intensity modulated radiotherapy and three-dimensional conformal radiotherapy in patients with gynecologic malignancies: a systematic review and meta-analysis. Radiat Oncol, 2012; 7: 197.\n\n",
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"medline_ta": "Nagoya J Med Sci",
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}
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"literaturereference": "MIYAUCHI R, ITOH Y, KAWAMURA M, HIRAKAWA A, SHIBATA K, KAJIYAMA H, ET AL.. POSTOPERATIVE CHEMORADIATION THERAPY USING HIGH DOSE CISPLATIN AND FLUOROURACIL FOR HIGH- AND INTERMEDIATE-RISK UTERINE CERVICAL CANCER.. NAGOYA-J-MED-SCI. 2017?79(2):211-220",
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"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190128",
"receivedate": "20190128",
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},
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
"companynumb": "JP-TEVA-2019-JP-1001438",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
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},
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"drugdosagetext": "ON DAY 1 OF EACH CYCLE EVERY 21 DAYS; 3 CYCLES WERE ADMINISTERED",
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"drugindication": "CERVIX CARCINOMA",
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"drugindication": "CERVIX CARCINOMA",
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}
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"reaction": [
{
"reactionmeddrapt": "Bladder perforation",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MIYAUCHI R, ITOH Y, KAWAMURA M, HIRAKAWA A, SHIBATA K, KAJIYAMA H, ET AL. POSTOPERATIVE CHEMORADIATION THERAPY USING HIGH DOSE CISPLATIN AND FLUOROURACIL FOR HIGH- AND INTERMEDIATE-RISK UTERINE CERVICAL CANCER. NAGOYA-J-MED-SCI 2017?79(2):211-220.",
"literaturereference_normalized": "postoperative chemoradiation therapy using high dose cisplatin and fluorouracil for high and intermediate risk uterine cervical cancer",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190124",
"receivedate": "20190124",
"receiver": {
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},
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"seriousnesscongenitalanomali": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
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] |
{
"abstract": "OBJECTIVE\nWe investigated the clinical courses before and during pregnancy and after delivery in patients with repaired anomalous origin of the left coronary artery from the pulmonary artery to determine the impact of the hemodynamic changes and cardiac function on the selection of the appropriate mode of delivery.\n\n\nMETHODS\nSix patients who underwent coronary artery reimplantation delivered 10 infants. We scrutinized the patients' hemodynamic changes on echocardiographs and the plasma brain natriuretic peptide levels before and during pregnancy and after delivery, the perinatal outcomes and maternal and fetal events.\n\n\nRESULTS\nAll patients were asymptomatic and categorized as having New York Heart Association functional class I before pregnancy. In 8 of 10 pregnancies, vaginal deliveries were performed; two elective cesarean sections were performed because of symptomatic heart failure. The hemodynamic parameters were stable throughout pregnancy and postdelivery, and no maternal or fetal events occurred in the patients who underwent vaginal deliveries. One cesarean section patient developed significant heart failure during the late second and third trimesters, which was accompanied by hemodynamic changes, including increased brain natriuretic peptide levels, left ventricular diastolic dysfunction and worsening arrhythmias, and thrombosis and post-partum hemorrhage occurred postdelivery. The baby had intrauterine growth retardation and small for gestational age. None of the babies had congenital anomalies.\n\n\nCONCLUSIONS\nPregnancy was safe in most of the asymptomatic patients long after anomalous origin of the left coronary artery from the pulmonary artery was repaired. Symptomatic heart failure might occur during pregnancy in patients with persisting myocardial damage. Pregnancy and delivery should be carefully managed.",
"affiliations": "Department of Pediatric Cardiology, Division of Adult Congenital Heart Disease Pathophysiology and Life-Long Care, Tokyo Women's Medical University, Tokyo, Japan.;Department of Pediatric Cardiology, Division of Adult Congenital Heart Disease Pathophysiology and Life-Long Care, Tokyo Women's Medical University, Tokyo, Japan.;Department of Pediatric Cardiology, Division of Adult Congenital Heart Disease Pathophysiology and Life-Long Care, Tokyo Women's Medical University, Tokyo, Japan.;Department of Pediatric Cardiology, Division of Adult Congenital Heart Disease Pathophysiology and Life-Long Care, Tokyo Women's Medical University, Tokyo, Japan.;Department of Pediatric Cardiology, Division of Adult Congenital Heart Disease Pathophysiology and Life-Long Care, Tokyo Women's Medical University, Tokyo, Japan.;Department of Pediatric Cardiology, Division of Adult Congenital Heart Disease Pathophysiology and Life-Long Care, Tokyo Women's Medical University, Tokyo, Japan.;Department of Obstetrics and Gynecology, Tokyo Women's Medical University, Tokyo, Japan.;Department of Pediatric Cardiology, Division of Adult Congenital Heart Disease Pathophysiology and Life-Long Care, Tokyo Women's Medical University, Tokyo, Japan.",
"authors": "Kanoh|Miki|M|;Inai|Kei|K|http://orcid.org/0000-0002-9995-778X;Shinohara|Tokuko|T|;Shimada|Eriko|E|;Shimizu|Mikiko|M|;Tomimatsu|Hirofumi|H|;Ogawa|Masaki|M|;Nakanishi|Toshio|T|",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/jog.13606",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-8076",
"issue": "44(5)",
"journal": "The journal of obstetrics and gynaecology research",
"keywords": "adult congenital heart disease; anomalous origin of the left coronary artery from the pulmonary artery; myocardial damage; pregnancy",
"medline_ta": "J Obstet Gynaecol Res",
"mesh_terms": "D000328:Adult; D003330:Coronary Vessel Anomalies; D036861:Delivery, Obstetric; D005260:Female; D006801:Humans; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome; D011651:Pulmonary Artery",
"nlm_unique_id": "9612761",
"other_id": null,
"pages": "899-906",
"pmc": null,
"pmid": "29400413",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Pregnancy and delivery outcomes from patients with repaired anomalous origin of the left coronary artery from the pulmonary artery.",
"title_normalized": "pregnancy and delivery outcomes from patients with repaired anomalous origin of the left coronary artery from the pulmonary artery"
} | [
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"companynumb": "JP-BAYER-2018-103324",
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},
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},
{
"reactionmeddrapt": "Low birth weight baby",
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"reactionoutcome": null
},
{
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}
],
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"literaturereference": "MIKI K, KEI I, TOKUKO S, ERIKO S, MIKIKO S, HIROFUMI T ECT.. PREGNANCY AND DELIVERY OUTCOMES FROM PATIENTS WITH REPAIRED ANOMALOUS ORIGIN OF THE LEFT CORONARY ARTERY FROM THE PULMONARY ARTERY. THE JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH. 2018?44:899-906",
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},
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},
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}
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"reaction": [
{
"reactionmeddrapt": "Contraindicated drug prescribed",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Activated partial thromboplastin time prolonged",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "21.0",
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}
],
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},
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"literaturereference": "MIKI K, KEI I, TOKUKO S, ERIKO S, MIKIKO S, HIROFUMI T., ET. AL. PREGNANCY AND DELIVERY OUTCOMES FROM PATIENTS WITH REPAIRED ANOMALOUS ORIGIN OF THE LEFT CORONARY ARTERY FROM THE PULMONARY ARTERY. THE JOURNAL OF OBSTETRICS AND GYNAECOLOGY RESEARCH. 2018?44(5):899-906",
"literaturereference_normalized": "pregnancy and delivery outcomes from patients with repaired anomalous origin of the left coronary artery from the pulmonary artery",
"qualification": "1",
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},
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"receiptdate": "20180608",
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"seriousnesscongenitalanomali": null,
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"transmissiondate": "20180711"
}
] |
{
"abstract": "We herein report a woman who was suffering from type 1 diabetes and hearing impairment and whose mother had mitochondrial disease. Abdominal ultrasound identified a hepatic tumour, and a further examination led to the diagnosis of rectal cancer with synchronous multiple liver metastases. A genetic test led to the diagnosis of mitochondrial disease with a mitochondrial gene 3243A>G mutation. After neoadjuvant chemotherapy, we performed hepatectomy and low anterior resection in one stage. Hepatic vascular exclusion was not performed in order to prevent damage to hepatocytes due to liver ischaemia, and Ringer's lactate solution was not used to prevent lactic acidosis. The postoperative course was uneventful. Only one other case involving hepatectomy being performed in a patient with mitochondrial disease has been reported. Considering the extreme rarity of such cases and the importance of perioperative management, we report this case here.",
"affiliations": "Department of Gastroenterological Surgery, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan shogo_takei37@outlook.jp.;Department of Gastroenterological Surgery, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan.;Department of Gastroenterological Surgery, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan.;Department of Gastroenterological Surgery, Yokohama City University School of Medicine Graduate School of Medicine, Yokohama, Kanagawa, Japan.",
"authors": "Takei|Shogo|S|http://orcid.org/0000-0003-0614-8383;Homma|Yuki|Y|;Matsuyama|Ryusei|R|;Endo|Itaru|I|",
"chemical_list": "D009944:Organoplatinum Compounds; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-238653",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(2)",
"journal": "BMJ case reports",
"keywords": "colon cancer; diabetes; gastrointestinal surgery; metabolic disorders",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D003924:Diabetes Mellitus, Type 2; D005260:Female; D005472:Fluorouracil; D006498:Hepatectomy; D006801:Humans; D002955:Leucovorin; D008113:Liver Neoplasms; D028361:Mitochondrial Diseases; D009944:Organoplatinum Compounds; D010375:Pedigree; D012004:Rectal Neoplasms",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33547122",
"pubdate": "2021-02-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hepatectomy for liver metastasis from rectal cancer in a patient with mitochondrial disease.",
"title_normalized": "hepatectomy for liver metastasis from rectal cancer in a patient with mitochondrial disease"
} | [
{
"companynumb": "JP-PFIZER INC-202100933587",
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],
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"reaction": [
{
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"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "TAKEI, S.. HEPATECTOMY FOR LIVER METASTASIS FROM RECTAL CANCER IN A PATIENT WITH MITOCHONDRIAL DISEASE. BMJ CASE REPORTS. 2021?14 (2):10.1136/BCR?2020?238653",
"literaturereference_normalized": "hepatectomy for liver metastasis from rectal cancer in a patient with mitochondrial disease",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20210810",
"receivedate": "20210803",
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},
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"abstract": "The unexpected occurrence of thrombotic microangiopathy (TMA), characterised by microangiopathic haemolytic anaemia and thrombocytopenia, in a patient with cancer requires urgent diagnosis and appropriate management. TMA in patients with metastatic cancer can be a manifestation of the malignancy itself or a therapeutic complication. Distinguishing the cause of TMA is complicated but clinically important to initiate appropriate treatment of metastatic cancer and avoid potential drug toxicity. Eculizumab, which inhibits alternative complement pathway activation, has been shown to be effective in chemotherapy-induced TMA. We report the case of a 69-year-old woman with breast cancer who experienced a mitomycin-C-induced TMA manifestation. TMA did not respond to conservative therapy, plasmapheresis or rituximab and rapidly lead to dialysis dependency. Despite disease progression and metastases, eculizumab treatment was associated with recovered renal function and enabled the patient to avoid dialysis, improving her quality of life.",
"affiliations": "Department of General Internal Medicine, Nephrology, Rheumatology and Pneumology, Karlsruhe General Hospital, Karlsruhe, Germany.;Department of General Internal Medicine, Nephrology, Rheumatology and Pneumology, Karlsruhe General Hospital, Karlsruhe, Germany.;Dialysis Center Ludwigsburg, Ludwigsburg, Germany.",
"authors": "Hausberg|Martin|M|;Felten|Helmut|H|;Pfeffer|Stefan|S|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000495031cro-0012-0001Case ReportTreatment of Chemotherapy-Induced Thrombotic Microangiopathy with Eculizumab in a Patient with Metastatic Breast Cancer Hausberg Martin a*Felten Helmut aPfeffer Stefan baDepartment of General Internal Medicine, Nephrology, Rheumatology and Pneumology, Karlsruhe General Hospital, Karlsruhe, GermanybDialysis Center Ludwigsburg, Ludwigsburg, Germany*Martin Hausberg, Department of General Internal Medicine, Nephrology, Rheumatology and Pneumology, Karlsruhe General Hospital, DE–76133 Karlsruhe (Germany), E-Mail Martin.hausberg@klinikum-karlsruhe.deJan-Apr 2019 3 1 2019 3 1 2019 12 1 1 6 30 10 2018 30 10 2018 2019 Copyright © 2019 by S. Karger AG, Basel2019This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.The unexpected occurrence of thrombotic microangiopathy (TMA), characterised by microangiopathic haemolytic anaemia and thrombocytopenia, in a patient with cancer requires urgent diagnosis and appropriate management. TMA in patients with metastatic cancer can be a manifestation of the malignancy itself or a therapeutic complication. Distinguishing the cause of TMA is complicated but clinically important to initiate appropriate treatment of metastatic cancer and avoid potential drug toxicity. Eculizumab, which inhibits alternative complement pathway activation, has been shown to be effective in chemotherapy-induced TMA. We report the case of a 69-year-old woman with breast cancer who experienced a mitomycin-C-induced TMA manifestation. TMA did not respond to conservative therapy, plasmapheresis or rituximab and rapidly lead to dialysis dependency. Despite disease progression and metastases, eculizumab treatment was associated with recovered renal function and enabled the patient to avoid dialysis, improving her quality of life.\n\nKey Words\naHUSAtypical Haemolytic SyndromeBevacizumabBreast cancerComplementEculizumabMetastasesMitomycinThrombotic microangiopathy\n==== Body\nIntroduction\nThrombotic microangiopathies (TMAs) represent a heterogeneous group of rare diseases characterised by the clinical manifestation of thrombocytopenia, microangiopathic haemolytic anaemia, and variable end-organ damage resulting from systemic microvascular thrombi [1, 2]. The occurrence of TMA in patients with cancer may be rare but has serious consequences [3]. There are two principle causes of TMA in cancer patients. Firstly, the cancer itself may cause TMA through systemic microvascular metastases or bone marrow metastases. Secondly, many common oncotherapy drugs can induce TMA through direct endothelial damage or through an immune-mediated reaction involving the development of drug-dependent autoantibodies [1, 4].\n\nOncotherapy-induced TMA can be classified into two types. Type I oncotherapy-induced TMA involves chemotherapeutic agents (e.g. mitomycin-C, cisplatin and gemcitabine [3, 5, 6, 7]) and is a serious complication with significant morbidity and mortality that requires early diagnosis and treatment [8]. Typically, the incidence of mitomycin-C-induced TMA is dose-dependent with patients who receive treatment for more than 1 year [4] and a cumulative dose that exceeds 40 mg/m2 [3] being at greater risk. The prognosis for patients with mitomycin-C-induced TMA is poor: mortality related to renal failure is reported at 75% [4]. Type II oncotherapy-induced TMA involves anti-VEGF agents (e.g. bevacizumab) that are not usually associated with cumulative dose-dependent cell damage [9]. The diagnosis of cancer-induced TMA or oncotherapy-induced TMA is important to allow initiation of the appropriate treatment for metastatic cancer or to avoid continued exposure to a potentially toxic drug [1]. There are limited data on the effective use of plasma therapy to manage chemotherapy-induced TMA. Currently there is no standard of care for the management of mitomycin-C-induced TMA.\n\nEculizumab, which inhibits alternative complement pathway activation by blocking C5, has recently been shown to be effective in treating chemotherapy-induced TMA [8, 10]. Here, we show that eculizumab may prove effective in treating mitomycin-C-induced aHUS and provide a significant quality of life benefit.\n\nCase Report\nA 69-year-old female patient was treated with paclitaxel and bevacizumab for relapsing metastatic breast cancer. After approximately 2 years of treatment (49 treatment cycles), the patient presented with severe neuropathy resulting in an inability to walk. The treatment regime was changed to mitomycin-C, bevacizumab and capecitabin. After less than 4 weeks, and a cumulative dose of 30 mg/m2 mitomycin-C, treatment was discontinued because drug toxicity was suspected due to falling platelet count (from 82 × 103/μL to 40 × 103/μL). The patient continued to receive bevacizumab and capecitabin.\n\nThe patient experienced a TMA of initially unclear aetiology: haemolytic anaemia with negative direct and indirect Coomb's test, haptoglobin below dictation level, elevated lactate dehydrogenase (LDH), thrombocytopenia with presence of schistocytes, and renal failure. Renal replacement therapy (daily plasmapheresis and haemodialysis for 10 days), rituximab (one 375 mg/m2 intravenous injection, weekly for 4 weeks) and steroid treatment were initiated. After 2 months, there was no clinical sign of improvement (Fig. 1). ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) activity assay results were normal, therefore, thrombotic thrombocytopenic purpura (TTP) was excluded. Moreover, there was no history of diarrhoea and Shiga toxin was not detected in the stool specimen. Therefore, mitomycin-C-induced aHUS was diagnosed and eculizumab treatment was initiated (4 weekly doses of 900 mg, followed by 1,200 mg dose on week 5 and every other week thereafter).\n\nEculizumab treatment resulted in a complete remission of TMA symptoms, reduced LDH (from 975 U/L to 260 U/L) and serum creatinine (from 2.6 mg/dL on dialysis to 1.8 mg/dL), and an increase in platelet count (from 64 × 103/μL to 82 × 103/μL). With improved renal function the dialysis catheter was removed. However, 6 months after treatment initiation, the patient presented with severe knee pain and requested to stop eculizumab treatment. Eculizumab treatment was discontinued with weekly monitoring. Two months after eculizumab discontinuation, laboratory parameters suggested a new manifestation of TMA (decreased platelet count, 76 × 103/μL; increased LDH, 362 U/L). Eculizumab treatment was subsequently restarted and kidney function stabilised (serum creatinine, 1.4 mg/dL). However, the patient showed signs of anaemia, high LDH (500 U/L), and platelet levels remained low (50–70 × 103/μL).\n\nThe continued increase of LDH and gamma-glutamyl transpeptidase were indicative of known liver metastasis progression. This was confirmed by MRI scan at which time brain metastases were also detected. Bone marrow histology showed an advanced metastasis with minimal residual haematopoiesis, possibly resulting in thrombocytopenia. Further chemotherapy was not feasible due to the extent of treatment already undergone and the risks associated with haematopoietic insufficiency. The patient continued to receive eculizumab alongside palliative care.\n\nDiscussion\nWe present a case of a 69-year-old woman with breast cancer who suffered a chemotherapeutic-induced TMA manifestation associated to aHUS.\n\nTMA in a patient with cancer requires urgent diagnosis and appropriate management. Commonly, the removal of the causative drug from the treatment regimen is sufficient to resolve haematological and renal parameters [4]. Our case, however, displayed no clinical signs of improvement 2 months after mitomycin-C cessation. aHUS unmasked by mitomycin-C toxicity was therefore suspected. Whether administration of mitomycin-C was singularly responsible for unmasking aHUS is unknown. Our patient received a cumulative dose of 30 mg/m2 mitomycin-C, however chemotherapy-induced TMA has been implicated with slightly higher doses [3]. Additionally, other chemotherapeutic agents such as gemcitabine, cisplatin and carboplatin, as well as anti-VEGF agents (bevacizumab) have also been implicated in TMA [8]. Our patient continued to receive bevacizumab, which could have impacted on the TMA and for which the direct, on-target, dose-independent mechanism of TMA has been described [9, 11].\n\nWeakness, weight loss, pulmonary symptoms, and pain are common symptoms in patients with cancer-induced TMA [1]. Our patient experienced severe arthritic knee joint pain, a symptom previously undocumented in the literature. The reason for this symptom remains unclear, however this report may serve to raise awareness for a potential causal relationship.\n\nNo universal classification of aHUS exists; aHUS has been used to describe any form of HUS not caused by Shiga toxin-producing Escherichia coli (STEC), any HUS not caused by infection, or only HUS where complement involvement can be demonstrated [12]. In a recently reported classification however, aHUS excludes HUS caused by STEC and is subcategorised into primary and secondary aHUS [12]. Another report however, suggested aHUS may not be an appropriate term and proposed terms that refer to the pathogenic mechanisms involved; complement-HUS, DGKE mutation-HUS, and cobalamin C defect-HUS [13]. A diagnosis of primary aHUS/complement-HUS can be made when an underlying complement abnormality is strongly suspected and other causes of secondary aHUS have been excluded [12, 13]. Our patient was diagnosed with mitomycin-C-induced aHUS due to the persistence of symptoms which became apparent when eculizumab was discontinued. Additionally, ADAMTS13 activity was normal, which ruled out TTP [14]. Treatment with eculizumab resulted in a complete remission of TMA symptoms and haematological normalisation, indicative of underlying complement dysregulation. Limitations of our observation include the lack of biopsy-confirmed evidence of TMA due to thrombocytopenia, and no conclusive evidence of complement involvement. However, using complement abnormality testing as part of the diagnostic workup is unreliable as > 30% of tested patients do not have identifiable defects [15], thus, complement/genetic testing should only be used to confirm a diagnosis and inform treatment. In our patient, the rapid return of symptoms when eculizumab was discontinued strongly suggests an underlying complement abnormality.\n\nThe relationship between thrombocytopenia and monitoring therapeutic effectiveness and disease progression is worth consideration. Normalised platelet counts are often viewed as a measure of treatment success, however our patient remained thrombocytopenic despite the re-initiation of eculizumab treatment and gain in renal function. Thrombocytopenia in our case was probably due to bone metastases and not ineffective treatment. Persistent thrombocytopenia despite eculizumab treatment in cancer patients with chemotherapeutic-induced aHUS may serve as an indicator for suspecting metastases and disease progression. A recent report of four patients with gemcitabine-induced-HUS who progressed despite stopping chemotherapy showed that eculizumab proved effective in all four patients, normalising haematological parameters and improving kidney function with no severe adverse events [8]. Beyond improvement of TMA symptoms, we demonstrate the patient benefit of treatment with eculizumab including avoiding the need for dialysis thus improving quality of life. Eculizumab appears to be a well-tolerated and effective treatment for mitomycin-C-induced aHUS.\n\nConclusion\nOur case provides three clinically valuable lessons. First, resolution of TMA symptoms in cancer patients in the presence of continued thrombocytopenia may indicate disease progression and serious metastatic bone marrow infiltration. Second, eculizumab is well-tolerated and effective in treating mitomycin-C-induced TMA in cancer patients. Finally, beyond the resolution of TMA parameters, eculizumab may also provide quality of life improvement to patients with metastatic cancer, avoiding the need for dialysis.\n\nStatement of Ethics\nInformed consent was obtained from the patient.\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nAcknowledgements\nMedical writing support was provided by Dr Jonathan Plumb and Dr Ciaran Wright of Bioscript, Macclesfield, UK, which was funded by Alexion Pharmaceuticals Inc.\n\nFig. 1 Response to eculizumab treatment in mitomycin-C-induced TMA. Laboratory parameters over the course of treatment. Treatment periods are indicated by coloured bars: yellow, PE; green, rituximab; red, haemodialysis; blue, eculizumab. Day 0 represents TMA manifestation.\n==== Refs\nReferences\n1 Morton JM George JN Microangiopathic Hemolytic Anemia and Thrombocytopenia in Patients With Cancer J Oncol Pract 2016 6 12 (6) 523 30 27288467 \n2 Ducos G Mariotte E Galicier L Canet E Boutboul D Lemiale V Metastatic cancer-related thrombotic microangiopathies: a cohort study Future Oncol 2014 8 10 (10) 1727 34 25303053 \n3 Garcia G Atallah JP Antineoplastic agents and thrombotic microangiopathy J Oncol Pharm Pract 2017 3 23 (2) 135 42 26854265 \n4 Govind Babu K Bhat GR Cancer-associated thrombotic microangiopathy Ecancermedicalscience 2016 6 10 649 27433282 \n5 Faguer S Huart A Frémeaux-Bacchi V Ribes D Chauveau D Eculizumab and drug-induced haemolytic-uraemic syndrome Clin Kidney J 2013 10 6 (5) 484 5 26120441 \n6 Turner JL Reardon J Bekaii-Saab T Cataland SR Arango MJ Gemcitabine-Associated Thrombotic Microangiopathy: Response to Complement Inhibition and Reinitiation of Gemcitabine Clin Colorectal Cancer 2016 9 16 (2) e119 22 \n7 Valavaara R Nordman E Renal complications of mitomycin C therapy with special reference to the total dose Cancer 1985 1 55 (1) 47 50 3917353 \n8 Al Ustwani O Lohr J Dy G Levea C Connolly G Arora P Eculizumab therapy for gemcitabine induced hemolytic uremic syndrome: case series and concise review J Gastrointest Oncol 2014 2 5 (1) E30 3 24490050 \n9 Izzedine H Perazella MA Thrombotic microangiopathy, cancer, and cancer drugs Am J Kidney Dis 2015 11 66 (5) 857 68 25943718 \n10 Starck M Wendtner CM Use of eculizumab in refractory gemcitabine-induced thrombotic microangiopathy Br J Haematol 2013 12 164 (6) 894 6 \n11 Eremina V Jefferson JA Kowalewska J Hochster H Haas M Weisstuch J VEGF inhibition and renal thrombotic microangiopathy N Engl J Med 2008 3 358 (11) 1129 36 18337603 \n12 Goodship TH Cook HT Fakhouri F Fervenza FC Frémeaux-Bacchi V Kavanagh D Conference Participants Atypical hemolytic uremic syndrome and C3 glomerulopathy: conclusions from a “Kidney Disease: Improving Global Outcomes” (KDIGO) Controversies Conference Kidney Int 2017 3 91 (3) 539 51 27989322 \n13 Fakhouri F Zuber J Frémeaux-Bacchi V Loirat C Haemolytic uraemic syndrome Lancet 2017 8 390 (10095) 681 96 28242109 \n14 Vincent JL Castro P Hunt BJ Jörres A Praga M Rojas-Suarez J Thrombocytopenia in the ICU: disseminated intravascular coagulation and thrombotic microangiopathies-what intensivists need to know Crit Care 2018 6 22 (1) 158 29895296 \n15 Fremeaux-Bacchi V Fakhouri F Garnier A Bienaimé F Dragon-Durey MA Ngo S Genetics and outcome of atypical hemolytic uremic syndrome: a nationwide French series comparing children and adults Clin J Am Soc Nephrol 2013 4 8 (4) 554 62 23307876\n\n",
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"abstract": "To estimate the risk of glaucoma or sustained ocular hypertension (OHT) related to anti-vascular endothelial growth factor (VEGF) injections for age-related macular degeneration (AMD).\nRetrospective chart review.\nPatients who received unilateral anti-VEGF injections for AMD at the Wheaton Eye Clinic (IL).\nChart analysis was performed on 1095 patients, without prior glaucoma or OHT, who received unilateral anti-VEGF injections for AMD from 2005 to 2012, with data collected through 2013. Data collection included demographics, lens status, date and medication type of each injection, and the date of diagnosis of glaucoma or OHT by a treating glaucoma specialist, which was the main outcome measure. Rare events logistic regression was performed to determine the risk of disease development based on sex, lens status, and injection frequency.\nUnilateral glaucoma or sustained OHT developed in 42 patients over the course of follow-up, with 40 events in the injected eye only, 2 in the contralateral eye only. Statistical modeling predicted elevated risk for onset of glaucomatous disease with a higher maximum frequency of injections (p < 0.0001, odds ratio [OR] 2.18 for each additional injection over the most injection-intense 6 months for a given subject) and with phakic lens status (p = 0.0009, OR 0.33 for pseudophakia).\nOur results show a significant risk for glaucoma or OHT development in patients undergoing repeated treatments with intravitreal anti-VEGF injections for AMD, establishing the first reliable connection between disease development and a period of high-frequency injections. In addition, we show a significantly increased risk of disease development in phakic patients, which we believe points to a mechanical explanation for this type of secondary glaucoma.",
"affiliations": "Wheaton Eye Clinic, Wheaton, IL 60187, USA.;Mathematics and Computer Science Department, Wheaton College, Wheaton, IL, 60187, USA.;Mathematics and Computer Science Department, Wheaton College, Wheaton, IL, 60187, USA.;Mathematics and Computer Science Department, Wheaton College, Wheaton, IL, 60187, USA.;Wheaton Eye Clinic, Wheaton, IL 60187, USA.",
"authors": "Wingard|Jeremy B|JB|;Delzell|Darcie Ap|DA|;Houlihan|Nathan V|NV|;Lin|Jonathan|J|;Gieser|Jon P|JP|",
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"fulltext": "\n==== Front\nClin OphthalmolClin OphthalmolOPTHclinopClinical Ophthalmology (Auckland, N.Z.)1177-54671177-5483Dove 23254810.2147/OPTH.S232548Original ResearchIncidence of Glaucoma or Ocular Hypertension After Repeated Anti-Vascular Endothelial Growth Factor Injections for Macular Degeneration Wingard et alWingard et alWingard Jeremy B 1Delzell Darcie AP 2Houlihan Nathan V 2Lin Jonathan 2Gieser Jon P 11 Wheaton Eye Clinic, Wheaton, IL\n60187, USA2 Mathematics and Computer Science Department, Wheaton College, Wheaton, IL, 60187, USACorrespondence: Jeremy B Wingard Wheaton Eye Clinic, 2015 N. Main Street, Wheaton, IL60187, USATel +1 630-668-8250 Email jbwingard@gmail.com24 12 2019 2019 13 2563 2572 23 10 2019 28 11 2019 © 2019 Wingard et al.2019Wingard et al.This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php).Purpose\nTo estimate the risk of glaucoma or sustained ocular hypertension (OHT) related to anti-vascular endothelial growth factor (VEGF) injections for age-related macular degeneration (AMD).\n\nDesign\nRetrospective chart review.\n\nSubjects\nPatients who received unilateral anti-VEGF injections for AMD at the Wheaton Eye Clinic (IL).\n\nMethods\nChart analysis was performed on 1095 patients, without prior glaucoma or OHT, who received unilateral anti-VEGF injections for AMD from 2005 to 2012, with data collected through 2013. Data collection included demographics, lens status, date and medication type of each injection, and the date of diagnosis of glaucoma or OHT by a treating glaucoma specialist, which was the main outcome measure. Rare events logistic regression was performed to determine the risk of disease development based on sex, lens status, and injection frequency.\n\nResults\nUnilateral glaucoma or sustained OHT developed in 42 patients over the course of follow-up, with 40 events in the injected eye only, 2 in the contralateral eye only. Statistical modeling predicted elevated risk for onset of glaucomatous disease with a higher maximum frequency of injections (p < 0.0001, odds ratio [OR] 2.18 for each additional injection over the most injection-intense 6 months for a given subject) and with phakic lens status (p = 0.0009, OR 0.33 for pseudophakia).\n\nConclusion\nOur results show a significant risk for glaucoma or OHT development in patients undergoing repeated treatments with intravitreal anti-VEGF injections for AMD, establishing the first reliable connection between disease development and a period of high-frequency injections. In addition, we show a significantly increased risk of disease development in phakic patients, which we believe points to a mechanical explanation for this type of secondary glaucoma.\n\nKeywords\nexudative macular degenerationsecondary glaucomaopen-angle glaucomaanti-vascular endothelial growth factor\n==== Body\nIntroduction\nAnti-vascular endothelial growth factor (VEGF) injections have become the mainstay of treatment for exudative age-related macular degeneration (AMD), with annual increases in the total number of injections from 2006 to 2015 in the United States.1 Currently available agents have been extensively studied for their benefit in AMD treatment and include ranibizumab (Lucentis; Genentech, South San Francisco, CA)2–4 and aflibercept (Eylea; Regeneron, Tarrytown, NY),5 both of which have been approved by the US Food and Drug Administration (FDA) for the treatment of neovascular AMD, and the non-FDA approved bevacizumab (Avastin; Genentech).6,7\n\nAdverse events from anti-VEGF treatment have been extensively reported in many 1- to 2-year clinical trials,2–7 and the incidence of ocular and systemic adverse events has been low. For example, a recent meta-analysis of 10 aflibercept trials for the treatment of various retinal diseases reported no difference between treated patients and controls for intraocular inflammation, endophthalmitis, or selected systemic adverse events.8\n\nNonetheless, various authors have reported glaucoma or sustained ocular hypertension (OHT) development associated, at least temporally, with intravitreal anti-VEGF injections.9–15 It is not surprising, of course, that an immediate rise in intraocular pressure (IOP) would be seen after an intravitreal injection, as a volume of fluid is added to the restricted intraocular space. A study of 213 consecutive injections in AMD patients showed that the mean immediate post-injection IOP was 44 mmHg but fell to <30 mmHg in 96% of patients by 15 mins and in 100% of patients within 30 mins.16\n\nA strong, or even causative, link between repeated intravitreal anti-VEGF injections and glaucoma development has been difficult to assess over a large population of injected patients. However, there are reasons to believe that repeated intravitreal injections with anti-VEGF agents may decrease the function of the aqueous outflow system and be associated with the development of glaucomatous disease. Wen et al recently showed that aqueous outflow facility was reduced by 12% in eyes undergoing 20 or more anti-VEGF injections for AMD, compared to uninjected fellow eyes.17 The same study showed no decrease in outflow facility for eyes receiving 10 or fewer injections. Separately, subjects receiving monthly ranibizumab injections for 2 years, as part of the MARINA (Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab) and ANCHOR (Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in AMD) trials,2–4 were evaluated for the incidence of elevated IOP across study visits, when IOP was measured prior to that day’s injection.18 The authors showed that the incidence of IOP >25 was significantly higher in the injection group (10.9%) versus sham or photodynamic therapy (PDT, 5.1% combined), and the incidence of an 8 mmHg IOP rise from baseline was 24.2% in the injection group, versus 13.6% in the sham or PDT subjects. In a separate analysis by Freund and colleagues of patients receiving every 4 weeks injections of ranibizumab (2 mg) or aflibercept (2 mg) as part of the VIEW (VEGF Trap-Eye: Investigation of Efficacy and Safety in Wet AMD) 1 and 2 studies,5 19.7% of ranibizumab eyes and 14.1% of aflibercept eyes developed a 5 mmHg or greater IOP rise from baseline at some point over the 96-week study, confirmed on two consecutive visits.19 However, the analogous proportions in untreated, fellow eyes, were 15.6% and 13.3%, respectively, clouding the interpretation. Also, regarding the potential difference in IOP outcomes between the two drugs, it is noteworthy that the ranibizumab group had a higher percentage of preexisting glaucoma, a higher baseline IOP, and a higher percentage of preexisting glaucoma medication use than the aflibercept group.\n\nDatabase studies have also been performed, seeking to quantify the potential interaction between either anti-VEGF injections and glaucoma or between anti-VEGF injections and IOP. Recently published work based on a health database in British Columbia suggested that the risk of glaucoma surgery was greatly increased in patients receiving seven or more bevacizumab injections per year.20 However, in this case–control study, over three-fourths of the included patients had pre-existing glaucoma, with implications regarding the effect of injections on glaucoma patients but perhaps not on the initial development of glaucoma itself. Atchison and colleagues used the American Academy of Ophthalmology Intelligent Research in Sight (IRIS) Registry to assess the proportion of patients undergoing injections at various thresholds who then displayed a sustained IOP rise of at least 6 mmHg from baseline to a value >21 mmHg.21 A relatively low rate of sustained IOP rise is reported (2.6% compared to 1.5% in the untreated fellow eye), but there are limitations to this dataset, including the absence of data on glaucoma medication use.\n\nThe presented research attempts to answer the fundamental question of whether the development of glaucoma or sustained OHT can be reliably linked to repeated intravitreal anti-VEGF injections in AMD patients. We report, to our knowledge, the largest chart review yet submitted to answer this question, while limiting our dataset to patients in whom unilateral injections were performed but both eyes were amenable to analysis for possible glaucoma development. Importantly, full chart reviews were performed on all patients, enabling us to be certain of the timing and extent of any IOP rise, and allowing us to judge outcomes based on a confirmed diagnosis of glaucoma or OHT by a treating glaucoma specialist. In addition, thorough statistical modeling was performed to analyze the risk of these diagnoses under varying injection and demographic parameters.\n\nMethods\nChart analysis was performed in patients receiving at least one intravitreal injection at the Wheaton Eye Clinic (Wheaton, IL) from January 1, 2005, to December 31, 2012. Follow-up data were collected through December 31, 2013. The described research adheres to the tenets of the Declaration of Helsinki as well as all relevant federal and state laws. The study protocol was reviewed and approved by the Ethics Committee of the Wheaton Eye Clinic. The requirement for informed consent was waived due to the anonymized and retrospective nature of the study.\n\nCharts were obtained for analysis by an internal billing query of the Current Procedural Terminology code for intravitreal injection, matched with any International Classification of Diseases-9 AMD code. A total of 3081 potential subjects were identified in this way. Individual charts were then accessed to complete further screening, selecting only patients who had the correct, exudative AMD diagnosis, and limiting the dataset to exclude any patient with a history of bilateral injections, a prior diagnosis of glaucoma or OHT before the first injection, or diseases of the contralateral eye that could lead to non-diagnosis or non-treatment of glaucoma. Examples of this last exclusion condition included fellow eye non-glaucomatous optic neuropathies, light perception or no light perception vision prior to the first injection, or true monocular status. Twelve incomplete cases due to missing demographic or injection data were also removed.\n\nA total of 1095 subjects met inclusion criteria, and data were collected from the clinical charts, including sex, date of birth, lens status in both the study and fellow eye (categorized as already pseudophakic prior to first injection, still phakic after last injection, or date of cataract surgery), the date of each intravitreal injection categorized by medication used, and the date of last follow-up. Race or ethnicity documentation was not consistently present within the medical records and therefore could not be included within the demographic data. Seventeen subjects with the last follow-up date less than 30 days after the first injection were excluded. The remaining 1078 subjects were then assessed for the diagnosis of glaucoma or OHT in either the study or fellow eye by thorough, full review of each patient’s clinical file, and the date of the elevated IOP leading to the diagnosis was called the event date. If an event was detected, the bilateral IOP on the date of detection was recorded, or, if treatment was not started on that date, and if bilateral Goldmann applanation tonometry (GAT) was not used, then the follow-up IOP by GAT, recorded at the glaucoma service consultation, was recorded.\n\nAll subjects with positive events in this study were referred from a retina specialist to a glaucoma specialist within the practice, and a complete glaucoma work-up was performed, typically including corneal pachymetry, optical coherence tomography of the retinal nerve fiber layer, and either automated or manual kinetic visual field testing, as required by each clinical situation. In no case was the onset of disease found to be diagnosed within a 90-day post-operative period (for example, after cataract surgery). All positive case diagnoses were associated with open angles by gonioscopic appearance in the opinion of the treating specialist, and in all cases chronic treatment regimens were introduced. In total, 63 positive events were identified, including 40 events in the injected eye only (22 initially diagnosed with OAG and 18 with sustained OHT requiring treatment), 2 events in the contralateral eye only (1 OAG and 1 OHT), and 21 events of bilateral disease (10 cases of OAG including 3 diagnosed as normal tension glaucoma and 11 OHT). Subjects who developed a positive event in only the contralateral eye or in both eyes were excluded from further risk modeling. It is noted that the opinion of the treating glaucoma specialist as to disease status and laterality has been used as the sole arbiter of event occurrence. This outcome measure was deliberately chosen to allow assessment of clinically significant disease occurrence requiring treatment and further monitoring, as opposed to an IOP-only strategy, with results that might be misinterpreted out of context, for example due to inaccurate or non-reproducible IOP readings, post-operative IOP spikes, or other clinically insignificant measurements that may cross a preset threshold. Descriptively, however, the 40 subjects diagnosed with unilateral glaucoma in the injected eye presented with a mean pre-treatment IOP of 34.9 mmHg (SD 9.7) in the treated eye versus 16.7 mm Hg (SD 2.9) in the contralateral eye. Thirty-eight of these 40 measurements were by GAT, as two Tonopen (Reichert, Depew, NY) measurements of 45 mmHg by retina specialists led to urgent treatment before the transfer of care to the glaucoma clinic.\n\nThere remained 1055 subjects for statistical modeling of disease risk, and the de-identified database of demographic information, lens status, list of injection dates, event dates, and last follow-up were then subjected to thorough statistical review. Injection information was used to compute the total number of injections (TOTINJ) during treatment and the highest number of injections given in any 6-month period (HIGH6MO). This HIGH6MO variable was included as a gauge of frequency of injections, to consider whether a series of closely spaced injections may be associated with some form of insult, or some lack of return to homeostasis, that may be associated with disease development. For patients with positive disease status, any injections received after the event date for glaucoma or OHT development were not included in the analysis. The majority of subjects received bevacizumab as the only administered medication, and there was not enough variation in medication data to model the potential effects of different medications. The proportion of bevacizumab injections was 78.8% and 78.2% of all injections in men and women, respectively, compared to 9.3% and 8.8% of injections with ranibizumab, and 10.8% and 11.4% of injections with aflibercept. Lens status was coded as “pseudophakic” if a patient underwent cataract surgery without a diagnosis of glaucoma or OHT, or underwent surgery prior to such a diagnosis, and “phakic” otherwise.\n\nDisease status was modeled with a rare-events logistic regression method that corrects for bias in the estimates due to the scarcity of disease in the population.22,23 Model selection was performed by both visual inspection of the relationships between disease status and potential explanatory variables and by penalized likelihood ratio tests. The model predicts the probability of disease by sex, age, TOTINJ, HIGH6MO, and pseudophakia.\n\nResults\nDemographic characteristics of the studied subjects are given in Table 1. Injection patterns by group are listed in Table 2, corresponding to the study variables listed above. The initial review of 1078 subjects identified 63 positive events, including 21 cases of glaucoma or sustained OHT diagnosed bilaterally. These bilateral events are presumed to relate to the underlying population risk for disease, and the incidence was 1.95% over the course of follow-up, with an average follow-up length of 32.01 ± 23.3 months. This is not dissimilar from incidence rates reported across broad populations, such as the Los Angeles Latino Eye Study (4-year incidence for open-angle glaucoma of 2.31% in a Latino population >40 years old)24 or the Rotterdam Study (5-year incidence of definite or probable open-angle glaucoma 1.8% for age 65–69 years, 2.4% for 70–74 years, 2.6% for 75+ years).25Table 1 Demographic Characteristics of Patients by Injected Medication\n\n\tBevacizumab Only\tPegaptanib Only\tRanibizumab Only\tAflibercept Only\tMixed Medications\t\nPatients, no\t812\t11\t18\t28\t186\t\nFemale, no (%)\t511 (63%)\t4 (36%)\t11 (61%)\t18 (64%)\t117 (63%)\t\nAge at first injection (years), mean (SD)\t80.9 (8.5)\t83.5(6.7)\t81.8(7.8)\t80.3(8.3)\t77.0(7.77)\t\nTotal injections, mean no (SD)\t6.9 (6.3)\t3 (1.9)\t6.7 (8.6)\t8.3 (5.0)\t16.3 (9.2)\t\nPseudophakia, %\t57%\t73%\t72%\t64%\t53%\t\nAverage, Median follow-up (months)\t31.1, 25.1\t33.6, 28.7\t28.2, 26.4\t13.7, 14.7\t39.2, 33.4\t\nRange of follow-up (months)\t1.1–92.3\t5.9–93.3\t1.1–69.9\t1.8–22.2\t5.9–94.7\t\n\nTable 2 Injection Patterns by Lens and Event Status\n\n\tNon-Event Patients (No Diagnosis of Glaucoma or Sustained Ocular Hypertension), n=1015\tEvent Patients (Diagnosed with Glaucoma or Ocular Hypertension in Follow-Up), n=40\t\nTotal Injections (TOTINJ), Mean (SE)\tHighest No. Injections in 6 Months (HIGH6MO), Mean (SE)\tTotal Injections (TOTINJ), Mean (SE)\tHighest No. Injections in 6 Months (HIGH6MO), Mean (SE)\t\nMale, Phakic\t7.8 (7.1)\t3.4 (1.2)\t14.6 (11.4)\t4.7 (1.2)\t\nFemale, Phakic\t8.4 (7.6)\t3.4 (1.2)\t16.2 (5.8)\t4.6 (1.3)\t\nMale, Pseudophakic\t8.6 (7.8)\t3.5 (1.3)\t22.0 (18.0)\t4.8 (1.5)\t\nFemale, Pseudophakic\t8.3 (7.8)\t3.4 (1.2)\t11.5 (6.9)\t4.4 (1.6)\t\n\n\n\nAn additional 40 subjects developed glaucoma or sustained OHT in only the injected eye, while 2 subjects developed glaucoma or sustained OHT in only the untreated, contralateral eye. Therefore, 95.2% of patients diagnosed with unilateral disease developed the disease in the treated eye only. The time to disease development for these 40 subjects is displayed in Figure 1.Figure 1 Histogram showing time from first intravitreal anti-vascular endothelial growth factor injection to development of glaucoma or sustained ocular hypertension, with each column representing 2 months. Incidence is distributed over 4+ years of follow-up, with 8 subjects developing disease before 1 year, 22 from years 1–3, and an additional 10 after 3 years from the first injection.\n\n\n\nThe final (or “reduced”) logistic regression model predicts the probability of disease by sex, HIGH6MO, and pseudophakia. The initial, “full” model also included TOTINJ and age at first injection. These, however, were non-significant (p = 0.68 for TOTINJ and p = 0.52 for age) in the full model and therefore were eliminated from the final, “reduced” logistic regression. The results are reported in Table 3. It is noteworthy that TOTINJ is indeed highly significant if HIGH6MO is excluded from the full model (p < 0.0001 for TOTINJ under this scenario). These two variables are, in fact, correlated, as patients who received more frequent injections also tended toward a higher total number of injections (correlation = 0.65). HIGH6MO, however, is the better explanatory variable, as it remains highly significant (p < 0.0001), and TOTINJ becomes non-significant (p = 0.68), when both variables are included in the model.Table 3 Logistic Regression Results Predicting the Probability of Glaucoma or Sustained Ocular Hypertension\n\nVariable\tCoefficient\tStandard Error\t95% Confidence Interval\tp-value\t\nA. Reduced Model\t\nSex (Female)\t−0.73\t0.33\t(−1.40, −0.08)\t0.028\t\nHIGH6MO\t0.78\t0.14\t(0.51, 1.07)\t<0.0001\t\nPseudophakia\t−1.12\t0.35\t(−1.85, −0.50)\t0.0009\t\nB. Full Model\t\nSex (Female)\t−0.75\t0.33\t(−1.41, −0.10)\t0.024\t\nHIGH6MO\t0.75\t0.18\t(0.40, 1.11)\t<0.0001\t\nPseudophakia\t−1.20\t0.37\t(−1.97, −0.48)\t0.0009\t\nTOTINJ\t0.01\t0.02\t(−0.03, 0.04)\t0.68\t\nAge at First Injection\t0.01\t0.02\t(−0.02, 0.06)\t0.52\t\n\n\n\nFigure 2 shows the effect of the three explanatory variables on the probability of disease. There is some evidence of a difference in disease risk between men and women, with men displaying a higher risk. A higher rate of injections (the maximum rate over any 6-month period, up to approximately 1 injection per month) is associated with a significantly higher risk of disease development. Finally, there is evidence that pseudophakic patients were at a greatly reduced risk for disease development compared with phakic patients.Figure 2 Using the results of the logistic regression (coefficients from the reduced model in Table 3), the predicted probability of disease is graphed against the highest injection rate over any 6-month period. This relationship is displayed distinctly for the four combinations of sex and lens status.\n\n\n\nTable 4 gives the model results in terms of odds ratios. The odds of disease for females is 48% of the odds for males, albeit with a wide 95% confidence interval that stretches from 25% up to 92%. Similarly, the odds of disease for pseudophakic patients is only 33% of the odds of disease for phakic patients. For maximum injection rate, the odds ratio describes the change in the predicted probability of disease based on a one-unit change in the explanatory variable. For example, patients who receive a maximum of two injections over any 6-month period are predicted to be 2.18 times more likely to be diagnosed with glaucoma or sustained OHT than those whose maximum frequency is one injection over any 6-month period. Applying this ratio to a three-unit difference, the model predicts a 10.40 times higher likelihood of disease when a patient’s maximum frequency is, for instance, 6 injections versus 3 over any 6-month period.Table 4 Odds Ratios for Firth’s Logistic Regression (See Table 3)\n\nVariable\tOdds Ratio\t95% CI\t\nSex (Female)\t0.48\t(0.25, 0.92)\t\nHIGH6MO\t2.18\t(1.66, 2.91)\t\nPseudophakia\t0.33\t(0.16, 0.64)\t\n\n\n\nDiscussion\nThe modeled data show a distinctly increased risk for glaucoma or sustained OHT development in patients undergoing intensive treatment regimens with anti-VEGF intravitreal injections for exudative AMD. Although odds ratios are reported and show an increased risk of glaucoma or OHT development with male sex, higher injection frequency, and phakic status, the data are best interpreted by modeling the effects of changes in the various parameters on probability of disease development.\n\nThe probabilities depicted in Figure 2 distinctly show that a 6-month period of high-frequency injections increases the predicted risk of disease significantly under all combinations of sex and lens status. For example, a phakic man with a 6-month high of five injections has a predicted 18.1% risk of disease, whereas a phakic man with a 6-month high of three injections has only a 4.4% estimated risk. This relationship may have implications for initiation and maintenance protocols in exudative AMD patients, favoring both lower frequency initiation therapy and extension of inter-injection intervals as possible with ongoing therapy (so-called treat-and-extend protocols26), presuming that similar clinical effectiveness in AMD treatment can be achieved. It is tempting to extend these data to favor one medication over another, if the same clinical effectiveness in AMD treatment can be achieved via less frequent injections of one medication versus another. However, our data cannot directly address this question given the preponderance of bevacizumab injections in our study set. In addition, the supposed advantage of a lower frequency but higher potency anti-VEGF injection regimen would only be beneficial as to glaucoma development if the effect is truly related to the injection event, as opposed to the pharmacologic VEGF blockage itself. This is a mechanistic question that cannot be fully answered but will be addressed below.\n\nThe data give convincing evidence of a relationship between lens status and disease development, and this may be instructive regarding the mechanism that leads to glaucoma or sustained OHT. We undertook this study to assess for a positive link, or lack thereof, between anti-VEGF injections and glaucoma or sustained OHT development. The fact that 95.2% (40/42) of patients diagnosed with unilateral glaucoma or sustained OHT during follow-up developed the disease in the injected eye, as opposed to the uninjected fellow eye, seems to establish this link quite securely. The fact that pseudophakia proved greatly protective may begin to suggest the disease mechanism, and in our analysis, this finding, more than any other, supports a mechanical cause for the disease. Potential medication-induced explanations for cases of post-injection glaucoma or sustained OHT have included clogging of the trabecular meshwork with silicone oil droplets27 or aggregated proteins,28 altered nitric oxide metabolism,29 or a direct effect of VEGF blockage on trabecular endothelial permeability,30 as reviewed by Aref.31 However, it is unclear why these effects, which presumably would operate at the level of the trabecular meshwork, would be greater in phakic eyes than in pseudophakic eyes, as clinical observation suggests that substances injected into the vitreous cavity are more likely to migrate to the anterior chamber, or are likely to migrate faster, in a pseudophakic eye than in a phakic one. This effect was seen in one study of intravitreal triamcinolone acetonide (TA) injections, where TA crystals were observed in the anterior chamber 1 hr after injection in 5 of 31 pseudophakic patients, but no anterior chamber crystals were observed at this time point in the 57 phakic patients who received injections.32\n\nIn our opinion, the predominance of glaucoma and sustained OHT in phakic patients following a series of intravitreal anti-VEGF injections align well with a mechanical theory of outflow system damage. This damage is presumably related to the process of the injections themselves, where the repeated injections of volume into the restricted space of the vitreous cavity create an immediate and substantial pressure imbalance between the vitreous cavity and the areas anterior to the lens that are filled with aqueous humor. As the zonular system suspending the lens is not indefinitely rigid, it is hypothesized that the anterior chamber volume compresses, as shown by Kerimoglu et al after TA injections,32 with anterior movement of the lens and iris. This movement may strain the outflow apparatus, perhaps at the longitudinal fibers of the ciliary muscle, thereby compromising outflow facility over time with repeated injections. Our data regarding injection frequency suggest that a sufficient return to homeostasis between injections may diminish the long-term risk of outflow system damage.\n\nThe strain on the outflow system may be reduced both by a more rapid volume equilibration from posterior to anterior through the zonules of the pseudophakic patient and by the quicker resolution of the immediate post-injection IOP spike that seems to occur in pseudophakic patients,32 perhaps due to the more widely open anterior chamber angle compared to phakic eyes. Alaghband and colleagues recently showed, using electronic Schiotz tonography, that outflow facility was improved 3, 6, and 12 months post-operatively following modern phacoemulsification cataract surgery.33 Improved outflow facility in pseudophakic patients would naturally lead to quicker resolution of post-injection IOP spikes.\n\nA decrease in outflow facility was in fact seen by Wen and colleagues after 20 intravitreal anti-VEGF injections, compared to the uninjected fellow eye.17 Further, Wen and colleagues evaluated 21 patients following intravitreal anti-VEGF injection, showing that there was significantly more narrowing of the nasal angle in phakic compared to pseudophakic eyes.34 This suggests that, following an injection, volume equilibration from posterior to anterior was more rapidly achieved in the pseudophakic group, again supporting our hypothesis, as described above. One author (JBW) notes that, clinically, patients undergoing cataract surgery after a history of repeated intravitreal injections are more likely to demonstrate shallowing of the lens capsule after lens nucleus removal, suggesting a generalized deficiency in zonular turgidity that may be consistent with the mechanism described. A subtly alternative hypothesis would be to suggest that pseudophakia is not so much protective against the anti-VEGF injection-induced damage to the outflow apparatus, but instead the pseudophakic eye, with its outflow facility already improved from baseline because of the prior cataract surgery, can still maintain a normal IOP even if outflow facility is later degraded by a series of injections.\n\nOur results are in step with early reports proposing a link between anti-VEGF injections and glaucoma development.9–15 Our study extends current knowledge of this link and verifies it with far more statistical power. Our results are also consistent with the recent analyses applied to MARINA and ANCHOR, as well as VIEW 1 and 2 databases, showing that a proportion of patients developed significant IOP elevations after a series of ranibizumab or aflibercept injections.18,19 Our study extends these findings by looking not just at IOP results but at the actual development of glaucomatous disease requiring treatment. Although it is outside the scope of this paper to describe patient experiences in terms of glaucoma severity and required treatment regimens, one author (JBW) has found it necessary to provide surgical glaucoma care, including filtering surgery, to numerous patients diagnosed with unilateral glaucoma following a series of same eye intravitreal anti-VEGF injections, underlining the significance of the problem in these patients.\n\nWith a link established between repeated intravitreal anti-VEGF injections and the development of glaucoma in certain patients, a number of questions follow, including those related to monitoring, treatment, and epidemiology. Our research cannot yet answer questions regarding disease severity in this population, but we can comment on the probability of disease with various patient factors and injection patterns. We show a high rate of disease in certain populations, especially phakic patients who have undergone a period of high-frequency injections. This level of detail in our analysis may explain why our risk prediction model does not appear to align particularly well with a recently published study of IOP results in patients undergoing anti-VEGF treatments from the IRIS Registry.21 However, by its nature, a registry study is unable to individually assess charts for context, making these results very difficult to interpret for the question at hand. For example, the authors of this study were unable to assess or report the frequency of use of glaucoma medications, which would presumably have lowered the IOP in treated patients but would not necessarily have registered as a clinically significant IOP increase based on the analysis criteria. In addition, over concerns of data quality, subjects were eliminated from this IRIS Registry study if there were too many reported IOP values, or if there were reported IOPs between 0 and 5 mmHg. However, a subject diagnosed with glaucoma during the study period might naturally have undergone an increased number of IOP checks and potentially, after glaucoma surgery, have experienced a period of hypotony. In fact, over 70% of initially screened registrants were eliminated from the analysis in this study due to lack of at least 1 baseline IOP value, lack of at least 1 IOP value after 1 year, or undergoing >75 IOP measurements. Then, 5.86% of the remaining subjects were eliminated from the analysis due to at least 1 IOP value between 0 and 5 mmHg. Finally, as our Figure 1 shows, it was not uncommon to find glaucoma or sustained OHT development even 3 years after the first anti-VEGF treatment, meaning that long-term follow-up and data analysis would be necessary to discover these cases.\n\nIn conclusion, our large chart review study shows a significant risk for glaucoma or sustained OHT development in patients undergoing repeated treatments with anti-VEGF intravitreal injections for exudative AMD. Further, we establish, to our knowledge, the first reliable connection between disease development and a period of high-frequency injections. In addition, we show, also for the first time, a significantly increased risk of disease development in phakic patients, and we present a plausible explanation for these findings. The connection between glaucoma or sustained OHT development and both high-frequency injections and phakic status suggests, in our opinion, a mechanical basis for this complication of repeated intravitreal anti-VEGF treatments. Further study should evaluate these connections further, explore alterations in anti-VEGF treatment protocols that may confer a lower risk of this complication, and describe results of treatment for this recently described type of secondary glaucoma.\n\nAcknowledgements\nThe authors wish to thank Dr. Ruth Williams for expert manuscript review. We are also grateful to the glaucoma and retina specialists of the Wheaton Eye Clinic for review and discussion of the research and its implications: Drs. Michael Andreoli, Susan Anderson-Nelson, Mark Daily, Greg Fenton, David Gieser, Richard Gieser, Stephen Gieser, Vikram Setlur, Edward Sung, and Ruth Williams.\n\nDisclosure\nThe authors report no conflicts of interest in this work.\n==== Refs\nReferences\n1. 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Good \nTJ , Kimura \nAE , Mandava \nN , Kahook \nMY . Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents . Br J Ophthalmol . 2011 ;95 :1111 –1114 . doi:10.1136/bjo.2010.180729 20702430 \n10. Bakri \nSJ , McCannel \nCA , Edwards \nAO , Moshfeghi \nDM . Persistent ocular hypertension following intravitreal ranibizumab . Graefes Arch Clin Exp Ophthalmol . 2008 ;246 :955 –958 . doi:10.1007/s00417-008-0819-2 18425523 \n11. Kahook \nMY , Kimura \nAE , Wong \nLJ , et al. Sustained elevation in intraocular pressure associated with intravitreal bevacizumab injections . Ophthalmic Surg Lasers Imaging . 2009 ;40 :293 –295 . doi:10.3928/15428877-20090430-12 19485295 \n12. Adelman \nRA , Zheng \nQ , Mayer \nHR . Persistent ocular hypertension following intravitreal bevacizumab and ranibizumab injections . J Ocul Pharmacol Ther . 2010 ;26 :105 –110 . doi:10.1089/jop.2009.0076 20187807 \n13. Tseng \nJJ , Vance \nSK , Della Torre \nKE , et al. Sustained increased intraocular pressure related to intravitreal anti-vascular endothelial growth factor therapy for neovascular age-related macular degeneration . J Glaucoma . 2012 ;21 :241 –247 . doi:10.1097/IJG.0b013e31820d7d19 21423038 \n14. Loukianou \nE , Brouzas \nD , Apostolopoulos \nM . Sustained ocular hypertension following intravitreal injections of 0.5 mg/0.05 mL ranibizumab . Int Ophthalmol . 2011 ;31 :211 –213 . doi:10.1007/s10792-010-9410-z 21611879 \n15. Choi \nDY , Ortube \nMC , McCannel \nCA , et al. Sustained elevated intraocular pressures after intravitreal injection of bevacizumab, ranibizumab, and pegaptanib . Retina . 2011 ;31 :1028 –1035 . doi:10.1097/IAE.0b013e318217ffde 21836409 \n16. Kim \nJE , Mantravadi \nAV , Hur \nEY , Covert \nDJ . Short-term intraocular pressure changes immediately after intravitreal injections of anti-vascular endothelial growth factor agents . Am J Ophthalmol . 2008 ;146 :930 –934 . doi:10.1016/j.ajo.2008.07.007 18775528 \n17. Wen \nJC , Reina-Torres \nE , Sherwood \nJM , et al. Intravitreal anti-VEGF injections reduce aqueous outflow facility in patients with neovascular age-related macular degeneration . Invest Ophthalmol Vis Sci . 2017 ;58 :1893 –1898 . doi:10.1167/iovs.16-20786 28358961 \n18. Bakri \nSJ , Moshfeghi \nDM , Francom \nS , et al. Intraocular pressure in eyes receiving monthly ranibizumab in 2 pivotal age-related macular degeneration clinical trials . Ophthalmology . 2014 ;121 :1102 –1108 . doi:10.1016/j.ophtha.2013.11.029 24393349 \n19. Freund \nKB , Hoang \nQV , Saroj \nN , Thompson \nD . Intraocular pressure in patients with neovascular age-related macular degeneration receiving intravitreal aflibercept or ranibizumab . Ophthalmology . 2015 ;122 :1802 –1810 . doi:10.1016/j.ophtha.2015.04.018 26025097 \n20. Eadie \nBD , Etminan \nM , Carleton \nBC . Association of repeated intravitreous bevacizumab injections with risk for glaucoma surgery . JAMA Ophthalmol . 2017 ;135 (4 ):363 –368 . doi:10.1001/jamaophthalmol.2017.0059 28301639 \n21. Atchison \nEA , Wood \nKM , Mattox \nCG , Barry \nCN , Lum \nF , MacCumber \nMW . The real-world effect of intravitreous anti-vascular endothelial growth factor drugs on intraocular pressure: an analysis using the IRIS Registry . Ophthalmology . 2018 . doi:10.1016/j.ophtha.2017.11.027 \n22. Heinze \nG , Schemper \nM . A solution to the problem of separation in logistic regression . Stat Med . 2002 ;21 :2409 –2419 . doi:10.1002/(ISSN)1097-0258 12210625 \n23. Firth \nD . Bias reduction of maximum likelihood estimates . Biometrika . 1993 ;80 (1 ):27 –38 . doi:10.1093/biomet/80.1.27 \n24. Jiang \nX , Varma \nR , Wu \nS , et al. Baseline risk factors that predict the development of open-angle glaucoma in a population: the Los Angeles latino eye study . Ophthalmology . 2012 ;119 :2245 –2253 . doi:10.1016/j.ophtha.2012.05.030 22796305 \n25. De Voogd \nS , Ikram \nMK , Wolfs \nRC , Jansonius \nNM , Hofman \nA , de Jong \nPT . Incidence of open-angle glaucoma in a general elderly population: the Rotterdam study . Ophthalmology . 2005 ;112 :1487 –1493 . doi:10.1016/j.ophtha.2005.04.018 16039716 \n26. Silva \nR , Berta \nA , Larsen \nM , Macfadden \nW , Feller \nC , Mones \nJ ; on behalf of the TREND Study Group . Treat-and-extend versus monthly regimen in neovascular age-related macular degeneration: results with ranibizumab from the TREND study . Ophthalmology . 2018 ;125 :57 –65 . doi:10.1016/j.ophtha.2017.07.014 28893454 \n27. Bakri \nSJ , Ekdawi \nNS . Intravitreal silicone oil droplets after intravitreal drug injections . Retina . 2008 ;28 (7 ):996 –1001 . doi:10.1097/IAE.0b013e31816c6868 18698303 \n28. Kahook \nMY , Liu \nL , Ruzycki \nP , et al. High-molecular-weight aggregates in repackaged bevacizumab . Retina . 2010 ;30 (6 ):887 –892 . doi:10.1097/IAE.0b013e3181d50cea 20458261 \n29. Ricca \nAM , Morshedi \nRG , Wirostko \nBM . High intraocular pressure following anti-vascular endothelial growth factor therapy: proposed pathophysiology due to altered nitric oxide metabolism . J Ocular Pharma Ther . 2015 ;31 (1 ):2 –10 . doi:10.1089/jop.2014.0062 \n30. Reina-Torres \nE , Wen \nJC , Liu \nKC , et al. VEGF as a paracrine regulator of conventional outflow facility . Invest Ophthalmol Vis Sci . 2017 ;58 :1899 –1908 . doi:10.1167/iovs.16-20779 28358962 \n31. Aref \nAA . Management of immediate and sustained intraocular pressure rise associated with intravitreal antivascular endothelial growth factor injection therapy . Curr Opin Ophthalmol . 2012 ;23 :105 –110 . doi:10.1097/ICU.0b013e32834ff41d 22249237 \n32. Kerimoglu \nH , Ozturk \nBT , Bozkurt \nB , Okka \nM , Okudan \nS . Does lens status affect the course of early intraocular pressure and anterior chamber changes after intravitreal injection? \nActa Ophthalmol . 2011 ;89 (2 ):138 –142 . doi:10.1111/j.1755-3768.2009.01656.x 19799586 \n33. Alaghband \nP , Beltran-Agullo \nL , Galvis \nEA , Overby \nDR , Lim \nKS . Effect of phacoemulsification on facility of outflow . Br J Ophthalmol . 2018 ;102 (11 ):1520 –1526 . doi:10.1136/bjophthalmol-2017-311548 29654113 \n34. Wen \nJC , Cousins \nSW , Schuman \nSG , Allingham \nRR . Dynamic changes of the anterior chamber angle produced by intravitreal anti-vascular growth factor injections . Retina . 2016 ;36 (10 ):1874 –1881 . doi:10.1097/IAE.0000000000001018 26938953\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1177-5467",
"issue": "13()",
"journal": "Clinical ophthalmology (Auckland, N.Z.)",
"keywords": "anti-vascular endothelial growth factor; exudative macular degeneration; open-angle glaucoma; secondary glaucoma",
"medline_ta": "Clin Ophthalmol",
"mesh_terms": null,
"nlm_unique_id": "101321512",
"other_id": null,
"pages": "2563-2572",
"pmc": null,
"pmid": "31920279",
"pubdate": "2019",
"publication_types": "D016428:Journal Article",
"references": "17021318;18698303;22555112;12210625;20187807;22249237;28358962;29654113;17021319;28301639;29336897;19485295;21526923;20458261;26025097;20702430;28358961;26938953;18425523;27890437;21836409;25369256;21423038;22796305;27084563;21611879;19118696;19799586;18775528;28893454;23084240;24393349;16039716",
"title": "Incidence of Glaucoma or Ocular Hypertension After Repeated Anti-Vascular Endothelial Growth Factor Injections for Macular Degeneration.",
"title_normalized": "incidence of glaucoma or ocular hypertension after repeated anti vascular endothelial growth factor injections for macular degeneration"
} | [
{
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},
{
"reactionmeddrapt": "Intentional product use issue",
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},
{
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{
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],
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},
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"literaturereference": "WINGARD J, DELZELL P, HOULIHAN N, LIN J AND GIESER J. INCIDENCE OF GLAUCOMA OR OCULAR HYPERTENSION AFTER REPEATED ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR INJECTIONS FOR MACULAR DEGENERATION. CLINICAL OPHTHALMOLOGY 2019?13:2563-2572.",
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}
] |
{
"abstract": "Intrauterine balloon tamponade is commonly used to treat postpartum hemorrhage refractory to pharmacologic interventions. It has not been well-studied in girls or adolescents for treatment of acute heavy menstrual bleeding.\n\n\n\nA 10-year old girl presented with heavy menstrual bleeding that did not respond to medical management. Placement of a Foley catheter for intrauterine tamponade was used to control bleeding. She was subsequently diagnosed with a platelet function disorder.\n\n\n\nFoley catheter placement is a low-risk, low-cost, and readily accessible option for intrauterine tamponade to consider for young girls and adolescents with acute heavy menstrual bleeding resistant to medical management.",
"affiliations": "Division of Pediatric and Adolescent Gynecology, Department of Obstetrics & Gynecology, Baylor College of Medicine, Houston, Texas.",
"authors": "Stanley|Jennifer|J|;Adeyemi-Fowode|Oluyemisi|O|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/AOG.0000000000003330",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0029-7844",
"issue": "134(1)",
"journal": "Obstetrics and gynecology",
"keywords": null,
"medline_ta": "Obstet Gynecol",
"mesh_terms": "D001791:Blood Platelet Disorders; D002648:Child; D005260:Female; D006801:Humans; D008595:Menorrhagia; D014546:Urinary Catheterization; D058738:Uterine Balloon Tamponade",
"nlm_unique_id": "0401101",
"other_id": null,
"pages": "77-80",
"pmc": null,
"pmid": "31188323",
"pubdate": "2019-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intrauterine Foley Balloon Catheter to Manage Acute Heavy Menstrual Bleeding in a Perimenarchal 10-Year-Old Girl.",
"title_normalized": "intrauterine foley balloon catheter to manage acute heavy menstrual bleeding in a perimenarchal 10 year old girl"
} | [
{
"companynumb": "US-BAYER-2019-158589",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVONORGESTREL"
},
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"drugdosageform": "INTRAUTERINE DELIVERY SYSTEM",
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"medicinalproduct": "MIRENA"
},
{
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"activesubstancename": "LEVONORGESTREL"
},
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{
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},
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"drugdosagetext": "20 MCG/24HR, CONT",
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{
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"activesubstancename": "NORETHINDRONE ACETATE"
},
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"drugdosagetext": "15 MG",
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}
],
"patientagegroup": "3",
"patientonsetage": "10",
"patientonsetageunit": "801",
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"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Device expulsion",
"reactionmeddraversionpt": "22.0",
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}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2019"
}
},
"primarysource": {
"literaturereference": "STANLEY J, ADEYEMI-FOWODE O. INTRAUTERINE FOLEY BALLOON CATHETER TO MANAGE ACUTE HEAVY MENSTRUAL BLEEDING IN A PERIMENARCHAL 10-YEAR-OLD GIRL. OBSTETRICS AND GYNECOLOGY. 2019?134:1:(77-80)",
"literaturereference_normalized": "intrauterine foley balloon catheter to manage acute heavy menstrual bleeding in a perimenarchal 10 year old girl",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190906",
"receivedate": "20190906",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16780946,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20191005"
}
] |
{
"abstract": "BACKGROUND\nWe report a case of acute rejection of a liver graft, together with the occurrence of de novo donor-specific antibodies (DSAs), in a 53-year-old Japanese man who had undergone deceased-donor liver transplantation.\n\n\nMETHODS\nThe graft rejection was triggered by low cyclosporine levels and pegylated interferon treatment for the recurrence of hepatitis C virus (HCV) infection 18 months after transplantation. Although the graft was ABO-compatible, pre-formed DSA B51 was detected; therefore, total plasma exchange was performed and intravenous rituximab (500 mg/body) was administered before transplantation.\n\n\nRESULTS\nDSA was absent 6 months after transplantation. HCV recurrence was treated with pegylated interferon-α-2a. Renal function deteriorated with this anti-HCV therapy, with serum cyclosporine levels decreasing to 50 ng/mL. A rapid virologic response was achieved, but liver function deteriorated after 3 months of anti-HCV therapy, with histologic evidence of acute cellular rejection and formation of de novo DSAs. Anti-thymocyte globulin was administered for 5 days, which led to immediate improvement in liver function. However, renal function declined, warranting hemodialysis. The patient recovered 2 months after acute rejection, although de novo DSAs persisted.\n\n\nCONCLUSIONS\nCareful immunologic monitoring may be required for patients receiving interferon therapy for HCV infection to maintain sufficient blood levels of immunosuppressive agents and to prevent acute liver graft rejection.",
"affiliations": "Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan. Electronic address: mohira@hiroshima-u.ac.jp.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Pathology, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterology and Metabolism, Applied Life Science, Institute of Biomedical and Health Science, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan.",
"authors": "Nakano|R|R|;Ohira|M|M|;Ishiyama|K|K|;Ide|K|K|;Kobayashi|T|T|;Tahara|H|H|;Shimizu|S|S|;Arihiro|K|K|;Imamura|M|M|;Chayama|K|K|;Tanaka|Y|Y|;Ohdan|H|H|",
"chemical_list": "D000906:Antibodies; D000961:Antilymphocyte Serum; D000998:Antiviral Agents; D003524:Cyclosporins; D007166:Immunosuppressive Agents; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols; C100416:peginterferon alfa-2a",
"country": "United States",
"delete": false,
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"mesh_terms": "D000906:Antibodies; D000918:Antibody Specificity; D000961:Antilymphocyte Serum; D000998:Antiviral Agents; D003524:Cyclosporins; D006084:Graft Rejection; D016174:Hepacivirus; D019698:Hepatitis C, Chronic; D006801:Humans; D007166:Immunosuppressive Agents; D016898:Interferon-alpha; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D015166:Monitoring, Immunologic; D010956:Plasmapheresis; D011092:Polyethylene Glycols; D011183:Postoperative Complications; D011994:Recombinant Proteins; D012008:Recurrence; D014019:Tissue Donors",
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"title": "Acute Graft Rejection and Formation of De Novo Donor-Specific Antibodies Triggered by Low Cyclosporine Levels and Interferon Therapy for Recurrent Hepatitis C Infection After Liver Transplantation: A Case Report.",
"title_normalized": "acute graft rejection and formation of de novo donor specific antibodies triggered by low cyclosporine levels and interferon therapy for recurrent hepatitis c infection after liver transplantation a case report"
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{
"abstract": "Severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) preferentially affects epithelia of the upper and lower respiratory tract. Thus, impairment of kidney function has been primarily attributed until now to secondary effects such as cytokine release or fluid balance disturbances. We provide evidence that SARS-CoV-2 can directly infiltrate a kidney allograft. A 69-year-old male, who underwent pancreas-kidney transplantation 13 years previously, presented to our hospital with coronavirus disease 2019 (COVID-19) pneumonia and impaired pancreas and kidney allograft function. Kidney biopsy was performed showing tubular damage and an interstitial mononuclear cell infiltrate. Reverse transcriptase polymerase chain reaction from the biopsy specimen was positive for SARS-CoV-2. In-situ hybridization revealed SARS-CoV-2 RNA in tubular cells and the interstitium. Subsequently, he had 2 convulsive seizures. Magnetic resonance tomography suggested meningoencephalitis, which was confirmed by SARS-CoV-2 RNA transcripts in the cerebrospinal fluid. The patient had COVID-19 pneumonia, meningoencephalitis, and nephritis. SARS-CoV-2 binds to its target cells through angiotensin-converting enzyme 2, which is expressed in a broad variety of tissues including the lung, brain, and kidney. SARS-CoV-2 thereby shares features with other human coronaviruses including SARS-CoV that were identified as pathogens beyond the respiratory tract as well. The present case should provide awareness that extrapulmonary symptoms in COVID-19 may be attributable to viral infiltration of diverse organs.",
"affiliations": "Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University Bochum, Bochum, Germany.;Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University Bochum, Bochum, Germany.;Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University Bochum, Bochum, Germany.;Center for Translational Medicine, University Hospital Marien Hospital Herne, Ruhr-University Bochum, Bochum, Germany.;Center for Translational Medicine, University Hospital Marien Hospital Herne, Ruhr-University Bochum, Bochum, Germany.;Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University Bochum, Bochum, Germany.;Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University Bochum, Bochum, Germany.;Institute of Radiology, University Hospital Marien Hospital Herne, Ruhr-University Bochum, Bochum, Germany.;Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen, Germany.;Department of Surgery, University Hospital Knappschaftskrankenhaus Bochum, Ruhr-University Bochum, Bochum, Germany.;Department of Nephropathology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany.;Department of Nephropathology, Friedrich-Alexander University (FAU) Erlangen-Nürnberg, Erlangen, Germany.;Department of Surgery, University Hospital Knappschaftskrankenhaus Bochum, Ruhr-University Bochum, Bochum, Germany.;Medical Department I, University Hospital Marien Hospital Herne, Ruhr-University Bochum, Bochum, Germany.",
"authors": "Westhoff|Timm H|TH|0000-0001-5797-834X;Seibert|Felix S|FS|;Bauer|Frederic|F|;Stervbo|Ulrik|U|0000-0002-2831-8868;Anft|Moritz|M|;Doevelaar|Adrian A N|AAN|;Rohn|Benjamin J|BJ|;Winnekendonk|Guido|G|;Dittmer|Ulf|U|;Schenker|Peter|P|;Vonbrunn|Eva|E|;Amann|Kerstin|K|;Viebahn|Richard|R|;Babel|Nina|N|0000-0003-3673-712X",
"chemical_list": "D012367:RNA, Viral",
"country": "United States",
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"issue": "20(11)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": null,
"medline_ta": "Am J Transplant",
"mesh_terms": "D000368:Aged; D000086382:COVID-19; D015897:Comorbidity; D006801:Humans; D016030:Kidney Transplantation; D008297:Male; D008590:Meningoencephalitis; D016035:Pancreas Transplantation; D058873:Pandemics; D011183:Postoperative Complications; D012367:RNA, Viral; D000086402:SARS-CoV-2; D066027:Transplant Recipients; D014184:Transplantation, Homologous",
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"pages": "3216-3220",
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"pmid": "32713123",
"pubdate": "2020-11",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Allograft infiltration and meningoencephalitis by SARS-CoV-2 in a pancreas-kidney transplant recipient.",
"title_normalized": "allograft infiltration and meningoencephalitis by sars cov 2 in a pancreas kidney transplant recipient"
} | [
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{
"abstract": "A patient on treatment for multibacillary leprosy for the past three years, presented with episodes of abdominal pain. Since the patient improved with conservative management, clofazimine induced enteropathy was considered as a remote possibility. A review of the mucosal biopsies showed macrophages with crystal-storing spaces consistent with clofazimine deposition in the duodenum. This case highlights the need to consider and investigate drug-induced disease as part of the differential diagnosis.",
"affiliations": "Department of Pharmacology and Clinical Pharmacology, Christian Medical College Hospital, Vellore 632004, Tamil Nadu, India. clinpharm@cmcvellore.ac.in",
"authors": "Mathew|Binu S|BS|;Pulimood|Anna B|AB|;Prasanna|C G|CG|;Ramakrishna|B S|BS|;Chandy|Sujith J|SJ|",
"chemical_list": "D007917:Leprostatic Agents; D002991:Clofazimine",
"country": "India",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-636X",
"issue": "27(2)",
"journal": "Tropical gastroenterology : official journal of the Digestive Diseases Foundation",
"keywords": null,
"medline_ta": "Trop Gastroenterol",
"mesh_terms": "D002991:Clofazimine; D004378:Duodenal Diseases; D005757:Gastritis, Atrophic; D006801:Humans; D007917:Leprostatic Agents; D015440:Leprosy, Lepromatous; D008297:Male; D008875:Middle Aged",
"nlm_unique_id": "8107122",
"other_id": null,
"pages": "87-8",
"pmc": null,
"pmid": "17089619",
"pubdate": "2006",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Clofazimine induced enteropathy--a case highlighting the importance of drug induced disease in differential diagnosis.",
"title_normalized": "clofazimine induced enteropathy a case highlighting the importance of drug induced disease in differential diagnosis"
} | [
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"companynumb": "PHBS2007IN12373",
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{
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{
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},
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},
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},
{
"reactionmeddrapt": "Decreased appetite",
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"reactionmeddrapt": "Computerised tomogram abnormal",
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{
"reactionmeddrapt": "Oedema mucosal",
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}
],
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}
},
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] |
{
"abstract": "Pain management at home for a patient, suffering from one or more advanced progressive diseases, goes beyond the prescription of an opioid. Apart from the importance of finding the most suitable analgesic drug (controlled pain with least possible adverse effects), three important dimensions will be addressed: interprofessionnal care (shared care goals, evaluation, monitoring of pain and other symptoms; physiotherapy, etc.) information, education and support for patients and relatives in particular on the use of opioids, and finally the importance of anticipation. This includes for example the requirement of breakthrough pain treatment in case of pain exacerbation or the definition of the place of hospitalization in case of worsening general condition or of death.",
"affiliations": "Service de médecine de premier recours, Hôpitaux Universitaires de Genève.",
"authors": "Pautex|Sophie|S|",
"chemical_list": "D000700:Analgesics; D000701:Analgesics, Opioid",
"country": "Switzerland",
"delete": false,
"doi": "10.1024/1661-8157/a001950",
"fulltext": null,
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"issn_linking": "1661-8157",
"issue": "104(5)",
"journal": "Praxis",
"keywords": "Analgetika; Opioidverabreichung und Dosierung; Palliativpflege; Pflege zuhause; Schmerztherapie; administration et dosage des opioïdes; analgesics; approche pharmacologique de la douleur; home care; opioid/administration and dosage; pain/drug therapy; palliative care; soins palliatifs; soins à domicile",
"medline_ta": "Praxis (Bern 1994)",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000698:Analgesia; D000700:Analgesics; D000701:Analgesics, Opioid; D002637:Chest Pain; D003131:Combined Modality Therapy; D004359:Drug Therapy, Combination; D018575:Home Care Services, Hospital-Based; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D010147:Pain Measurement; D010166:Palliative Care",
"nlm_unique_id": "101468093",
"other_id": null,
"pages": "229-32",
"pmc": null,
"pmid": "25711785",
"pubdate": "2015-02-25",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Specifics of Analgesia in Palliative Care Patients at Home.",
"title_normalized": "specifics of analgesia in palliative care patients at home"
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"medicinalproduct": "TRAMADOL."
}
],
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"reactionmeddraversionpt": "19.0",
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},
{
"reactionmeddrapt": "Hallucination, visual",
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},
{
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{
"reactionmeddrapt": "Circadian rhythm sleep disorder",
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],
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},
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"abstract": "Ibrutinib (Imbruvica; Pharmacyclics) is the first Food and Drug Administration-approved inhibitor of Burton's tyrosine kinase (BTK). Attenuation of BTK signaling ultimately leads to inhibition of B-cell proliferation and apoptosis. After a series of clinical trials, the Food and Drug Administration approved ibrutinib in patients with relapsed chronic lymphocytic leukemia in 2014 and Waldenström's macroglobulinemia in 2015. Those trials included rare grade 3+ hemorrhagic events associated with ibrutinib. Herein, we report a unique presentation of back pain due to iliopsoas muscle hemorrhage in a patient with Waldenström's macroglobulinemia after initiation of ibrutinib.",
"affiliations": "Scripps Green Hospital, La Jolla, CA, USA.;Scripps Green Hospital, La Jolla, CA, USA.;Scripps Green Hospital, La Jolla, CA, USA.;Scripps Green Hospital, La Jolla, CA, USA.",
"authors": "Sarcon|Anna|A|;Botta|Gregory P|GP|;Patel|Nikunj|N|;Saven|Alan|A|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961664845710.1177_2324709616648457Case ReportSpontaneous Iliopsoas Muscle Hemorrhage Secondary to Ibrutinib (Imbruvica; Pharmacyclics) Brief ReportSarcon Anna MD1Botta Gregory P. MD, PhD1Patel Nikunj MD1Saven Alan MD11 Scripps Green Hospital, La Jolla, CA, USAAnna Sarcon, MD, Department of Internal Medicine, Scripps Green Hospital, 10666 N Torrey Pines Road, La Jolla, CA 92037, USA. Email: aksarcon@ucdavis.edu09 5 2016 Apr-Jun 2016 4 2 232470961664845723 3 2016 29 3 2016 5 4 2016 © 2016 American Federation for Medical Research2016American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Ibrutinib (Imbruvica; Pharmacyclics) is the first Food and Drug Administration–approved inhibitor of Burton’s tyrosine kinase (BTK). Attenuation of BTK signaling ultimately leads to inhibition of B-cell proliferation and apoptosis. After a series of clinical trials, the Food and Drug Administration approved ibrutinib in patients with relapsed chronic lymphocytic leukemia in 2014 and Waldenström’s macroglobulinemia in 2015. Those trials included rare grade 3+ hemorrhagic events associated with ibrutinib. Herein, we report a unique presentation of back pain due to iliopsoas muscle hemorrhage in a patient with Waldenström’s macroglobulinemia after initiation of ibrutinib.\n\nhemorrhageImbruvicailiopsoas musclecover-dateApril-June 2016\n==== Body\nIntroduction\nIbrutinib (Imbruvica; Pharmacyclics) is the first Food and Drug Administration–approved inhibitor of Burton’s tyrosine kinase (BTK). Attenuation of BTK signaling ultimately leads to inhibition of B-cell proliferation and apoptosis. After a series of clinical trials, the Food and Drug Administration approved ibrutinib in patients with relapsed chronic lymphocytic leukemia in 2014 and Waldenström’s macroglobulinemia in 2015.1,2 Those trials included rare grade 3+ hemorrhagic events associated with ibrutinib.\n\nHerein, we report a unique presentation of back pain due to iliopsoas muscle hemorrhage in a patient with Waldenström’s macroglobulinemia after initiation of ibrutinib.\n\nCase Presentation\nAn 80-year-old male with history of demyelinating polyneuropathy, chronic hyponatremia, and Waldenström’s macroglobulinemia presented to the emergency room with 3-day history of swelling and pain in the right medial thigh region as well as lower back. He was initially diagnosed with Waldenström’s macroglobulinemia 8 years prior, after a bone marrow biopsy was performed in the setting of progressive anemia. Pathology revealed lymphoplasmacytic lymphoma comprising 30% of marrow cellularity, consistent with Waldenström’s macroglobulinemia. Initially, 4 doses of rituximab were prescribed and he received 1 cycle of bendamustine as well as 2 episodes of plasma exchange. Subsequently, he was initiated on 420 mg of ibrutinib 1 year prior to presentation and overall tolerated it well, only suffering a maculopapular rash of the extremities as well as mild lower extremity edema.\n\nThere was no clinical history of him consuming aspirin, nonsteroidal anti-inflammatory drugs, or any coagulation cascade inhibitors. There had been no trauma prior to presentation, and there was no history of spontaneous bleeding. On presentation to the emergency room, lower extremity ultrasound was performed, which was negative for deep vein thrombosis. Laboratory data revealed a hemoglobin of 12 g/dL (reference 13.5-17.0 g/dL), hematocrit of 36.4 (ref. 41-53), and platelet count of 159 k/mcl (ref. 150-450 k/mcl), which were all at baseline. Given the negative workup the patient was discharged home. He subsequently presented to the emergency room, 3 days later, with progressive severe right thigh and back pain. Laboratory data revealed hemoglobin of 9.1 g/dL, hematocrit of 25.8, platelets 171 k/mcl, prothrombin time of 10.3 seconds, and international normalized ratio of 1.0.\n\nComputed tomography of the abdomen and pelvis was obtained, which showed extensive intramuscular hemorrhage within the right iliopsoas musculature, extending from the level of the right renal pelvis into the right inguinal region, as well as a small amount of hemorrhage in the adjacent retroperitoneum (Figure 1). Computed tomography did not reveal any active bleeding however. The patient was admitted to the hospital for further care and stabilization. There was no evidence of femoral nerve compression and surgical intervention was not indicated. Furthermore, serial complete blood counts were obtained and his hemoglobin remained stable. Therefore, he was not transfused with any blood products. He was eventually discharged and ibrutinib was discontinued on diagnosis of iliopsoas hemorrhage. One-month follow-up showed stable hemoglobin, and the patient remains off ibrutinib due to ongoing concern about spontaneous hemorrhage.\n\nFigure 1. Top arrow, abnormal right iliopsoas–intramuscular hemorrhage; Lower arrow, hemorrhage in the retroperitoneum; contralateral, normal left iliopsoas.\n\nDiscussion\nWe presented a case of retroperitoneal hemorrhage approximately 1 year after initiation of ibrutinib.\n\nPresentation of retroperitoneal hemorrhage varies and can be rather nonspecific. Patients can have lower back, groin discomfort, and even hemodynamic instability. Hemorrhage in the iliopsoas muscle often leads to femoral neuropathy causing groin pain or leg weakness. The exact pathophysiology of spontaneous retroperitoneal bleeding is unclear. A retrospective study of 12 patients on anticoagulation with large rectus sheath hematoma revealed that 6 of these patients had a history of coughing fits.3 On the other hand, in patients with hemophilia, often a minor trauma can lead to spontaneous retroperitoneal bleeding.4 Without evidence of hemodynamic instability conservative therapy is recommended. This includes withdrawing the offending agent, correction of coagulopathy, and volume resuscitation.5\n\nCommon complications of ibrutinib have been reported in the literature, which include hemorrhage, infections, myelosuppression, renal toxicity, secondary primary malignancies, and embryo-fetal toxicity.6 Hemorrhage (including ecchymosis of any grade) has been observed in 63% of patients with chronic lymphocytic leukemia, of which 6% of cases included subdural hematoma, gastrointestinal bleeding, and hematuria.1,2 Due to complications associated with increased bleeding risk, withholding ibrutinib is recommended prior and after surgery by the manufacturer, Pharmacyclics.6\n\nThe initial RESONATE trial in 2014 found a significant improvement in progression-free survival when comparing ibrutinib to the anti-CD20 antibody ofatumumab at 9.4 months (end point not reached with ibrutinib vs 9.1 months with ofatumumab, respectively).7 Bleeding events (including petechiae and minor ecchymoses) were more common with ibrutinib compared with ofatumumab (44% vs 12%) while grade 3 or higher hemorrhage was reported in 2 patients taking ibrutinib (1%, one with a subdural hematoma) and 3 patients in the ofatumumab group (2%). The RESONATE-2 clinical trial found significant improvement in progression-free survival in the ibrutinib group versus standard of care (end point not reached with ibrutinib vs 18.9 months with chlorambucil). Specifically, 4 patients in the ibrutinib group had a grade 3 hemorrhage and one with grade 4 hemorrhage.8 Specifically, ibrutinib in Waldenström’s macroglobulinemia had a significant 100% overall response and 91.2% major response rate in MYD88L265PCXCRWT patients.9 This study found grade 2 epistaxis-related bleeding in 2 patients (3% of study population). Furthermore, 2 other patients (3% of study population) had unspecified postprocedural bleeding that was attenuated with cessation of fish oil supplements.9\n\nTo our knowledge, no cases of retroperitoneal bleeding in patients with Waldenström’s macroglobulinemia treated with ibrutinib have been reported in the literature thus far. Clearly, risks and benefits of treatment initiation should be considered closely in patients.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1 \nUS Food and Drug Administration . FDA approves Imbruvica to treat chronic lymphocytic leukemia. Press release . http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm385764.htm. Published 2 \n12 , 2014 \nAccessed April 22, 2016 .\n2 \nUS Food and Drug Administration . FDA expands approved use of Imbruvica for rare form of non-Hodgkin lymphoma . Press release. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm432123.htm. 1 \n29 , 2015 \nAccessed April 22, 2016 .\n3 \nBerná JD Zuazu I Madrigal M García-Medina V Fernández C Guirado F. \nConservative treatment of large rectus sheath hematoma in patients undergoing anticoagulant therapy . Abdom Imaging . 2000 ;25 :230 -234 .10823439 \n4 \nYlmaz S Oren H Irken G \nLife-threatening mediastinal-retroperitoneal hemorrhage in a child with moderate hemophilia A and high inhibitor titer: successful management with recombinant activated factor VII . J Pediatr Hematol Oncol . 2005 ;27 :400 -402 .16012333 \n5 \nSharafuddin MJ Andresen KJ Sun S Lang E Stecker MS Wibbenmeyer LA. \nSpontaneous extraperitoneal hemorrhage with hemodynamic collapse in patients undergoing anticoagulation: management with selective arterial embolization . J Vasc Interv Radiol . 2001 ;12 :1231 -1234 .11585893 \n6 \nImbruvica (ibrutinib) capsules [Prescribing information]. \nSunnyvale, CA : Pharmacyclics ; 2 \n2014 .\n7 \nByrd JC Brown JR O’Brien S \nIbrutinib versus ofatumumab in previously treated chronic lymphoid leukemia . N Engl J Med . 2014 ;371 :213 -223 .24881631 \n8 \nBurger JA Tedeschi A Barr PM \nIbrutinib as initial therapy for patients with chronic lymphocytic leukemia . N Engl J Med . 2015 ;373 :2425 -2437 .26639149 \n9 \nTreon SP Tripsas MA Meid K \nIbrutinib in previously treated Waldenström’s macroglobulinemia . N Engl J Med . 2015 ;372 :1430 -1440 .25853747\n\n",
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"title": "Establishment of a Seronegative Occult Infection With an Active Hepatitis B Virus Reservoir Enriched of Vaccine Escape Mutations in a Vaccinated Infant After Liver Transplantation.",
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"medicinalproduct": "TACROLIMUS."
}
],
"patientagegroup": null,
"patientonsetage": "2",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hepatitis B",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Intestinal obstruction",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2013"
}
},
"primarysource": {
"literaturereference": "SALPINI R, PIETROBATTISTA A, PIERMATTEO L, BASSO MS, BELLOCCHI MC, LICCARDO D ET AL. ESTABLISHMENT OF A SERONEGATIVE OCCULT INFECTION WITH AN ACTIVE HEPATITIS B VIRUS RESERVOIR ENRICHED OF VACCINE ESCAPE MUTATIONS IN A VACCINATED INFANT AFTER LIVER TRANSPLANTATION. THE JOURNAL OF INFECTIOUS DISEASES. 2019?220(12):1935-9",
"literaturereference_normalized": "establishment of a seronegative occult infection with an active hepatitis b virus reservoir enriched of vaccine escape mutations in a vaccinated infant after liver transplantation",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20200103",
"receivedate": "20200103",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17227120,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200409"
}
] |
{
"abstract": "Bosentan is an endothelin receptor antagonist approved for treatment of pulmonary arterial hypertension. Mild liver reactions occur in about 10% of treated patients but severe hepatotoxicity is rare. We present clinical data and treatment outcome of a severe drug induced liver injury due to bosentan in a patient with non-cirrhotic portopulmonary hypertension. After 18 months of uncomplicated therapy with bosentan 125 mg b.i.d., the patient developed a severe mixed hepatic injury. Serum levels of bilirubin were 316 µmol/l (ref. value <20 micromol/l), AST 14 µkat/l (ref. value < 0.9 µkat/l), ALT 10 µkat/l (ref. value < 0.9 µkat/l), ALP 8 µkat/l (ref. value <1.8 µkat/l) and INR 1.8 (ref. value 0.9-1.1). Complete diagnostic work-up disclosed no other cause of hepatotoxicity. Treatment with prednisolone 40 mg/day in tapering doses was ultimately added and the patient made a full recovery. Subsequent treatment with sildenafil and ambrisentan for pulmonary arterial hypertension was well tolerated and liver function tests have remained normal during 12 months' follow-up. A review of the literature revealed three other women with severe hepatotoxicity due to bosentan. Bosentan may cause severe liver injury, even after long uneventful therapy, and current recommendations on regular monitoring of liver function tests are reinforced. Ambrisentan may be a therapeutic alternative in patients with pulmonary arterial hypertension and hepatotoxicity by bosentan.",
"affiliations": "Department of Medicine, Division of Gastroenterology, Örebro University Hospital, Örebro, Sweden.",
"authors": "Eriksson|Carl|C|;Gustavsson|Anders|A|;Kronvall|Thomas|T|;Tysk|Curt|C|",
"chemical_list": "D000959:Antihypertensive Agents; D013449:Sulfonamides; D000077300:Bosentan",
"country": "Romania",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1841-8724",
"issue": "20(1)",
"journal": "Journal of gastrointestinal and liver diseases : JGLD",
"keywords": null,
"medline_ta": "J Gastrointestin Liver Dis",
"mesh_terms": "D000328:Adult; D000959:Antihypertensive Agents; D000077300:Bosentan; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D006975:Hypertension, Portal; D006976:Hypertension, Pulmonary; D013449:Sulfonamides",
"nlm_unique_id": "101272825",
"other_id": null,
"pages": "77-80",
"pmc": null,
"pmid": "21451802",
"pubdate": "2011-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Hepatotoxicity by bosentan in a patient with portopulmonary hypertension: a case-report and review of the literature.",
"title_normalized": "hepatotoxicity by bosentan in a patient with portopulmonary hypertension a case report and review of the literature"
} | [
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"reaction": [
{
"reactionmeddrapt": "Blood alkaline phosphatase increased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug-induced liver injury",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatic failure",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Autoimmune hepatitis",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood bilirubin increased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Jaundice",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Malaise",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "General physical health deterioration",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "International normalised ratio increased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Transaminases increased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Aspartate aminotransferase increased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Mixed liver injury",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Alanine aminotransferase increased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Decreased appetite",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Weight decreased",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20081009"
}
},
"primarysource": {
"literaturereference": "ERIKSSON C, GUSTAVSSON A, KRONVALL T, TYSK C. HEPATOTOXICITY BY BOSENTAN IN A PATIENT WITH PORTOPULMONARY HYPERTENSION: A CASE - REPORT AND REVIEW OF THE LITERATURE. J GASTROINTESTIN LIVER DIS. 2011?20(1):77-80",
"literaturereference_normalized": "hepatotoxicity by bosentan in a patient with portopulmonary hypertension a case report and review of the literature",
"qualification": "3",
"reportercountry": "SE"
},
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"receiptdate": "20191211",
"receivedate": "20081028",
"receiver": {
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"receivertype": "6"
},
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"safetyreportversion": 8,
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200122"
}
] |
{
"abstract": "Major histocompatibility complex class II (MHCII) deficiency is a rare autosomal recessive immunodeficiency disorder characterized by lack of expression of MHCII molecules, causing defective CD4 lymphocyte function and an impaired immune response. Clinical manifestations include susceptibility to severe bacterial, viral, and fungal infections which can lead to failure to thrive and childhood death. The only definitive treatment to date is allogeneic stem cell transplantation. Here, we share our experience of 2 patients who presented with MHCII deficiency. We will discuss the role of diagnostic modalities and stem cell transplantation.",
"affiliations": "Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA.",
"authors": "Kallen|Michael E|ME|;Pullarkat|Sheeja T|ST|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/MPH.0000000000000278",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1077-4114",
"issue": "37(4)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D016516:CD4-CD8 Ratio; D005434:Flow Cytometry; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007223:Infant; D008297:Male; D016511:Severe Combined Immunodeficiency",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e245-9",
"pmc": null,
"pmid": "25354255",
"pubdate": "2015-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Type II bare lymphocyte syndrome: role of peripheral blood flow cytometry and utility of stem cell transplant in treatment.",
"title_normalized": "type ii bare lymphocyte syndrome role of peripheral blood flow cytometry and utility of stem cell transplant in treatment"
} | [
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"companynumb": "US-MYLANLABS-2016M1014487",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tachycardia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cystitis haemorrhagic",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Malaise",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pruritus",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KALLEN ME, PULLARKAT ST. TYPE II BARE LYMPHOCYTE SYNDROME: ROLE OF PERIPHERAL BLOOD FLOW CYTOMETRY AND UTILITY OF STEM CELL TRANSPLANT IN TREATMENT. J-PEDIATR-HEMATOL-ONCOL 2015;37(4):E245-E249.",
"literaturereference_normalized": "type ii bare lymphocyte syndrome role of peripheral blood flow cytometry and utility of stem cell transplant in treatment",
"qualification": "1",
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20160815"
},
{
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"literaturereference": "Kallen, M.. Type II Bare Lymphocyte Syndrome: Role of Peripheral Blood Flow Cytometry and Utility of Stem Cell Transplant in Treatment. Journal of Pediatric Hematology/Oncology. 2015;37 (4):e245-e249",
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{
"abstract": "BACKGROUND\nThe aim of this paper is to underline the need of a systematic monitoring (1) of atypical antipsychotics and (2) of catatonic symptoms in child psychiatry. We present in this paper the clinical history of a 16-year-old adolescent inpatient needing a prescription of atypical antipsychotic drug. We present the most relevant results of our clinical monitoring over 7 months.\n\n\nMETHODS\nA 16-year-old Caucasian male adolescent, by the name of Paul, was admitted in August 2009 to an Adolescent University Psychiatry Unit for an acute psychotic disorder. On admission, he presented paranoid delusion, auditory hallucinations and impulsive movements. The score on the Bush-Francis Catatonia Rating Scale (BFCRS) was 17 (the threshold score for the diagnosis of catatonic symptoms is 2). Laboratory tests showed the lack of blood toxic levels, creatine phosphokinase (CPK) level was 684 IU/L. Paul was treated with clonazepam (0.05 mg/kg/d). This particular day was considered to be day #1 of the clinical drug monitoring. Immediately after, regular follow-up of catatonic symptoms was performed. On day #15, the CPK level returned to normal with improvement of clinical catatonia but with still a score of 4 on the BFCRS scale. Auditory hallucinations and delusion persisted. Risperidone treatment was begun (1mg/d and 1.5mg/d after 24 hours), associated with oral clonazepam (0.05 mg/kg/d). On day #17, after 48 hours of improvement of delusion, the catatonic symptoms rapidly worsened. Risperidone was stopped; Paul was transferred to intensive care where he was treated with clonazepam IV (0.1mg/kg/d). The score on BFCRS scale was 20, Paul presented no fever and the CPK level was below 170 IU/L. The diagnosis was a relapse of the catatonic episode, which was caused by the administration of risperidone. On day #24, no improvement in the state of catatonia was obtained. The treatment was changed with the following combination of medicine: clonazepam (0.1mg/kg/d)-lorazepam (5mg/d)-carbamazepine (10mg/kg/d). With this combination, the state of catatonia improved quickly and on day #31, he was transferred to the adolescent psychiatry unit. However, delusion and hallucinations persisted; a treatment with olanzapine was started at 5mg/d and then progressively increased to 20mg/d for 10 days. On day #115, after 3 months with olanzapine, no improvement of the hallucinatory and delusional symptoms was observed; the diagnosis of early-onset refractory schizophrenia was established. The Therapeutic Drug Monitoring (TDM) confirmed the good compliance; clozapine was introduced and progressively increased up to 250 mg/d. On day #199, after 3 months under clozapine (250 mg/d), the speech was coherent and delusion was rare. During this period, no relapse of the catatonic state was observed.\n\n\nCONCLUSIONS\nIn this case, the BFCRS scale was sensitive to catatonic symptom diagnosis. CPK levels vary differently for each atypical antipsychotic and are not a specific complication indicator. In complex cases, the TDM seems useful when choosing atypical antipsychotics.\n\n\nCONCLUSIONS\nThe association of two benzodiazepines (clonazepam-lorazepam) with carbamazepin allowed the improvement of catatonic symptoms. Plasma levels of atypical antipsychotics helped the practitioner in deciding the type of care required: plasma levels confirmed the patient's treatment adherence and thus reinforced the choice of clozapine.",
"affiliations": "Service universitaire de psychiatrie de l'enfant et de l'adolescent, hôpitaux pédiatriques de Nice, CHU Lenval, 57, avenue de la Californie, 06200 Nice, France. ml.menard@hotmail.fr",
"authors": "Menard|M-L|ML|;Yagoubi|F|F|;Drici|M|M|;Lavrut|T|T|;Askenazy|F|F|",
"chemical_list": "D001569:Benzodiazepines; D002220:Carbamazepine; D002998:Clonazepam; D003402:Creatine Kinase; D003024:Clozapine; D018967:Risperidone; D000077152:Olanzapine; D008140:Lorazepam",
"country": "France",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-7006",
"issue": "39 Suppl 1()",
"journal": "L'Encephale",
"keywords": null,
"medline_ta": "Encephale",
"mesh_terms": "D000293:Adolescent; D001569:Benzodiazepines; D002220:Carbamazepine; D002998:Clonazepam; D003024:Clozapine; D003402:Creatine Kinase; D003937:Diagnosis, Differential; D004351:Drug Resistance; D057915:Drug Substitution; D004359:Drug Therapy, Combination; D006801:Humans; D008140:Lorazepam; D008297:Male; D000077152:Olanzapine; D010343:Patient Admission; D011569:Psychiatric Status Rating Scales; D011594:Psychometrics; D012008:Recurrence; D018967:Risperidone; D012560:Schizophrenia, Catatonic",
"nlm_unique_id": "7505643",
"other_id": null,
"pages": "S29-35",
"pmc": null,
"pmid": "23219595",
"pubdate": "2013-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Follow-up of a 16-year-old adolescent with early-onset schizophrenia and catatonic symptoms.",
"title_normalized": "follow up of a 16 year old adolescent with early onset schizophrenia and catatonic symptoms"
} | [
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},
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Sedation",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Parkinsonism",
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},
{
"reactionmeddrapt": "Fatigue",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Weight increased",
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "MENARD ML, YAGOUBI F, DRICI M, LAVRUT T, ASKENAZY F. [FOLLOW-UP OF A 16-YEAR-OLD ADOLESCENT WITH EARLY-ONSET SCHIZOPHRENIA AND CATATONIC SYMPTOMS]. ENCEPHALE. 2013;SUPPL 1:S29-35. FRENCH",
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"qualification": "3",
"reportercountry": "FR"
},
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"receiptdate": "20140411",
"receivedate": "20140411",
"receiver": {
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150720"
}
] |
{
"abstract": "This study shows clinical efficacy and safety profile of an off-label use of caplacizumab for the treatment of immune-mediated thrombotic thrombocytopenic purpura in a middle-aged obese male patient manifesting aphasia, weakness and unconsciousness. Routine blood tests revealed haemolytic anaemia, severe thrombocytopenia (platelet count=20×109/L) and moderate creatinine increase. Diagnosis was based on the clinical judgement and laboratory determinations (undetectable ADAMTS13 activity and presence of anti-ADAMTS13 antibodies). The patient underwent plasma-exchange and an adjunctive treatment with prednisone (1mg/Kg/day), but the occurrence of a refractory and exacerbated form of disease suggested also using rituximab (375mg/m2 weekly for 4 weeks) and caplacizumab as salvage treatments. The caplacizumab was given at 10mg/day subcutaneously without the first intravenous bolus. Because von Willebrand factor inhibition, platelet count recovery and remission of symptoms were achieved, use of caplacizumab with this scheme appeared to be as effective as the approved one. Although this is an off-label use, this case highlights the potential of this new treatment, in terms of drug's efficacy and safety.",
"affiliations": "Transfusion Medicine, Azienda Ospedaliero Universitaria Consorziale Policlinico, Bari, Italy.;Thrombosis and Haemostasis Unit, Fondazione IRCCS \"Casa Sollievo della Sofferenza\", San Giovanni Rotondo (Foggia), Italy.;Transfusion Medicine, Azienda Ospedaliero Universitaria Consorziale Policlinico, Bari, Italy.;Thrombosis and Haemostasis Unit, Fondazione IRCCS \"Casa Sollievo della Sofferenza\", San Giovanni Rotondo (Foggia), Italy.;Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari \"Aldo Moro\", Bari, Italy.;Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari \"Aldo Moro\", Bari, Italy.;Thrombosis and Haemostasis Unit, Fondazione IRCCS \"Casa Sollievo della Sofferenza\", San Giovanni Rotondo (Foggia), Italy.;Thrombosis and Haemostasis Unit, Fondazione IRCCS \"Casa Sollievo della Sofferenza\", San Giovanni Rotondo (Foggia), Italy.;Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari \"Aldo Moro\", Bari, Italy.;Thrombosis and Haemostasis Unit, Fondazione IRCCS \"Casa Sollievo della Sofferenza\", San Giovanni Rotondo (Foggia), Italy; Ob/Gyn Department of the First I.M. Sechenov Moscow State Medical University, Moscow, Russian Federation. Electronic address: e.grandone@operapadrepio.it.",
"authors": "Ostuni|A|A|;Tiscia|G|G|;Battista|C|C|;Favuzzi|G|G|;Montinaro|V|V|;Pronzo|V|V|;Cappucci|F|F|;Fischetti|L|L|;Gesualdo|L|L|;Grandone|E|E|",
"chemical_list": "D061905:Single-Domain Antibodies; C585343:caplacizumab; D000071120:ADAMTS13 Protein",
"country": "France",
"delete": false,
"doi": "10.1016/j.tracli.2020.11.003",
"fulltext": null,
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"issn_linking": "1246-7820",
"issue": "28(1)",
"journal": "Transfusion clinique et biologique : journal de la Societe francaise de transfusion sanguine",
"keywords": "ADAMTS13; Caplacizumab; Outcome; Purpura thrombotique thrombocytopénique; Résultat; Thrombotic thrombocytopenic purpura",
"medline_ta": "Transfus Clin Biol",
"mesh_terms": "D000071120:ADAMTS13 Protein; D006801:Humans; D008297:Male; D008875:Middle Aged; D009765:Obesity; D056687:Off-Label Use; D010951:Plasma Exchange; D011697:Purpura, Thrombotic Thrombocytopenic; D061905:Single-Domain Antibodies",
"nlm_unique_id": "9423846",
"other_id": null,
"pages": "89-91",
"pmc": null,
"pmid": "33285299",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Effective and safe off-label use of caplacizumab treatment in a middle-aged obese male.",
"title_normalized": "effective and safe off label use of caplacizumab treatment in a middle aged obese male"
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"literaturereference": "OSTUNI A, TISCIA G, BATTISTA C, FAVUZZI G, MONTINARO V, PRONZO V, CAPPUCCI F, FISCHETTI L, GESUALDO L, GRANDONE E. EFFECTIVE AND SAFE OFF-LABEL USE OF CAPLACIZUMAB TREATMENT IN A MIDDLE-AGED OBESE MALE. TRANSFUS CLIN BIOL. 2020 DEC 4:S1246-7820(20)30162-2. DOI: 10.1016/J.TRACLI.2020.11.003. EPUB AHEAD OF PRINT. PMID: 33285299.",
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{
"abstract": "Testicular cancer is a type of malignancy that affects young adults and has high rates of cure; however, as any malignancy, it is associated with an increased risk of ischemic or hemorrhagic cerebrovascular disease, given the systemic tumor effects or side effects of chemotherapy, which in turn increases morbidity, functional impairment, and additional risk of early death.",
"affiliations": "Department of Neurology, Carlos Andrade Marin Hospital, San Francisco of Quito University, Quito, Ecuador.;Department of Neurology, Carlos Andrade Marin Hospital, San Francisco of Quito University, Quito, Ecuador.",
"authors": "Martinez|Braulio Alexander|BA|;Correa|Edgar Patricio|EP|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case RepJ Investig Med High Impact Case RepHICsphicJournal of Investigative Medicine High Impact Case Reports2324-7096SAGE Publications Sage CA: Los Angeles, CA 10.1177/232470961559019810.1177_2324709615590198ArticleUnusually Located Stroke After Chemotherapy in Testicular Germ Cell Tumors Martinez Braulio Alexander MD1Correa Edgar Patricio MD11 Department of Neurology, Carlos Andrade Marin Hospital, San Francisco of Quito University, Quito, EcuadorEdgar Patricio Correa, Carlos Andrade Marin Hospital, COOP IESS-FUT Oe5425, Quito 170601, Ecuador. Email: patocorrea2010@yahoo.com9 6 2015 Apr-Jun 2015 3 2 2324709615590198© 2015 American Federation for Medical Research2015American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution 3.0 License (http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page (http://www.uk.sagepub.com/aboutus/openaccess.htm).Testicular cancer is a type of malignancy that affects young adults and has high rates of cure; however, as any malignancy, it is associated with an increased risk of ischemic or hemorrhagic cerebrovascular disease, given the systemic tumor effects or side effects of chemotherapy, which in turn increases morbidity, functional impairment, and additional risk of early death.\n\ntesticular cancerischemic strokechemotherapycisplatincover-dateApril-June 2015\n==== Body\nIntroduction\nPatients with systemic cancer have a high risk of suffering arterial or venous thromboembolic events (TEEs), which include deep-vein thrombosis, pulmonary embolus, stroke, and unstable angina/myocardial infarction (MI). The arterial TEEs are less frequent. Studies have shown that the annual incidence of venous thromboembolism in the general population is 117 per 100 000 males per year; however, in cancer patients, it is increased to 1 event in 200 males per year.1,2\n\nUp to 90% of cancer patients suffer hemostatic alterations, represented by an increased platelet aggregation, increased activity of procoagulant factors, decreased activity of anticoagulant factors, and increased levels of fibrinogen, which induce a state of hypercoagulability,3-6 increasing the risk of ischemic stroke (IS). Nonetheless, there are other influencing mechanisms, such as tumor vascular compression or infiltration and toxic side effects of radiotherapy or chemotherapy (CHT).6 A cohort study demonstrated that cancer itself is associated with a higher risk of TEEs (relative risk = 4.1); this risk rises 6.5 times when CHT is added.7\n\nThe association between anticancer CHT and thromboembolic phenomena was first reported among patients with breast cancer. Since then, similar events have been reported with a variety of anticancer agents.5 The associated drugs include cyclophosphamide, methotrexate, 5-fluoracil, and tamoxifen. Association with cisplatin and bleomicin has also been described. These last 2 drugs produce vascular toxicity as a collateral effect.3,5,6,8,9 The TEEs can result in higher morbidity rates, impaired quality of life, and, in some cases, may put the patient’s life at risk.5\n\nGerm cell tumors (GCT) are relatively infrequent. They represent 1% of malignancies in the United States. CHT cures 90% of the patients and increases the survival rate in up to 80% of the cases, but this can be affected by vascular complications.5,8,10-12\n\nTesticular GCTs are the most common solid tumors in men between ages 15 to 35.11-14 Randomized studies have shown that PEB-based CHT (cisplatin, etoposide, and bleomicin) is the key to the treatment. However, cisplatin is related to arterial TEEs,8,10,11,13,15-18 which include thrombotic microangiopathy, MI, and stroke.19-22 This risk is increased in patients who have hepatic metastasis or who receive high doses of steroids.23\n\nMany reports have been written about ischemic or hemorrhagic stroke that occurred several days after cisplatin infusion and which have possible etiological factors related with vascular injury, altered platelet aggregation, or increased plasma levels of von Willebrand factor antigen (vWF:Ag).3,6,22,24\n\nWe report the case of a patient with a testicular seminomatous tumor, who received PEB-based CHT and developed an IS located in the diencephalon and mesencephalon, the present case being different to other published cases in which great vessel infarctions affecting the brain hemispheres are reported.\n\nClinical Case\nThe patient was a 28-year-old man, with a 1-year diagnosis of a right-sided testicular tumor, without cardiovascular risk factors or any other medical condition. In his family history he had a brother who died from testicular cancer at the age of 38 years. The patient underwent a right orchiectomy, and a histopathological study reported a classic seminoma. Preoperative tumor markers such as HCG (human chorionic gonadotropin) and lactic dehydrogenase (LDH) were elevated, while α-fetoprotein levels were normal. Computed tomography of the abdomen reported retroperitoneal lymphatic nodes. Therefore, it was classified as a classic stage IIB seminoma with a good prognosis following the criteria of the International Germ Cell Cancer Collaborative Group. The cardiopulmonary parameters of the patient, which included an electrocardiogram and pulmonary function, were normal. Two months after the orchiectomy, treatment with standard PEB-based CHT was established. After the first cycle, the patient presented febrile neutropenia, which he overcame. There were no complications during the second cycle. Twenty-four hours after the third cycle of CHT, he presented nausea and vomiting. At 48 hours, he had diplopia, and at 72 hours he presented alteration in the level of awareness. Initially, the patient exhibited somnolence that escalated to stupor after 12 hours. In the neurological exam a palsy of the third right nerve was found. Furthermore, he presented tetraparesia mostly in his right limbs and bilateral Babinski reflex.\n\nThe patient was hospitalized under the suspicion of brain metastasis. For this reason, a magnetic resonance imaging simple with contrast agents was prescribed, which demonstrated the presence of a T1 and T2 hyperintense signal with restricted diffusion in the posterior portion of the pons, the midsection of the mesencephalon, and the ventromedial region of the thalamus (Figure 1), which is compatible with infarction. In addition, metastasis to the brain were not found.\n\nFigure 1. Acute IS within the pons on T1-weighted imaging (a), midbrain on T1- and T2-weighted imaging (b and c), and left thalamus on diffusion (d).\n\nThe patient had normal blood pressure and heart rate values. On day 15 of hospitalization, the patient presented a dystonic position of the right arm, and a mixed postural-kinetic tremor. In order to determine the cause, the following laboratory tests were prescribed: clotting times, fibrinogen, plasminogen, α-2-antiplasmin, antithrombin III, protein C, protein S, magnesium, renin, and complement, which were all within normal range. Additionally, antiphospholipid antibodies, antinuclear antibodies, venereal disease research laboratory, human immunodeficiency virus, and hepatitis B and C tests were negative. Because of the lack of resources in our hospital, the vWF:Ag level could not be determined.\n\nMagnetic resonance imaging spectroscopies showed an injury with high levels of lipids and lactate and lowered levels of aspartate, findings that are associated with an infarction area. Magnetic resonance angiography and catheter angiography did not show any injury in large arteries or cerebral vasculitis. The transesophageal echocardiography was normal, and the Holter monitoring did not reveal paroxysmal atrial fibrillation.\n\nAfter approximately 6 months, the patient was admitted into the Internal Medicine department due to a septic shock secondary to pneumonia and infected bed sores, and due to these infections, he died.\n\nDiscussion\nThe incidence of testicular cancer varies considerably around the world. In the United States, nearly 7200 cases are diagnosed every year, and the incidence adjusted by age is 5.2 per 100 000 males per year; on the contrary, in European countries the incidence has increased from 2% to 5% per year. The risk is 4 times greater in white individuals than in black individuals.25 Ninety-five percent of all malignant testicular tumors are GCTs, and they are classified into 2 major types, seminomatous (40%) and nonseminomatous (60%); the advances in treatment in the past few years have improved disease-free survival rates, with a low mortality rate of 0.38 per 100000 cases per year. However, survivors have been affected by the secondary effects of the CHT used, such as late toxicity, which has led this group of patients to develop a significant associated morbidity rate.10,11,14,15,18,25 The cause of GCT is unknown. However, familial clustering has been observed, and factors like cryptorchidism and Klinefelter’s syndrome have been mentioned.14,18,25 In the case of our patient, there is a family history (brother).\n\nWhen testicular cancer is suspected, inguinal orchiectomy is the standard treatment. Independent of the tumor stage, seminomas have high rates of cure, from 100% for tumors in stage I to 95% for stages II and III.18,26 In stage IIB (our patient) and after the orchiectomy, CHT is the standard treatment. When CHT is administered, it is based on cisplatin, which is the cornerstone of the standard treatment, and it consists of 3 cycles of administration of the PEB scheme.10,11,14,15,17,18\n\nEven though cisplatin is part of the treatment of seminomas, this drug appears as the major cause of long-term toxicity (late) in patients treated for testicular cancer, producing nephrotoxicity, ototoxicity, neurotoxicity, and vascular toxicity, among others.13,17,21,27 IS has also been identified as a complication, although its appearance, as in the present case, is rare.24 So a retrospective study that included 932 patients with cancer of different etiology (39 patients with GCT) treated with cisplatin-based CHT found that the incidence of arterial or venous TEEs between the first dosage and 4 weeks after the last dosage was 18.1% (169 patients), of which 1.1% (10 patients) were IS events.22\n\nThere are few reports written about cerebrovascular events related to the administration time of CHT, as in this case in which the patient developed an IS 48 hours after the third PEB cycle. This finding is similar to the case reported by El Amrani et al, where 5 patients with oropharyngeal cancer presented IS within 2 to 5 days after receiving cisplatin and 5-flouracil.28 In reported cases of GCT, this time relationship has also been observed, such as the one presented by Vos et al, in which a 30-year-old patient suffered 3 occlusive-arterial infarcts after 10 days of each CHT cycle.26 Another case report by Karagoz et al presented a 34-year-old patient who developed aphasia and hemiplegia 10 days after the third CHT cycle,29 and the report of Santos et al, whose 20-year-old patient developed hemiparesis and hemihypoesthesia 14 days after the second CHT cycle.3 Azak et al described the case of a 17-year-old patient who presented an IS 7 days after the fourth CHT cycle. With this case, in particular, the ischemic events were hemorrhagic infarctions.30 Gerl et al described a case of a fatal IS post-CHT, but we could not get major details from that case.31 As can be appreciated, the majority of the ischemic events occurred within 10 days after receiving a CHT cycle. In every case described above, there were no atherosclerotic cardiovascular risk factors, as demonstrated by Doll et al in 4 patients under 30 years of age with GCT who were receiving CHT and suffered ischemic vascular events (2 MIs and 2 ISs), in which no cardiovascular risk factor was found.32 It calls for attention that our case, as with the other IS events previously described, occurred in young patients, contrasting with the literature description in which the majority of ischemic events in patients in CHT occur in the fifth and sixth decade of life.29\n\nThe pathophysiological mechanism of cerebral infarction in these cases is not known, but many theories suggest that it is a direct effect of CHT. It has been proposed that cisplatin is associated with vascular injury, platelet-aggregation alterations, augmented serum levels of vWF:Ag, and autonomic dysfunction. The last factor would lead to an augmented α-adrenergic tone that, combined with a state of hypomagnesemia, could cause a vascular spasm.3,19,21,24,33 Bleomicin, on the other hand, would cause endothelial alterations in capillaries and arterioles, such as vacuolization, necrosis, and occlusion. Furthermore, the tumor itself can cause thrombosis directly (synthesizing procoagulant factors, factors that modify fibrinolysis, and proinflammatory cytokines) or indirectly (by interaction with platelets, endothelium, and reticuloendothelial cells).21,34,35 Finally, it has been proposed that cancer produces embolization of tumor particles, nonbacterial thrombotic endocarditis, and intraarterial precipitation of cryoglobulins.3,7\n\nIn our case, we performed many studies but we could not establish the etiology of this IS, so it was considered an IS secondary to the received CHT, and as described above, it is possible that bleomicin and cisplatin have influenced its development.\n\nIn terms of the localization of the IS caused by CHT, according to reports on cancer patients and specifically in GCT, the condition occurred in larger vessels like the carotid, anterior cerebral, and medial cerebral arteries.3,29,36-38 However, in our case the lesion occurred in small-caliber arteries irrigating pons, midbrain, and thalamus, which are anatomic regions and vascular territories in which this entity has never been described, which makes this case unique.\n\nThe healing prognosis in this group of patients is high; the affected age-group is young and generally without comorbidity. Furthermore, they were economically active, and for this reason it is important to consider these cerebrovascular complications (whether they are cancer-secondary or above all, secondary to the CHT), because they have the capacity of impairing the patient’s functionality, diminish their quality of life, and, worst of all, lead them to death.\n\nIn the future, closer controls should be performed in patients receiving the mentioned CHT schemes and others that have potential vascular toxicity through markers such as the vWF:Ag, which allow us to establish the risk and possibly foresee these complications.3,33,35\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or publication of this article.\n==== Refs\nReferences\n1. \nSilverstein MD Heit JA Mohr DN Petterson TM O’Fallon WM Melton LJ 3rd \nTrends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study . Arch Intern Med . 1998 ;158 :585 -593 .9521222 \n2. \nLee AY Levine MN \nVenous thromboembolism and cancer: risks and outcomes . Circulation . 2003 ;107 (23 \nsuppl 1):I17 -I21 .12814981 \n3. \nSantos AJ Malheiros SM Borges LR Dzik C Nalli DG Gabbai AA \nIschemic stroke after chemotherapy with cisplatin, etoposide and bleomycin: case report . Arq Neuropsiquiatr . 2003 ;61 :129 -133 .12715037 \n4. \nKhorana AA \nThe NCCN Clinical Practice Guidelines on Venous Thromboembolic Disease: strategies for improving VTE prophylaxis in hospitalized cancer patients . Oncologist . 2007 ;12 :1361 -1370 .18055857 \n5. \nMano MS Guimarães JL Sutmöller SF Reiriz AB Sutmöller CS Di Leo A \nExtensive deep vein thrombosis as a complication of testicular cancer treated with the BEP protocol (bleomycin, etoposide and cisplatin): case report . Sao Paulo Med J . 2006 ;124 :343 -345 .17322957 \n6. \nRogers L \nCerebrovascular complications in patients with cancer . Semin Neurol . 2010 ;30 :311 -319 .20577937 \n7. \nHeit JA Silverstein MD Mohr DN Petterson TM O’Fallon WM Melton LJ 3rd \nRisk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study . Arch Intern Med . 2000 ;160 :809 -815 .10737280 \n8. \nMeattini I Scotti V Pescini F \nIschemic stroke during cisplatin-based chemotherapy for testicular germ cell tumor: case report and review of the literature . J Chemother . 2010 ;22 :134 -136 .20435575 \n9. \nZhao J Zhao M Jin B \nTumor response and survival in patients with advanced non-small-cell lung cancer: the predictive value of chemotherapy-induced changes in fibrinogen . BMC Cancer . 2012 ;12 :330 .22852778 \n10. \nSchmoll HJ Jordan K Huddart R \nTesticular seminoma: ESMO clinical recommendations for diagnosis, treatment and follow-up . Ann Oncol . 2009 ;20 (suppl 4 ):iv83 -iv88 .\n11. \nSchmoll HJ Jordan K Huddart R \nTesticular seminoma: ESMO clinical practice guidelines for diagnosis, treatment and follow-up . Ann Oncol . 2010 ;21 (suppl 5 ):v140 -v146 .20555065 \n12. \nEinhorn LH \nCuring metastatic testicular cancer . Proc Natl Acad Sci U S A . 2002 ;99 :4592 -4595 .11904381 \n13. \nChaudhary UB Haldas JR \nLong-term complications of chemotherapy for germ cell tumours . Drugs . 2003 ;63 :1565 -1577 .12887263 \n14. \nKhan O Proetheroe A \nTestis cancer . Postgrad Med J . 2007 ;83 :624 -632 .17916870 \n15. \nAlbers P Albrecht W Algaba F \nEAU guidelines on testicular cancer: 2011 update . Eur Urol . 2012 ;36 :127 -145 .\n16. \nSchmoll HJ Souchon R Krege S \nEuropean consensus on diagnosis and treatment of germ cell cancer: a report of the European Germ Cell Cancer Consensus Group (EGCCCG) . Ann Oncol . 2004 ;15 :1377 -1399 .15319245 \n17. \nCathomas R Helbling D Stenner F \nInterdisciplinary evidence-based recommendations for the follow-up of testicular cancer patients: a joint effort . Swiss Med Wkly . 2010 ;140 :356 -369 .20544409 \n18. \nBoujelbene N Cosinschi A Boujelbene N \nPure seminoma: a review and update . Radiat Oncol . 2011 ;6 :90 .21819630 \n19. \nTogna GL Togna AR Franconi M Caprino L \nCisplatin triggers platelet activation . Thromb Res . 2000 ;99 :503 -509 .10973681 \n20. \nDoll DC Ringenberg QS Yarbro JW \nVascular toxicity associated with antineoplastic agents . J Clin Oncol . 1986 ;4 :1405 -1417 .3528405 \n21. \nDieckmann KP Struss WJ Budde U \nEvidence for acute vascular toxicity of cisplatin-based chemotherapy in patients with germ cell tumour . Anticancer Res . 2011 ;31 :4501 -4506 .22199322 \n22. \nMoore R Adel N Riedel E \nHigh incidence of thromboembolic events in patients treated with cisplatin-based chemotherapy: a large retrospective analysis . J Clin Oncol . 2011 ;29 :3466 -3473 .21810688 \n23. \nWeijl NI Rutten MF Zwinderman AH \nThromboembolic events during chemotherapy for germ cell cancer: a cohort study and review of the literature . J Clin Oncol . 2000 ;18 :2169 -2178 .10811682 \n24. \nDropcho EJ \nNeurotoxicity of cancer chemotherapy . Semin Neurol . 2010 ;30 :273 -286 .20577934 \n25. \nSturgeon CM Duffy MJ Stenman UH \nNational Academy of Clinical Biochemistry laboratory medicine practice guidelines for use of tumor markers in testicular, prostate, colorectal, breast, and ovarian cancers . Clin Chem . 2008 ;54 :e11 -e79 .19042984 \n26. \nVos AH Splinter TA van der Heul C \nArterial occlusive events during chemotherapy for germ cell cancer . Neth J Med . 2001 ;59 :295 -299 .11744182 \n27. \nKollmannsberger C Kuzcyk M Mayer F Hartmann JT Kanz L Bokemeyer C \nLate toxicity following curative treatment of testicular cancer . Semin Surg Oncol . 1999 ;17 :275 -281 .10588857 \n28. \nEl Amrani M Heinzlef O Debroucker T Roullet E Bousser MG Amarenco P \nBrain infarction following 5-fluorouracil and cisplatin therapy . Neurology . 1998 ;51 :899 -901 .9748055 \n29. \nKaragoz B Bilgi O Akyol I Ozgun A Turken O Kandemir EG \nCerebrovascular accident after chemotherapy for testicular cancer . Mil Med . 2009 ;174 :320 -321 .19354100 \n30. \nAzak A Oksüzoğlu B Deren T Oneç BM Zengin N \nCerebrovascular accident during cisplatin-based combination chemotherapy of testicular germ cell tumor: an unusual case report . Anticancer Drugs . 2008 ;19 :97 -98 .18043135 \n31. \nGerl A Clemm C Schleuning M Wilmanns W \nFatal cerebrovascular accident associated with chemotherapy for testicular cancer . Eur J Cancer . 1993 ;29A :1220 -1221 .7686022 \n32. \nDoll DC List AF Greco FA Hainsworth JD Hande KR Johnson DH \nAcute vascular ischemic events after cisplatin-based combination chemotherapy for germ-cell tumors of the testis . Ann Intern Med . 1986 ;105 :48 -51 .2424354 \n33. \nSteingart R \nMechanisms of late cardiovascular toxicity from cancer chemotherapy . J Clin Oncol . 2005 ;23 :9051 -9052 .16301591 \n34. \nÁlvarez-Pérez FJ Verde I Usón-Martín M Figuerola-Roig A Ballabriga-Planas J Espino-Ibañez A \nFrequency and mechanism of ischemic stroke associated with malignancy: a retrospective series . Eur Neurol . 2012 ;68 :209 -213 .23018798 \n35. \nVaughn DJ Palmer SC Carver JR Jacobs LA Mohler ER \nCardiovascular risk in long-term survivors of testicular cancer . Cancer . 2008 ;112 :1949 -1953 .18338810 \n36. \nSerrano-Castro PJ Guardado-Santervás P Olivares-Romero J \nIschemic stroke following cisplatin and 5-fluorouracil therapy: a transcranial Doppler study . Eur Neurol . 2000 ;44 :63 -64 .10895000 \n37. \nRussmann S Winkler A Lövblad KO Stanga Z Bassetti C \nLethal ischemic stroke after cisplatin-based chemotherapy for testicular carcinoma and cannabis inhalation . Eur Neurol . 2002 ;48 :178 -180 .12373036 \n38. \nDieckmann KP Gerl A Witt J Hartmann JT \nMyocardial infarction and other major vascular events during chemotherapy for testicular cancer . Ann Oncol . 2010 ;21 :1607 -1611 .20067918\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2324-7096",
"issue": "3(2)",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "chemotherapy; cisplatin; ischemic stroke; testicular cancer",
"medline_ta": "J Investig Med High Impact Case Rep",
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"pages": "2324709615590198",
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"title": "Unusually Located Stroke After Chemotherapy in Testicular Germ Cell Tumors.",
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},
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160304"
},
{
"companynumb": "DE-ACCORD-034632",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
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"drugindication": "TESTICULAR GERM CELL CANCER",
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"medicinalproduct": "CISPLATIN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
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"drugauthorizationnumb": "074513",
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"drugindication": "TESTICULAR GERM CELL CANCER",
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"medicinalproduct": "ETOPOSIDE."
}
],
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"patientonsetage": "46",
"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Myocardial infarction",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MARTINEZ BA, CORREA EP. UNUSUALLY LOCATED STROKE AFTER CHEMOTHERAPY IN TESTICULAR GERM CELL TUMORS. J INVESTIG MED HIGH IMPACT CASE REP. 2015 JUN 9?3(2):2324709615590198.",
"literaturereference_normalized": "unusually located stroke after chemotherapy in testicular germ cell tumors",
"qualification": "1",
"reportercountry": "EC"
},
"primarysourcecountry": "DE",
"receiptdate": "20151020",
"receivedate": "20151020",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11642703,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160304"
}
] |
{
"abstract": "The licensed intravenous acetylcysteine regimen for treating paracetamol overdose in most countries uses three separate infusions over 21 h. This complex regimen, requiring different infusion concentrations and rates, has been associated with administration errors. The aim of the present study was to assess the extent of administration delays occurring during this acetylcysteine regimen.\n\n\n\nA 6-month retrospective observational study was conducted at three English teaching hospitals with clinical toxicology services from October 2014. Patients aged 16 years and over, treated with intravenous acetylcysteine for paracetamol overdose, were included. The start times for infusions were recorded and the delays compared with the prescribed infusion times were calculated. Anaphylactoid reactions, intravenous cannula problems, overdose intent and smoking status were recorded to assess their contribution to delays.\n\n\n\nFrom 263 cases identified, 198 met the study inclusion criteria. The median time between the start of infusions 1 and 3 was delayed from the intended 5 h by a median (interquartile range) of 90 (50-163) min, with 135 (68%) cases delayed by more than 1 h. Significantly longer delays were observed in patients with anaphylactoid reactions [median delay 267 (217-413) min, n = 8] and accidental/supratherapeutic overdose [median delay 170 (95-260) min, n = 29]. There were no significant differences between smokers and nonsmokers, or for patients with intravenous cannula problems.\n\n\n\nLong delays were identified during the three-infusion acetylcysteine regimen for the treatment of paracetamol overdose. These were of clinical significance and could lead to periods of subtherapeutic plasma acetylcysteine concentrations and potentially avoidable hepatotoxicity, as well as delaying hospital discharge.",
"affiliations": "Clinical Toxicology, Guy's and St. Thomas' NHS Foundation Trust and King's Health Partners, London, UK.;Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;York Teaching Hospital NHS Foundation Trust, York, UK.;Newcastle Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.;Clinical Toxicology, Guy's and St. Thomas' NHS Foundation Trust and King's Health Partners, London, UK.;Clinical Toxicology, Guy's and St. Thomas' NHS Foundation Trust and King's Health Partners, London, UK.;Clinical Toxicology, Guy's and St. Thomas' NHS Foundation Trust and King's Health Partners, London, UK. paul.dargan@gstt.nhs.uk.",
"authors": "Bailey|George P|GP|;Najafi|Javad|J|;Elamin|Muhammad E M O|ME|;Waring|W Stephen|WS|;Thomas|Simon H L|SH|;Archer|John R H|JR|;Wood|David M|DM|;Dargan|Paul I|PI|",
"chemical_list": "D000931:Antidotes; D000082:Acetaminophen; D000111:Acetylcysteine",
"country": "England",
"delete": false,
"doi": "10.1111/bcp.13063",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0306-5251",
"issue": "82(5)",
"journal": "British journal of clinical pharmacology",
"keywords": "acetaminophen overdose; acetylcysteine; drug administration; intravenous infusions; paracetamol overdose",
"medline_ta": "Br J Clin Pharmacol",
"mesh_terms": "D000082:Acetaminophen; D000111:Acetylcysteine; D000293:Adolescent; D000328:Adult; D000931:Antidotes; D004334:Drug Administration Schedule; D062787:Drug Overdose; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D008297:Male; D008508:Medication Errors; D012189:Retrospective Studies; D013997:Time Factors; D055815:Young Adult",
"nlm_unique_id": "7503323",
"other_id": null,
"pages": "1358-1363",
"pmc": null,
"pmid": "27412926",
"pubdate": "2016-11",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "25083244;21561983;2598989;11736866;18445707;23912471;24290406;14700565;27412926;26594846;26464438;18803085;24666324;23697458;26666290;26691690",
"title": "Delays during the administration of acetylcysteine for the treatment of paracetamol overdose.",
"title_normalized": "delays during the administration of acetylcysteine for the treatment of paracetamol overdose"
} | [
{
"companynumb": "GB-JNJFOC-20161023664",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
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"drugauthorizationnumb": "019872",
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"medicinalproduct": "PARACETAMOL"
},
{
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"activesubstancename": "ACETAMINOPHEN"
},
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"drugdosageform": "UNSPECIFIED",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"drugrecurreadministration": "2",
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"medicinalproduct": "PARACETAMOL"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Accidental overdose",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatotoxicity",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Intentional overdose",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BAILEY GP, NAJAFI J, ELAMIN ME, WARING WS, THOMAS SH, ARCHER JR, ET AL. DELAYS DURING THE ADMINISTRATION OF ACETYLCYSTEINE FOR THE TREATMENT OF PARACETAMOL OVERDOSE. BRITISH JOURNAL OF CLINICAL PHARMACOLOGY 2016;82 (5):1358-1363.",
"literaturereference_normalized": "delays during the administration of acetylcysteine for the treatment of paracetamol overdose",
"qualification": "3",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20161103",
"receivedate": "20161103",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
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"sender": {
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170207"
}
] |
{
"abstract": "The results of pulmonary embolism treatment with streptase in 76 patients are discussed. All patients had submassive or massive pulmonary embolism. 66 (86%) of patients recovered. Thrombolysis with the use of heparin was performed in 9 patients, death occurred in 5 of them. Of 20 patients treated with \"Actilize\", death was reported in three cases. Authors consider alteplase to be highly effective in the treatment of massive pulmonary embolism. In case of late diagnostics of pulmonary embolism, especially recurrent, thrombolytic therapy remains to be effective up to 2 weeks after primary embolization.",
"affiliations": null,
"authors": "Malinovskiĭ|N N|NN|;Gruzdev|A K|AK|;Beskaeva|L M|LM|;Sal' nikov|D V|DV|;Nikerov|K Iu|KIu|;Abramov|A S|AS|;Fineshin|I N|IN|",
"chemical_list": "D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D006493:Heparin; D013300:Streptokinase; D010959:Tissue Plasminogen Activator; D001241:Aspirin",
"country": "Russia (Federation)",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-1207",
"issue": null,
"journal": "Khirurgiia",
"keywords": null,
"medline_ta": "Khirurgiia (Mosk)",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000792:Angiography; D001241:Aspirin; D005260:Female; D005343:Fibrinolytic Agents; D006493:Heparin; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D011655:Pulmonary Embolism; D013300:Streptokinase; D013997:Time Factors; D010959:Tissue Plasminogen Activator; D016896:Treatment Outcome",
"nlm_unique_id": "0412765",
"other_id": null,
"pages": "4-7",
"pmc": null,
"pmid": "18833155",
"pubdate": "2008",
"publication_types": "D003160:Comparative Study; D023362:Evaluation Study; D016428:Journal Article",
"references": null,
"title": "The efficacy of alteplase in pulmonary embolism treatment.",
"title_normalized": "the efficacy of alteplase in pulmonary embolism treatment"
} | [
{
"companynumb": "RU-ROCHE-1210994",
"fulfillexpeditecriteria": "1",
"occurcountry": "RU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ALTEPLASE"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "103172",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "SOLUTION FOR INFUSION",
"drugdosagetext": "100 MG NOT EXCEEDING A TOTAL DOSE OF 1.5 MG/KG (NR,15 MG AS BOLUS, 85 MG AS 2-H INFUSION)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PULMONARY EMBOLISM",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "ALTEPLASE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ANTICOAGULANT THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "HEPARIN"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Shock",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Respiratory failure",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MALINOVSKY N, GRUZDEV A, BESKAEVA L, SALNIKOV D, NIKEROV K, ABRAMOV A, AND FINESHIN I. THE EFFICACY OF ALTEPLASE IN PULMONARY EMBOLISM TREATMENT. KHIRURGIIA 2008;7:4-7.",
"literaturereference_normalized": "the efficacy of alteplase in pulmonary embolism treatment",
"qualification": "3",
"reportercountry": "RU"
},
"primarysourcecountry": "RU",
"receiptdate": "20170421",
"receivedate": "20130409",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 9220082,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170830"
}
] |
{
"abstract": "Imatinib mesylate is a specific inhibitor of BCR-ABL tyrosine kinase, which is now widely used for the treatment of chronic myeloid leukemia (CML) with a high efficacy. Although severe hepatic injury caused by imatinib mesylate is rare, such a side effect may force patients to discontinue taking imatinib mesylate. In the present paper, we report on the case of a 51-year-old woman with CML who experienced hepatic injury with severe hyperbilirubinemia caused by imatinib mesylate. The findings from a liver biopsy specimen and her clinical course suggested the hepatic injury to presumably have been caused by an allergic mechanism. The co-administration of prednisolone was thus tried, and she has been able to continue imatinib mesylate administration without any liver dysfunction and finally was able to obtain a complete cytogenetic response.We therefore recommend that prednisolone should be tried when severe hepatic injury caused by imatinib mesylate is observed, since it might enable such patients to continue imatinib mesylate treatment and thereby improve the prognosis in such cases.",
"affiliations": "Third Department of Internal Medicine, Asahikawa Medical College, Japan. ikuta@asahikawa-med.ac.jp",
"authors": "Ikuta|Katsuya|K|;Torimoto|Yoshihiro|Y|;Jimbo|Junko|J|;Inamura|Junki|J|;Shindo|Motohiro|M|;Sato|Kazuya|K|;Tokusashi|Yoshihiko|Y|;Miyokawa|Naoyuki|N|;Kohgo|Yutaka|Y|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D011239:Prednisolone; D011505:Protein-Tyrosine Kinases; D016044:Fusion Proteins, bcr-abl",
"country": "Japan",
"delete": false,
"doi": "10.1532/IJH97.05034",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "82(4)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000970:Antineoplastic Agents; D001549:Benzamides; D001706:Biopsy; D056486:Chemical and Drug Induced Liver Injury; D004791:Enzyme Inhibitors; D005260:Female; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008099:Liver; D008107:Liver Diseases; D008875:Middle Aged; D010879:Piperazines; D011239:Prednisolone; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "343-6",
"pmc": null,
"pmid": "16298828",
"pubdate": "2005-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11873781;11773186;11567987;11740802;1359888;15512829;12357373;11287972;12637616;11870257;8568266;14568907;12750713;11870241",
"title": "Severe hepatic injury caused by imatinib mesylate administered for the treatment of chronic myeloid leukemia and the efficacy of prednisolone for its management.",
"title_normalized": "severe hepatic injury caused by imatinib mesylate administered for the treatment of chronic myeloid leukemia and the efficacy of prednisolone for its management"
} | [
{
"companynumb": "PHBS2005JP18877",
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"occurcountry": "JP",
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{
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"activesubstancename": "IMATINIB MESYLATE"
},
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},
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},
{
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{
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"drugdosagetext": "400 MG, QD",
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"drugindication": "CHRONIC MYELOID LEUKAEMIA",
"drugintervaldosagedefinition": "804",
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},
{
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"drugdosagetext": "100 MG, QD",
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"drugintervaldosagedefinition": "804",
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},
{
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},
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}
],
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"reaction": [
{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Alanine aminotransferase increased",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
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"reactionoutcome": "1"
},
{
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},
{
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},
{
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"reactionoutcome": "1"
},
{
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"reactionoutcome": "1"
},
{
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"reactionoutcome": "1"
},
{
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},
{
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},
{
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},
{
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},
{
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},
{
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"reactionoutcome": "1"
},
{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20020808"
}
},
"primarysource": {
"literaturereference": "IKUTA K, TORIMOTO Y, JIMBO J, INAMURA J, SHINDO M, SATO K ET AL. SEVERE HEPATIC INJURY CAUSED BY IMATINIB MESYLATE ADMINISTERED FOR THE TREATMENT OF CHRONIC MYELOID LEUKEMIA AND THE EFFICACY OF PREDNISOLONE FOR ITS MANAGEMENT. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2005?82(4):343-6",
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"qualification": "3",
"reportercountry": "JP"
},
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"receiptdate": "20190821",
"receivedate": "20190821",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16723904,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"transmissiondate": "20191005"
}
] |
{
"abstract": "Pneumocystis jirovecii pneumonia is a life-threatening opportunistic infection in children receiving immunosuppressive chemotherapy. Without prophylaxis, up to 25% of pediatric oncology patients receiving chemotherapy will develop Pneumocystis jirovecii pneumonia. Trimethoprim-sulfamethoxazole is the preferred agent for prophylaxis against Pneumocystis jirovecii pneumonia. Pentamidine may be an acceptable alternative for pediatric patients unable to tolerate trimethoprim-sulfamethoxazole. A retrospective review was conducted of pediatric oncology patients who received ≥1 dose of pentamidine for Pneumocystis jirovecii pneumonia prophylaxis between January 2007 and August 2014. Electronic medical records were reviewed to determine the incidence of breakthrough Pneumocystis jirovecii pneumonia or discontinuation of pentamidine associated with adverse events. A total of 754 patients received pentamidine prophylaxis during the period. There were no cases of probable or proven Pneumocystis pneumonia, and 4 cases (0.5%) of possible Pneumocystis pneumonia. The incidence of possible breakthrough Pneumocystis pneumonia was not significantly different between subgroups based on age (<12 months [1.7%] versus ≥12 months [0.4%], P = 0.3), route of administration (aerosolized [0%] versus intravenous [1.0%], P = 0.2), or hematopoietic stem cell transplant status (transplant [0.4%] versus no transplant [0.8%], P = 0.6). Pentamidine was discontinued due to an adverse drug event in 23 children (3.1%), more frequently for aerosolized than for intravenous administration (7.6% versus 2.2%, respectively, P = 0.004). Intravenous or inhaled pentamidine may be a safe and effective second-line alternative for prophylaxis against Pneumocystis jirovecii pneumonia in children with cancer receiving immunosuppressive chemotherapy or hematopoietic stem cell transplantation.",
"affiliations": "Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA melissa.quinn@stjude.org william.greene@stjude.org.;Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Department of Oncology, Leukemia/Lymphoma Division, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Department of Oncology, Leukemia/Lymphoma Division, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.;Pharmaceutical Department, St. Jude Children's Research Hospital, Memphis, Tennessee, USA melissa.quinn@stjude.org william.greene@stjude.org.",
"authors": "Quinn|Melissa|M|;Fannin|J T|JT|;Sciasci|Joseph|J|;Bragg|Allison|A|;Campbell|Patrick K|PK|;Carias|Delia|D|;Crews|Kristine R|KR|;Gregornik|David|D|;Jeha|Sima|S|;Maron|Gabriela|G|;Pauley|Jennifer L|JL|;Swanson|Hope D|HD|;Wolf|Joshua|J|;Greene|William|W|",
"chemical_list": "D000336:Aerosols; D000935:Antifungal Agents; D007166:Immunosuppressive Agents; D010419:Pentamidine; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.00173-18",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "62(8)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": "Pneumocystis jirovecii; oncology; pediatric; pentamidine; prophylaxis",
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D061605:Administration, Intravenous; D000336:Aerosols; D000935:Antifungal Agents; D002675:Child, Preschool; D005260:Female; D019337:Hematologic Neoplasms; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D016867:Immunocompromised Host; D007166:Immunosuppressive Agents; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009423:Nervous System Neoplasms; D010419:Pentamidine; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D012189:Retrospective Studies; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29866879",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "17803871;5312203;17635000;27214074;4572932;2331119;27467366;26824946;8270969;27407129;412099;26418240;9142782;28074607;11466718;8113834;8086550;25712369;27164533;23538522",
"title": "Pentamidine for Prophylaxis against Pneumocystis jirovecii Pneumonia in Pediatric Oncology Patients Receiving Immunosuppressive Chemotherapy.",
"title_normalized": "pentamidine for prophylaxis against pneumocystis jirovecii pneumonia in pediatric oncology patients receiving immunosuppressive chemotherapy"
} | [
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],
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}
],
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},
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},
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},
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"transmissiondate": "20181010"
},
{
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},
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"medicinalproduct": "PENTAMIDINE"
}
],
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"reaction": [
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "QUINN M, FANNIN JT, SCIASCI J, BRAGG A, CAMPBELL PK, CARIAS D, ET AL. PENTAMIDINE FOR PROPHYLAXIS AGAINST PNEUMOCYSTIS JIROVECII PNEUMONIA IN PEDIATRIC ONCOLOGY PATIENTS RECEIVING IMMUNOSUPPRESSIVE CHEMOTHERAPY. ANTIMICROB?AGENTS?CHEMOTHER 2018?62(8):E00173?18.",
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},
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"seriousnessother": 1,
"transmissiondate": "20181010"
},
{
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},
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},
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},
{
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"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PENTAMIDINE"
},
"drugadditional": null,
"drugadministrationroute": "042",
"drugauthorizationnumb": "019264",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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},
{
"actiondrug": null,
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"activesubstancename": "PENTAMIDINE ISETHIONATE"
},
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"drugadministrationroute": "055",
"drugauthorizationnumb": "019887",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
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"drugindication": "ANTIFUNGAL PROPHYLAXIS",
"drugintervaldosagedefinition": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PENTAMIDINE FOR INHALATION (MANUFACTURER UNKNOWN)"
}
],
"patientagegroup": "3",
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"reaction": [
{
"reactionmeddrapt": "Anaphylactic reaction",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
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{
"abstract": "The physiological, psychological, and social consequences associated with illicit drug use are well documented. In addition to the effects directly related to the drug(s), the delivery mechanism can precipitate other serious health conditions. A case is reported where an individual stopped by law enforcement was discovered to be in possession of a vial containing a red-colored fluid, which the person stated was blood and contained fentanyl. Analysis by headspace GC, ELISA, and LC-TOF/MS screening in with mass spectral confirmation revealed the presence of several substances, including ethanol, methamphetamine, amphetamine, MDA, 6-monoacetylmorphine, codeine, morphine, alprazolam, delta-9 THC, ephedrine, pseudoephedrine, and norpseudoephedrine; serology testing verified the fluid was consistent with human blood. Methamphetamine was present at a dosage form amount (11 mg). The purpose of this study was to detail the analytical findings, interpret their meaning, and discuss the public health concerns associated with the drug delivery by the administration of human blood.",
"affiliations": "NMS Labs, 3701 Welsh Road, Willow Grove, PA, 19090.;Private Practice, P.O. Box 712, Goshen, NY, 10924.",
"authors": "Labay|Laura M|LM|;Catanese|Charles A|CA|",
"chemical_list": "D013287:Illicit Drugs; D009294:Narcotics",
"country": "United States",
"delete": false,
"doi": "10.1111/1556-4029.13573",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "63(2)",
"journal": "Journal of forensic sciences",
"keywords": "drug delivery; forensic science; human blood; injection; public health; toxicology",
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000328:Adult; D001774:Blood Chemical Analysis; D001800:Blood Specimen Collection; D002853:Chromatography, Liquid; D016503:Drug Delivery Systems; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D013287:Illicit Drugs; D008297:Male; D013058:Mass Spectrometry; D009294:Narcotics",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "644-647",
"pmc": null,
"pmid": "28580580",
"pubdate": "2018-03",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Illicit Drug Delivery Via Administration of Human Blood.",
"title_normalized": "illicit drug delivery via administration of human blood"
} | [
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"abstract": "Atypical hemolytic uremic syndrome is a thrombotic microangiopathy that can cause life-threatening anemia, thrombocytopenia, and acute renal failure. When triggered during pregnancy or the acute postpartum period, the disease is referred to as pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS). Women who suffer P-aHUS may later want to consider future pregnancy. These patients are at high, though not well-estimated, risk of relapse. Eculizumab, a monoclonal antibody against complement 5 (C5), has been highly successful in treating acute attacks of P-aHUS, but little is known about the effectiveness of eculizumab maintenance therapy throughout pregnancy. In this case report, we present a woman whose first pregnancy was complicated by severe P-aHUS. In her next pregnancy, she was maintained on eculizumab. She delivered a healthy infant at term and had no recurrences of P-aHUS during the pregnancy or in the postpartum period.",
"affiliations": "Department of Obstetrics and Gynecology, Kansas University Medical Center, Kansas City, KS 64113, USA.;Department of Internal Medicine, KC Hospitalists, 4831 W 136th St., Unit A Leawood, KS 66224, USA.;Department of Obstetrics and Gynecology, Kansas University Medical Center, Kansas City, KS 64113, USA.;Department of Obstetrics and Gynecology, Kansas University Medical Center, Kansas City, KS 64113, USA.",
"authors": "Winchester|Mae-Lan|ML|;Platzbecker|Ryan|R|;McMahon|Megan|M|;Parrish|Marc|M|",
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"doi": "10.14740/jmc3397",
"fulltext": "\n==== Front\nJ Med Cases\nJ Med Cases\nElmer Press\nJournal of Medical Cases\n1923-4155\n1923-4163\nElmer Press\n\n10.14740/jmc3397\nCase Report\nEculizumab Maintenance and the Prevention of Atypical Hemolytic Uremic Syndrome Relapse During Pregnancy: A Case Report\nEculizumab Maintenance in P-aHUS\nWinchester Mae-Lan ac\nPlatzbecker Ryan b\nMcMahon Megan a\nParrish Marc a\na Department of Obstetrics and Gynecology, Kansas University Medical Center, Kansas City, KS 64113, USA\nb Department of Internal Medicine, KC Hospitalists, 4831 W 136th St., Unit A Leawood, KS 66224, USA\nc Corresponding Author: Mae-Lan Winchester, Department of Obstetrics and Gynecology, Kansas University Medical Center, Kansas City, KS 64113, USA. Email: mwinchester@kumc.edu\n12 2019\n31 12 2019\n10 12 343344\n29 11 2019\n9 12 2019\nCopyright 2019, Winchester et al.\n2019\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution Non-Commercial 4.0 International License, which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.\nAtypical hemolytic uremic syndrome is a thrombotic microangiopathy that can cause life-threatening anemia, thrombocytopenia, and acute renal failure. When triggered during pregnancy or the acute postpartum period, the disease is referred to as pregnancy-associated atypical hemolytic uremic syndrome (P-aHUS). Women who suffer P-aHUS may later want to consider future pregnancy. These patients are at high, though not well-estimated, risk of relapse. Eculizumab, a monoclonal antibody against complement 5 (C5), has been highly successful in treating acute attacks of P-aHUS, but little is known about the effectiveness of eculizumab maintenance therapy throughout pregnancy. In this case report, we present a woman whose first pregnancy was complicated by severe P-aHUS. In her next pregnancy, she was maintained on eculizumab. She delivered a healthy infant at term and had no recurrences of P-aHUS during the pregnancy or in the postpartum period.\n\nPregnancy\naHUS\nEculizumab\n==== Body\nIntroduction\n\nAtypical hemolytic uremic syndrome (aHUS) is a rare disease that has a high degree of morbidity and mortality if not treated promptly. Pregnancy can occasionally serve as a trigger, and pregnancy-associated aHUS (P-aHUS) has been estimated to complicate 1 in 25,000 pregnancies [1]. Patients with a history of P-aHUS are at increased risk of relapse during subsequent pregnancy. Eculizumab is a terminal complement inhibitor that received the approval from the Food and Drug Administration (FDA) for treatment of aHUS in 2011. It has been successfully used in pregnancy during acute aHUS and more extensively in paroxysmal nocturnal hemoglobinuria, but little is known about the safety and efficacy of eculizumab maintenance during pregnancy.\n\nCase Report\n\nA 37-year-old Caucasian female presented to our maternal fetal medicine clinic with her second pregnancy at 7 weeks of gestation. Her first pregnancy had been complicated by P-aHUS. That pregnancy had been rather uneventful until 40 weeks gestation, when she was induced at an outside hospital for suspected preeclampsia, based on elevated blood pressures and an elevated protein/creatinine ratio. She had an uncomplicated vaginal delivery and was discharged home on postpartum day 2. She re-presented on postpartum day 4 complaining of headache and malaise. She was noted to have severely elevated blood pressures, anemia (hemoglobin: 5 g/dL), thrombocytopenia (platelets: 32 × 103/µL), and acute kidney injury (creatinine: 7.2 mg/dL) later requiring dialysis. She quickly developed acute hypoxic respiratory failure requiring intubation. ADAMTS-13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif, member 13) activity was obtained and ultimately returned as normal. With multidisciplinary team involvement, she was diagnosed with P-aHUS, and started on plasmapheresis and eculizumab. She experienced marked improvement in both clinical and laboratory parameters.\n\nSince her initial diagnosis, the patient was maintained on eculizumab infusions (900 mg) every 2 weeks and experienced full recovery of renal function (creatinine: 0.6 mg/dL, protein/creatinine ratio: 0.2). Her blood pressures, however, never quite normalized and she was kept on carvedilol 6.25 mg twice daily. She declined any genetic workup.\n\nAside from P-aHUS and hypertension, the patient had no other significant past medical or surgical history. She was informed of the risks of P-aHUS relapse and pregnancy complications. Given her risk of relapse during this subsequent pregnancy, she continued to receive eculizumab infusions every 2 weeks throughout the pregnancy. Complement 5 (C5) and free eculizumab levels were not available at our institution. The patient was kept on carvedilol and did not require dose increase during pregnancy. Assessment of renal function and complete blood count were obtained every 2 weeks and remained normal. Aside from gestational diabetes controlled with oral medications, the remainder of her pregnancy was uncomplicated. Fetal size was appropriate for gestational age on routine growth ultrasounds. The patient underwent induction of labor at 39 weeks gestation and had a spontaneous vaginal delivery. She received a supplemental dose of eculizumab within 24 h of delivery (despite receiving her usual dose 7 days prior) as recommended by her hematologist. She then resumed infusions every 2 weeks. Pediatricians were alerted as to the mother’s use of eculizumab. The healthy male infant was monitored in the full-term nursery and no evidence of infection was found during observation.\n\nDiscussion\n\nThough rare, P-aHUS can threaten the life of both mother and fetus. Most cases occur during the woman’s first pregnancy [2]. Some of these women may later desire another pregnancy. The risk of relapse during a subsequent pregnancy is thought to be high, but is not well studied. And while brief eculizumab treatment has been greatly effective at treating active disease during pregnancy, less is known about eculizumab maintenance during pregnancy [3].\n\nOnly seven pregnancies in patients previously diagnosed with P-aHUS and maintained on eculizumab are reported in the literature [4-6]. Of these seven patients, only one patient experienced an uncomplicated pregnancy and delivered at term. The remaining six pregnancies were all delivered before 34 weeks gestation. Two developed P-aHUS relapse, one suffered an intrauterine fetal demise at 24 weeks, and the remaining three developed preeclampsia/HELLP (hemolysis, elevated liver enzymes, and low platelets) syndrome. Only one patient received a supplemental dose of eculizumab within 24 h of delivery, but this was after development of HELLP syndrome with concerns for full P-aHUS relapse. Our patient received a supplemental eculizumab dose as a form of prophylaxis.\n\nIn limited human data, eculizumab has not been found to be associated with congenital anomalies, increased risk of stillbirth, neonatal death, or serious neonatal infectious morbidity. Indeed, complement activity has been measured in the serum of babies born to mothers treated with eculizumab and those that were not treated [7]. Similar complement levels were found, which suggests that eculizumab does not affect the neonatal complement syndrome. The infant born to the presented patient did not demonstrate any concerns for potential infection, and complement levels were not checked after birth. More data are needed to confirm the safety of eculizumab maintenance during pregnancy for both the mother and fetus. However, given the life-threatening nature of P-aHUS to both mother and fetus, eculizumab maintenance therapy during pregnancy may confer more benefit than risk to the dyad.\n\nNone.\n\nFinancial Disclosure\n\nNone to declare.\n\nConflict of Interest\n\nNone to declare.\n\nInformed Consent\n\nObtained.\n\nAuthor Contributions\n\nMW wrote the manuscript. RP, MM, and MP edited and provided expertise. All authors have read and approved the manuscript.\n==== Refs\nReferences\n\n1 Huerta A Arjona E Portoles J Lopez-Sanchez P Rabasco C Espinosa M Cavero T et al A retrospective study of pregnancy-associated atypical hemolytic uremic syndrome Kidney Int 2018 93 2 450 459 10.1016/j.kint.2017.06.022 28911789\n2 Bruel A Kavanagh D Noris M Delmas Y Wong EKS Bresin E Provot F et al Hemolytic uremic syndrome in pregnancy and postpartum Clin J Am Soc Nephrol 2017 12 8 1237 1247 10.2215/CJN.00280117 28596415\n3 Sarno L Tufano A Maruotti GM Martinelli P Balletta MM Russo D Eculizumab in pregnancy: a narrative overview J Nephrol 2019 32 1 17 25 10.1007/s40620-018-0517-z 30159857\n4 Fontana F Alfano G Bardhushi E Ligabue G Giovanella S Neri I Cappelli G Relapse of atypical hemolytic uremic syndrome during pregnancy in a patient on eculizumab maintenance treatment: a case report Am J Case Rep 2019 20 1460 1465 10.12659/AJCR.916994 31582717\n5 Servais A Devillard N Fremeaux-Bacchi V Hummel A Salomon L Contin-Bordes C Gomer H et al Atypical haemolytic uraemic syndrome and pregnancy: outcome with ongoing eculizumab Nephrol Dial Transplant 2016 31 12 2122 2130 10.1093/ndt/gfw314 27587606\n6 Bateman S Ladhani M Jesudason S Successful subsequent pregnancy in a woman receiving eculizumab for pregnancy-associated atypical haemolytic uraemic syndrome Case Rep Nephrol 2019 2019 2738723 10.1155/2019/2738723 31687234\n7 Hallstensen RF Bergseth G Foss S Jaeger S Gedde-Dahl T Holt J Christiansen D et al Eculizumab treatment during pregnancy does not affect the complement system activity of the newborn Immunobiology 2015 220 4 452 459 10.1016/j.imbio.2014.11.003 25468724\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1923-4155",
"issue": "10(12)",
"journal": "Journal of medical cases",
"keywords": "Eculizumab; Pregnancy; aHUS",
"medline_ta": "J Med Cases",
"mesh_terms": null,
"nlm_unique_id": "101551824",
"other_id": null,
"pages": "343-344",
"pmc": null,
"pmid": "34434305",
"pubdate": "2019-12",
"publication_types": "D002363:Case Reports",
"references": "27587606;25468724;31687234;30159857;28911789;31582717;28596415",
"title": "Eculizumab Maintenance and the Prevention of Atypical Hemolytic Uremic Syndrome Relapse During Pregnancy: A Case Report.",
"title_normalized": "eculizumab maintenance and the prevention of atypical hemolytic uremic syndrome relapse during pregnancy a case report"
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"abstract": "We report a case in a young man who developed acute, persistent and painful tongue protrusion followed by swelling for more than 24 hours. He had relapse symptoms of schizophrenia and had recently received a single dose of parenteral haloperidol to manage his agitation. His record showed history of similar event and he has been taking atypical antipsychotic for maintenance. Mental state examination on admission revealed an agitated man with disorganised speech, restricted affect, auditory hallucination and persecutory delusion. His dystonia and oedema improved after 3 days. His mental status also recovered with the maintenance of low-potency antipsychotic and anticholinergic antiparkinsonian medications.",
"affiliations": "Department of Psychiatry, Universiti Putra Malaysia, Serdang, Selangor, Malaysia.",
"authors": "Masiran|Ruziana|R|",
"chemical_list": "D014150:Antipsychotic Agents; D006220:Haloperidol",
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"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "drugs: psychiatry; psychiatry (drugs and medicines); schizophrenia",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000799:Angioedema; D014150:Antipsychotic Agents; D003937:Diagnosis, Differential; D004421:Dystonia; D006220:Haloperidol; D006801:Humans; D008297:Male; D012559:Schizophrenia; D014060:Tongue Diseases",
"nlm_unique_id": "101526291",
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"pages": null,
"pmc": null,
"pmid": "28978587",
"pubdate": "2017-10-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24116333;23183389;23836783;20370804;23282406;22772698;25901135;21172575;21537720",
"title": "Persistent oromandibular dystonia and angioedema secondary to haloperidol.",
"title_normalized": "persistent oromandibular dystonia and angioedema secondary to haloperidol"
} | [
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{
"abstract": "Multifocal motor neuropathy (MMN) is a rare disease with a prevalence of less than 1 per 100,000 people. Intravenous immunoglobulin (IVIG) therapy, performed for a long-term period, has been demonstrated able to improve the clinical picture of MMN patients, ameliorating motor symptoms and/or preventing disease progression. Treatment with subcutaneous immunoglobulin (SCIg) has been shown to be as effective as IVIG. However, previously published data showed that follow-up of MMN patients in treatment with SCIg lasted no more than 56 months. We report herein the results of a long-term SCIg treatment follow up (up to 96 months) in a group of 8 MMN patients (6 M; 2F), previously stabilized with IVIG therapy. Clinical follow-up included the administration of Medical Research Council (MRC) sum-score, the Overall Neuropathy Limitation Scale (ONLS) and the Life Quality Index questionnaire (LQI) at baseline and then every 6 months. Once converted to SCIg, patients' responsiveness was quite good. Strength and motor functions remained stable or even improved during this long-term follow-up with benefits on walking capability, resistance to physical efforts and ability in hand fine movements.",
"affiliations": "Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy. lucagentile84@yahoo.it.;Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.;Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy.",
"authors": "Gentile|Luca|L|;Russo|Massimo|M|;Rodolico|Carmelo|C|;Arimatea|Ilenia|I|;Vita|Giuseppe|G|;Toscano|Antonio|A|;Mazzeo|Anna|A|",
"chemical_list": "D016756:Immunoglobulins, Intravenous",
"country": "England",
"delete": false,
"doi": "10.1038/s41598-021-88711-9",
"fulltext": "\n==== Front\nSci Rep\nSci Rep\nScientific Reports\n2045-2322\nNature Publishing Group UK London\n\n88711\n10.1038/s41598-021-88711-9\nArticle\nLong-term treatment with subcutaneous immunoglobulin in multifocal motor neuropathy\nGentile Luca lucagentile84@yahoo.it\n\n12\nRusso Massimo 1\nRodolico Carmelo 1\nArimatea Ilenia 1\nVita Giuseppe 1\nToscano Antonio 1\nMazzeo Anna 1\n1 grid.10438.3e 0000 0001 2178 8421 Unit of Neurology and Neuromuscular Diseases, Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy\n2 UOC Neurologia e Malattie Neuromuscolari, Policlinico G. Martino, via Consolare Valeria 1, 98124 Messina, ME Italy\n28 4 2021\n28 4 2021\n2021\n11 921622 2 2021\n16 4 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.\nMultifocal motor neuropathy (MMN) is a rare disease with a prevalence of less than 1 per 100,000 people. Intravenous immunoglobulin (IVIG) therapy, performed for a long-term period, has been demonstrated able to improve the clinical picture of MMN patients, ameliorating motor symptoms and/or preventing disease progression. Treatment with subcutaneous immunoglobulin (SCIg) has been shown to be as effective as IVIG. However, previously published data showed that follow-up of MMN patients in treatment with SCIg lasted no more than 56 months. We report herein the results of a long-term SCIg treatment follow up (up to 96 months) in a group of 8 MMN patients (6 M; 2F), previously stabilized with IVIG therapy. Clinical follow-up included the administration of Medical Research Council (MRC) sum-score, the Overall Neuropathy Limitation Scale (ONLS) and the Life Quality Index questionnaire (LQI) at baseline and then every 6 months. Once converted to SCIg, patients’ responsiveness was quite good. Strength and motor functions remained stable or even improved during this long-term follow-up with benefits on walking capability, resistance to physical efforts and ability in hand fine movements.\n\nSubject terms\n\nNeuroscience\nPeripheral nervous system\nissue-copyright-statement© The Author(s) 2021\n==== Body\nIntroduction\n\nMultifocal motor neuropathy (MMN) is a rare disorder, affecting peripheral motor nerves, with a prevalence ranging from 0.29 to 0.70 per 100,0001. MMN is more frequent in men than in women (ratio of 2.7:1)2 and 80% of patients experienced their first symptoms at a relatively young age (20–50 years)3. The most common presenting symptom is asymmetric distal weakness (wrist drop, reduced grip strength, foot drop) due to impairment of single nerve’s function3,4. A retrospective study of 88 MMN patients demonstrated the presence of symptoms at lower limbs in up to one-third of cases1. Minor sensory symptoms have been observed in at least 20% of patients3.\n\nThe diagnosis of MMN is based on the clinical and electrodiagnostic criteria developed by the European Federation of Neurological Societies (EFNS) and the Peripheral Nerve Society (PNS) Task Force in 2006 and revised in 20101. The hallmark of MMN is the most frequent neurophysiological sign, i.e., the multifocal presence of persistent, partial conduction blocks (CB) of motor axons, without signs of demyelination. For definition, CB should be searched outside the usual sites of nerve compression5. The 2010 guidelines also reported four supportive criteria: (1) elevated IgM antiganglioside GM1 antibodies; (2) increased cerebrospinal fluid (CSF) protein (< 1 g/l); (3) MRI showing increased signal intensity on T2-weighted imaging; (4) objective clinical improvement following intravenous immunoglobulin therapy (IVIG) treatment6.\n\nThe course of MMN is often slowly progressive. However, a patient could also present a step-wise progression. MMN diagnosis can be a challenge, especially outside referral centers for neuromuscular disorders, with a mean delay of 4 years from symptoms onset to diagnosis5. The natural history of MMN is unfavourable, with most of the patients gathering progressive disabilities that highly compromise their daily-life activities. However, some patients have a favourable long-term prognosis in absence of specific therapy or may have occasionally a spontaneous remission3.\n\nVarious immunomodulatory treatments have been used in MMN patients. Some of them (glucocorticoids, plasma exchange, rituximab, cyclophosphamide and mycophenolate mofetil) have showed poor or any efficacy at all, when they have not even worsened the course of disease (plasma exchange and corticosteroids). Moreover, seeing as their potentially dangerous side effects, their use is not recommended4. IVIG, performed for long-term period, has been demonstrated able to improve the clinical picture of MMN patients, ameliorating motor symptoms and/or preventing disease progression. IVIG are usually administered at a dose of 2 g/kg perfused over a 4–5 days period. IVIG cycles are periodically repeated, with a frequency that depends on personal responsiveness to the treatment. Commonly, most of the patients need an IVIG cycle every 4–6 weeks, and this implies that patients must frequently be admitted to the hospital. This, altogether with venous access problem or possible systemic adverse reactions to IVIG infusion, have been reported as the main reason of complain to the treatment7. In patients with MMN, treatment with subcutaneous immunoglobulin (SCIg) has been shown to be as effective as IVIG in improving motor parameters or in stabilizing patients’ clinical condition. In open-labelled studies, a long-term follow-up for one to two years has shown that SCIg can maintain muscle strength and prevent relapse of symptoms8. In addition, SCIg delivery, after an adequate training of the patient, can be independently performed at home, without the necessity of any venous access7. It has to be outlined that, during IVIG courses, variations of hemoglobin levels and of other hemolytic parameters have been detected. About this side effect, it has been observed a better tolerability after having switched from IVIG to more frequent but smaller SCIg injections9. The majority of patients reached clinical stability using a SCIg dose equivalent to IVIG, although this aspect seems to be in contrast with previous reports suggesting the need of an increase of SCIg dosage10. However, it appears from the literature data that the longest SCIg treatment follow-up lasted no longer than 56 months11. We report herein the retrospective results of a long-term SCIg treatment in a group of MMN patients, with a follow up period up to 8 years, including safety, tolerability, clinical outcome measures variations and patients’ perception of SCIg treatment.\n\nPatients\n\nWe retrospectively examined eight patients, all > 18 year-old, with a diagnosis of MMN defined according to the EFNS/PNS criteria. They were successfully treated with IVIG (2 g/kg in 4–5 days) with stabilization of clinical conditions. All patients started IVIG administration every 4/6 weeks before switching to SCIg treatment. SCIg infusions were performed with an interval (2–3 times/week) that differed from patient to patient, depending on the intervals between previously administered IVIG courses and on the quantity of immunoglobulin perfused. A SCIg dosage equivalent to IVIG (1:1) was used.\n\nMethods\n\nStudy procedures were the same of a previously published study on chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) patients12. First SCIg injection was administered at the hospital under surveillance of a study nurse. Subsequently, injections were controlled at home via a programmable infusion pump (crono-speed 50 by Canè S.p.A, Italy) coupled with a 50 ml syringe connected with catheters to a butterfly subcutaneous needle. The nurse was always available for contacts if needed12.\n\nAll patients signed an informed consent form and the study has been approved by the Ethics Committee of the University Hospital of Messina (address: AOU “G. Martino”, via Consolare Valeria n. 1, 98125-Messina (ME), Italy. E-mail: aoucomitatoetico@unime.it). This protocol has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. We considered baseline records and follow-up data collected between 2012 and 2020. During this period, patients were evaluated at baseline and every 6-months by the same neurologist. They were also interviewed by the study nurse as regard as quality of life and on feasibility, safety and side effects at baseline and at the following visits12.\n\nClinical follow-up included:Medical Research Council (MRC) sum-score (MRC-SS) to check muscle strength (0 = complete paralysis, 80 = normal strength) bilaterally in eight muscle groups (shoulder abduction, elbow flexion, wrist extension, index finger abduction, hip flexion, knee extension, foot dorsiflexion and great toe dorsiflexion)12.\n\nThe Overall Neuropathy Limitation Scale (ONLS: 0 = normal, 11 = worst) to assess motor disability12.\n\nThe Life Quality Index questionnaire (LQ I) as a quality of life measures. 15-items examining the respondents perception of immunoglobulins treatment impact on daily activities, summarized to four sub-scales: “treatment interference”, “therapy related problems”, “therapy setting” and “treatment costs”12.\n\nPatients with ONLS reduction of at least 1 point were considered improved. Neither MRC score nor ONLS scale variations were considered as evidence of strength or motor ability stabilization. In case of adverse reactions, deterioration of muscle strength or development of paresthesias, the patients were revaluated. Relapses were identified as clinical deterioration with increase of ONLS and decrease of MRC-SS at least of one point. In case of relapse, SCIg dose was increased by 25% for 4 weeks and the patient was then reassessed. If the increase did not produce clinical improvement, an IVIG course was administered to the patient, not interrupting SCIg treatment. The patient was then revaluated after 2 weeks: if the clinical condition was improved, IVIG course was not repeated and only SCIg treatment was continued, at pre-relapse dose12.\n\nResults\n\nDemographic and disease history\n\nAt baseline, the eight patients (6 M; 2 F) had a mean age of 55.9 years (years) (range 31–80 years) and they all presented with a long history of MMN (mean age at disease onset: 44.6 years) (Table 1). Two patients were also affected by diabetes type 2, and one of the two also had a cutaneous T-cell lymphoma, whereas a third one was affected by an autoimmune hypothyroidism. Five patients correctly received the diagnosis of MMN at first, and they began a specific treatment a mean of 1.5 years after onset (range 0–2.5 years). On the other hand, three patients were misdiagnosed as having a cervical radiculopathy, a right plexopathy/motor neuron disease or a carpal tunnel syndrome. These mistakes led to a considerable delay of MMN diagnosis and treatment (mean delay: 8.5 years; range 5–11 years).Table 1 Clinical and demographic characteristics of MMN patients.\n\nPt\tAge at baseline (years)\tSex\tComorbidity\tAge at disease onset\tFirst diagnosis\tOnset symptoms\tSecondary symptoms\tSensory symptoms\tLatency onset/secondary symptoms\tLatency onset/FLT\tPresent phenotype\t\n1\t53\tF\t–\t36 yrs\tCarpal tunnel syndrome\tFasciculations UL and LL\tProximal right UL weakness and burning\tYes\t3 yrs\t11 yrs\tProximal and distal right and left UL weakness, distal left LL weakness\t\n2\t74 (d)\tM\tDiabetes, cutaneous t cell lymphoma\t64 yrs\tMMN\tDistal right UL weakness and paresthesias\tDistal left UL weakness and paresthesias\tYes\t1 yrs\t0\tTetraparesis\t\n3\t48\tF\t–\t40 yrs\tCervical radiculopathy\tDistal right UL weakness\tProximal right UL weakness ad cramps\t–\t5 yrs\t5 yrs\tWeakness Proximally at right UL and lower limbs and distally at upper limbs and left LL\t\n4\t80 (d)\tM\tAutoimmune hypothyroidism\t58 yrs\tMMN\tFasciculations, proximal left UL weakness, distal left LL weakness, dysesthesias at left hand and foot\tDistal right UL weakness and paresthesias\tYes\t5 yrs\t2.5 yrs\tProximal weakness at left UL, distal weakness at right UL and lower limbs\t\n5\t59\tM\t–\t52 yrs\tRight plexopathy/2nd motoneuron disease\tDistal right UL weakness\t–\t–\t–\t9.5 yrs\tDistal right UL weakness\t\n6\t61\tM\tDiabetes\t45 yrs\tMMN\tProximal right UL weakness and pain\tProximal left UL weakness and pain, motor disturbances at lower limbs\t–\t1 month\t2 yrs\tProximal and distal weakness at the 4 limbs\t\n7\t31\tM\t–\t29 yrs\tMMN\tDistal left LL weakness\tDistal left UL weakness\t–\t1 yrs\t1 yrs\tDistal weakness at left UL and lower limbs\t\n8\t41\tM\t–\t33 yrs\tMMN\tProximal right LL weakness\tProximal right and left UL weakness, distal right UL weakness\tYes\t7 yrs\t2 yrs\tRight hemiatrophy of the tongue. Proximal and distal upper and lower limbs weakness. Hypoesthesia in right ulnar nerve territory and from both knees to feet\t\nPt patient, (d) dead, – not applicable. Yrs years, MMN multifocal motor neuropathy, UL upper limb, LL lower limb, FLT first line treatment.\n\nThe onset of symptoms was characterized by distal weakness in 5/8, proximal weakness in 2/8 and fasciculations in 1/8. After the disease onset, all patients but one complained of secondary symptoms as new motor deficits or sensory disturbances, with a mean latency of 2.75 years (1 month–7 years) (Table 1). At onset, or even as secondary symptoms, three patients complained of pain or cramps at proximal limbs. Only the patient #8 showed sensory deficits (hypoesthesia and hypopallesthesia at right ulnar nerve and at lower limbs from the knee to feet). At the last neurological examination before starting treatment, in comparison with neurological evaluation at onset, 7/8 patients showed a progression of the disease. On the other hand, patient #5 maintained the same neurological features since onset.\n\nFirst/second/third line treatments\n\nIVIG were used as first line treatment in 5/8, always with good response (Table 2). On the other hand, patient #2, #4 and #6, before starting IVIG, had been treated with cyclophosphamide 300 mg/die respectively for 6 years, 6 months and 12 years globally. However, these periods are not to be intended as consecutive: once disease regression was reached, cyclophosphamide was stopped and restarted only in case of relapses. This treatment was then definitely interrupted because of side effects (hemorrhagic cystitis in two cases, leukopenia and thrombocytopenia in the other). These three patients, after cyclophosphamide, underwent other immunomodulatory treatment (rituximab, azathioprine, interferon-beta) with no or only partial benefits. IVIG treatment was then started for all three patients. Globally, the mean duration of IVIG treatment in this group of eight patients was of 6.5 years (range 1–19 years).Table 2 Type and length of treatment courses.\n\nPt\tFirst line treatment (FLT)\tFLT duration (years)\tFLT efficacy\tSecond and third line treatment\tSecond and third treatment efficacy\tIVIG duration (years)\t\n1\tIVIG\t6\tYes (stabilization)\t–\t–\t6\t\n2\tCiclophosfamide\t6\tYes (complete regression)\tIVIG\tYes\t4\t\n3\tIVIG\t3\tYes (initial almost complete regression)\t–\t–\t3\t\n4\tCiclophosfamide\t0.5\tYes (almost complete regression)\t(1) AZT, (2) interferon beta, (3) IVIG\tPartial/no/yes\t19\t\n5\tIVIG\t7\tYes (initial complete regression, then partial benefit)\t–\t–\t7\t\n6\tCiclophosfamide\t12\tYes (almost complete regression)\t(1) Rituximab, (2) IVIG\tPartial/yes\t2\t\n7\tIVIG\t1\tYes (initial almost complete regression)\t–\t–\t1\t\n8\tIVIG\t6\tYes (stabilization)\t–\t–\t6\t\nPt patient, IVIG intravenous immunoglobulin, AZT azathioprine.\n\nSCIg treatment\n\nSCIg treatment was started in all patients a mean of 12.4 years (range 7–22 years) after the disease onset. SCIg were chosen after IVIG because: (1) patients discomfort caused by repeated and long journeys to the infusion site (7/8 pts.), (2) economic burden (5/8), (3) work problems when moving to the infusion site (6/8), (4) difficulties related to venous access (1/8). The mean dose of SCIg used was of 21.7 g/week. Table 3 summarizes the results of the scores applied (ONLS, MRC-SS and LQI variation). However, in 7/8 patients ONLS remained stable or even decreased. We observed an increase of ONLS, representing a sign of clinical deterioration, only in one patient, whereas his result on MRC-SS was equivalent to baseline. Considering MRC-SS, 4/8 patients remained stable and 2/8 patients had a significant increase of 5 and 4 points, consisting with an improvement of their clinical condition, even if ONLS remained unchanged in these two patients. Only two patients presented a slight deterioration (only one point) in MRC-SS. Considering LQI results, a significant increase of patient satisfaction was recorded (mean LQI increase: + 22.5 points). Globally, SCIg length have lasted an average of 6.4 years. Two patients (#1 and 6), during SCIg treatment, experienced some relapse of the disease and needed the administration of IVIG cycle (once every 12–18 months after beginning of SCIg therapy).Table 3 SCIg administration results.\n\nPt\tDose SCIg (g/week)\tDisease duration at T0 (years)\tSCIg duration (years)\tONLS\tMRC s.s\tLQI\t\nT0\tT1\tT0\tT1\tT0\tT1\t\n1\t24\t17\t8\t4\t3\t72\t71\t81\t96\t\n2\t20\t10\t6\t5\t5\t69\t73\t78\t93\t\n3\t20\t8\t8\t4\t4\t63\t68\t62\t99\t\n4\t30\t22\t5\t5\t6\t64\t64\t65\t79\t\n5\t20\t16.5\t4.5\t3\t3\t73\t72\t62\t90\t\n6\t20\t16\t7\t7\t7\t33\t33\t54\t81\t\n7\t20\t2\t5\t4\t4\t76\t76\t70\t92\t\n8\t20\t8\t8\t4\t3\t58\t58\t82\t94\t\nPt patient, ONLS overall neuropathy limitation scale, MRC s.s. medical research council sum score, LQI life quality index questionnaire, T0 baseline (at SCIg treatment beginning), T1 last follow-up.\n\nAdverse events\n\nAdverse events (AEs) reported were mostly redness, swelling, induration, and pruritus in the infusion area. We also recorded three serious adverse events (SAEs): pt. 1, 5 years after SCIg starting, experienced a cerebral venous sinus thrombosis, resolved after adequate medical therapy. After this episode, SCIg were suspended for a brief period and restarted once thrombosis disappeared. Pt. 2, 6 years after SCIg start, developed progressive dysphagia, dysphonia and dysarthria. Repetitive stimulation and single fiber electromyography (SFEMG) demonstrated the presence of myasthenia gravis, which caused his death for respiratory failure. Finally, pt. 4 experienced a sudden death of probable cardiac origin five years after SCIg starting.\n\nDiscussion\n\nFew previous studies have showed that SCIg treatment is feasible for MMN. A randomized controlled study was conducted in MMN to compare SCIg and IVIG efficacy on a primary parameter (isokinetic muscle strength) or secondary parameters (MRC score, nerve conduction study, 9-hole-peg test, 10-meterwalking test, P-IgG, anti-GM1). Nine IVIG responsive patients were received SCIg or IVIG at an equivalent dose. Then, after a wash out, they were switched to the other treatment arm. Neither differences in motor performances nor in secondary parameters were reported13. This trial was prolonged with an open label extension phase, in which six patients were examined after 3, 6, 12 and 24 months. Muscle strength remained stable but four patients had to increase the dose by 20–25% during the study10. In another study, five IVIG-responder patients were switched to SCIg, with an equivalent dose. MRC-SS remained stable in 4/5 during the follow-up of 6 months14. In 2011, Misbah and colleagues established a “smooth” protocol of transition from IVIG to SCIg for 8 MMN patients, who started with 25% of the IVIG dose for the first week, then 50% in the second week and later 100% from the third to 24th week. In seven patients who completed the study, the MRC-SS and the disability score did not change during the follow-up, although two patients needed an increase of 25% of the SCIg dose15.\n\nIn 2014, Cocito et al. studied 21 MMN patients, responsive to IVIG, who were followed up to four months, before being switched to SCIg at a 1:1 dose. At follow-up, ONLS and MRC-SS remained unchanged. An adverse event was registered for one patient, who developed a painful erythema 46 days after being switched to SCIg. Then, he underwent two cycles of IVIG treatment. After that, SCIg was restarted without any more AE16. The same Italian cohort was studied for two further years. Primary outcome was the adherence to SCIg therapy. SCIg dose was increased of 15% in one patient, 24 months after having switched therapy. Four patients needed an extra IVIG course between 1 and 12 months after being switched to SCIg. Four patients returned to IVIG treatment because of clinical worsening17.\n\nIn 2015, Hadden et al. converted 4 MMN patients from IVIG to SCIg at a 1:1 regimen. Motor abilities and disability scores remained unchanged for all the patients. All patients reported a high personal satisfaction for SCIg treatment, which were continued by all of them even after the study period10. Finally, in 2015 Katzberg et al. published a series of 15 IVIG responsive MMN patients switched to SCIg with a dose equivalent of 1:1.53. Eleven of the 15 patients completed the six-month study period and remained stable18. Considering all these studies, as well as some case reports, it is to be noticed that the longest SCIg treatment follow up lasted no longer than 56 months (4.6 years)11.\n\nThe eight patients herein reported have been studied for a considerably longer period, lasting 4.5–8 years (mean 6.4). At baseline, they had a long history of MMN with a mean value of 12.4 years (range 7–22 years). Curiously, the three patients who did not undergo IVIG as first line treatment, had the worst ONLS values (≥ 5) at baseline. However, they were also the only three patients presenting comorbidity (diabetes type 2, cutaneous T-cell lymphoma, autoimmune hypothyroidism), that could have influenced their global clinical picture and the response to therapy. Their disease course, in fact, was characterized by an unbalanced disease control, using at least two different drugs or more (cyclophosphamide in three cases; rituximab, azathioprine and interferon-beta in one cases). Even if response to cyclophosphamide was satisfying, with periods of complete disease regression, SAEs led to switch to other therapies. Partial benefit was reported from the patient who underwent rituximab treatment (four cycles); no results obtained with azathioprine or interferon-beta. On the other hand, all patient improved with IVIG treatment that slowed down the disease.\n\nOnce converted to SCIg, their responsiveness was quite good. Strength and motor functions remained stable or even improved during this long-term follow-up with benefits on walking capability, resistance to physical efforts and ability in hand fine movements. In fact, in two patients ONLS score reduced of 1 point and other two patients had a significant increase in MRC-SS ≥ 4 points. Only for one patient, many years after SCIg start, we recorded an increase in ONLS, but without variation of MRC-SS result. When this happened, the patient was well over 80 years and surely some concomitant aging-related event contributed to his worsening.\n\nRelapse rate was of 25%: two patients reported periodic disease relapse (every 12–18 months); in these cases, an IVIG course had to be added to obtain clinical improvement. Similarly to what we previously reported about CIDP patients under SCIg treatment12, SCIg were usually well tolerated. Mainly, local and rapidly reversible AEs were reported. About the three SAEs reported, two patients (#1, cerebral venous sinus thrombosis; #4, sudden death of probable cardiac origin) could be supposed to be related to the already known pro-thrombotic effects of immunoglobulin therapy, which can cause thrombotic events with an incidence of 1–16.9%19. However, the cause of death in patient #1 was not precisely determined, and since he was 85-year-old at the time, his death has been interpreted as an age-related event. Instead, #1 had a documented thrombosis and she needed anticoagulant therapy that is still ongoing.\n\nWhen requested to compare SCIg and IVIG treatments, the patients reported an increase in global personal satisfaction. They noticed a significant improvement of their quality of life after having switched to SCIg. In particular, they appreciated the possibility of injecting themselves at home, without interruption of working, social or daily life activities and with any necessity to afford extra-costs to reach the infusion site or even to reside nearby for the daily IVIG infusions.\n\nThe relatively small number of patients and the retrospective design could be considered as limitations of this study. In addition, the absence of both attempts of withdrawal from SCIg treatment and of a control group, prevent us to definitively declare that SCIg treatment has been fully effective in our patients. A longer follow-up of larger cohorts of MMN patients, in association with attempts either of gradual reduction of SCIg dosage or of cessation of treatment, would be necessary to more precisely evaluate the effects of long-term SCIg treatment.\n\nThe main strength of our study is the long-term follow up up to 96 months, during which SCIg therapy has been proved as a safe and tolerable treatment option in MMN patients. Patients’ quality of life clearly improved after switching from IVIG to SCIg that were surely preferred as a chronic treatment. These results strengthen the recommendation to use SCIg as an alternative chronic therapy in patients with MMN previously responders to IVIG courses.\n\nAuthor contributions\n\nL.G. writes the main manuscript text. M.R., C.R., A.M. and I.A. contributed tocollect patients’ data and prepared Tables 1, 2 and 3. A.T., G.V. and A.M. reviewed the manuscript.\n\nCompeting interests\n\nLuca Gentile is sub-investigator in clinical trials of Alnylam, Ionis, Takeda. He also reports trav-el grants from Kedrion and CSL Behring to attend scientific meeting and acknowledge speaker fee and consulting honoraria from Pfizer. Massimo Russo acknowledges receiving speaker fee and consulting honoraria from Akcea and Alnylam and a travel grant from Pfizer. Anna Mazzeo is Principal Investigator in clinical trials of Alnylam and Ionis, sub-investigator in clinical trials of Alnylam, Ionis, Takeda. She also re-ports travel grants from Kedrion and CSL Behring to attend scientific meeting and acknowledge speaker fee and consulting honoraria from Alnylam, Akcea and Pfizer. Giuseppe Vita is Princi-pal Investigator in clinical trials of Roche, Sarepta, Santhera, Italfarmaco, Biogen, Avexis, Al-nylam, Ionis, Wave. He is also consulent of Advisory Board for Roche, Avexis, Alnylam, Akcea and he acknowledges speaker fee and consulting honoraria from Alnylam, Akcea and Pfizer. Antonio Toscano is Principal Investigator in clinical trials of Takeda and Genzyme. He acknowledges speaker fee and consulting honoraria from Kedrion, CSL Behring and Genzyme. Carmelo Rodolico and Ilenia Arimatea declare no competing interests.\n\nPublisher's note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Beadon K Guimarães-Costa R Léger JM Multifocal motor neuropathy Curr. Opin. Neurol. 2018 31 5 559 564 10.1097/WCO.0000000000000605 30102608\n2. Jovanovich E Karam C Human immune globulin infusion in the management of multifocal motor neuropathy Degener. Neurol. Neuromuscul. Dis. 2015 22 6 1 12 10.2147/DNND.S96258\n3. Nobile-Orazio E Gallia F Multifocal motor neuropathy: Current therapies and novel strategies Drugs 2013 73 5 397 406 10.1007/s40265-013-0029-z 23516024\n4. Kumar A Patwa HS Nowak RJ Immunoglobulin therapy in the treatment of multifocal motor neuropathy J. Neurol. Sci. 2017 15 375 190 197 10.1016/j.jns.2017.01.061\n5. Vlam L Multifocal motor neuropathy: Diagnosis, pathogenesis and treatment strategies Nat. Rev. Neurol. 2011 8 1 48 58 10.1038/nrneurol.2011.175 22105211\n6. Joint Task Force of the EFNS and the PNS European Federation of Neurological Societies/Peripheral Nerve Society guideline on management of multifocal motor neuropathy. Report of a joint task force of the European Federation of Neurological Societies and the Peripheral Nerve Society-first revision J. Peripher. Nerv. Syst. 2010 15 4 295 301 10.1111/j.1529-8027.2010.00290.x 21199100\n7. Braine ME Woodall A A comparison between intravenous and subcutmaneous immunogobulin Br. J. Nurs. 2012 21 8 S21 S22 10.12968/bjon.2012.21.Sup8.S21 22629593\n8. Christiansen I Markvardsen LH Jakobsen J Comparisons in fluctuation of muscle strength and function in patients with immune-mediated neuropathy treated with intravenous versus subcutaneous immunoglobulin Muscle Nerve. 2018 57 4 610 614 10.1002/mus.25967 28881389\n9. Markvardsen LH Christiansen I Jakobsen J Improvement of hemoglobin levels after a switch from intravenous to subcutaneous administration of immunoglobulin in chronic inflammatory demyelinating polyneuropathy and multifocal motor neuropathy Transfusion 2016 56 10 2443 2448 10.1111/trf.13727 27401495\n10. Hadden RD Marreno F Switch from intravenous to subcutaneous immunoglobulin in CIDP and MMN: Improved tolerability and patient satisfaction Ther. Adv. Neurol. Disord. 2015 8 1 14 19 10.1177/1756285614563056 25584070\n11. Markvardsen LH Harbo T Subcutaneous immunoglobulin treatment in CIDP and MMN. Efficacy, treatment satisfaction and costs J. Neurol. Sci. 2017 378 19 25 10.1016/j.jns.2017.04.039 28566163\n12. Gentile L Mazzeo A Russo M Arimatea I Vita G Toscano A Long-term treatment with subcutaneous immunoglobulin in patients with chronic inflammatory demyelinating polyradiculoneuropathy: A follow-up period up to 7 years Sci. Rep. 2020 10 1 7910 10.1038/s41598-020-64699-6 32404895\n13. Harbo T Andersen H Hess A Hansen K Sindrup SH Jakobsen J Subcutaneous versus intravenous immunoglobulin in multifocal motor neuropathy: A randomized, single-blinded cross-over trial Eur. J. Neurol. 2009 16 5 631 638 10.1111/j.1468-1331.2009.02568.x 19236457\n14. Eftimov F Vermeulen M de Haan RJ van den Berg LH van Schaik IN Subcutaneous immunoglobulin therapy for multifocal motor neuropathy J. Peripher. Nerv. Syst. 2009 14 2 93 100 10.1111/j.1529-8027.2009.00218.x 19691531\n15. Misbah SA A smooth transition protocol for patients with multifocal motor neuropathy going from intravenous to subcutaneous immunoglobulin therapy: An open-label proof-of-concept study J. Peripher. Nerv. Syst. 2011 16 2 92 97 10.1111/j.1529-8027.2011.00330.x 21692906\n16. Cocito D SCIg and chronic dysimmune neuropathies Italian Network. Subcutaneous immunoglobulin in CIDP and MMN: A short-term nationwide study J. Neurol. 2014 261 11 2159 2164 10.1007/s00415-014-7444-2 25149866\n17. Cocito D Subcutaneous immunoglobulin in CIDP and MMN: A different long-term clinical response? J. Neurol. Neurosurg. Psychiatry. 2016 87 7 791 793 10.1136/jnnp-2014-310280 26109674\n18. Katzberg, H., Rasutis, V. & Bril, V. Subcutaneous immunoglobulin (IgPRO20) for maintenance treatment in patients with multifocal motor neuropathy (P7.094). Neurology 84(Suppl 14) (2015).\n19. Guo Y Tian X Wang X Xiao Z Adverse effects of immunoglobulin therapy Front. Immunol. 2018 9 1299 10.3389/fimmu.2018.01299 29951056\n\n",
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"issue": "11(1)",
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"medline_ta": "Sci Rep",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D016756:Immunoglobulins, Intravenous; D055104:Infusions, Subcutaneous; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease; D011115:Polyneuropathies; D011379:Prognosis; D011788:Quality of Life; D012189:Retrospective Studies",
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"pubdate": "2021-04-28",
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"references": "32404895;27401495;28566163;23516024;22629593;29951056;25149866;19236457;25584070;19691531;26109674;30050363;28320129;21692906;30102608;21199100;22105211;28881389",
"title": "Long-term treatment with subcutaneous immunoglobulin in multifocal motor neuropathy.",
"title_normalized": "long term treatment with subcutaneous immunoglobulin in multifocal motor neuropathy"
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{
"abstract": "Molecularly targeted therapy has revolutionized the treatment of advanced gastrointestinal stromal tumors (GISTs). Specifically, the consistent dependence of GISTs on proto-oncogene c-KIT signaling led to the development and successful implementation of imatinib, a small-molecule c-KIT inhibitor. Imatinib induces, rapid and sustained clinical benefit by blocking the signaling via c-KIT. The most frequently reported adverse reactions (>30%) include edema, nausea, vomiting, muscle cramps, musculoskeletal pain, diarrhea, rash, fatigue and abdominal pain.\n\n\n\nHerein, we report a case series of cutaneous squamous cell carcinoma (SCC) occurring secondary to imatinib in two patients treated for GISTs. Both patients were successfully managed with surgical resection of SCC and the discontinuation of the drug. Furthermore, we undertook a comprehensive literature review on this association. Few cases of cutaneous SCC secondary to imatinib therapy were reported in patients with chronic myeloid leukemia. However, there was no clinical evidence on causation of imatinib-associated SCC in patients with GIST.\n\n\n\nTo our knowledge, the present report is the first to describe imatinib-related SCC in patients undergoing treatment for GISTs. This implicates that safety and long-term tolerability of imatinib in patients with GISTs warrant rigorous testing and close monitoring.",
"affiliations": "Department of Medicine, New York-Presbyterian Hospital, Weill Cornell Medical College, New York, NY, U.S.A.;Department of Hematology/Oncology, Tufts Medical Center, Tufts University School of Medicine, Boston, MA, U.S.A. WSaif@tuftsmedicalcenter.org.",
"authors": "Inayat|Faisal|F|;Saif|Muhammad Wasif|MW|",
"chemical_list": "C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D000068877:Imatinib Mesylate",
"country": "Greece",
"delete": false,
"doi": "10.21873/anticanres.11214",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "36(11)",
"journal": "Anticancer research",
"keywords": "Gastrointestinal stromal tumors; adverse effect; drug safety; imatinib; skin toxicity; squamous cell carcinoma; tyrosine kinase inhibitor",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000368:Aged; D002294:Carcinoma, Squamous Cell; D005260:Female; D046152:Gastrointestinal Stromal Tumors; D006801:Humans; D000068877:Imatinib Mesylate; D008297:Male; D008875:Middle Aged; D016609:Neoplasms, Second Primary; D000090063:Proto-Oncogene Mas; D012878:Skin Neoplasms",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "6201-6204",
"pmc": null,
"pmid": "27793952",
"pubdate": "2016-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "New Drug and Possible New Toxicity - Squamous Cell Carcinoma Following Imatinib in Patients with Gastrointestinal Stromal Tumors.",
"title_normalized": "new drug and possible new toxicity squamous cell carcinoma following imatinib in patients with gastrointestinal stromal tumors"
} | [
{
"companynumb": "PHHY2016US166032",
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"activesubstancename": "IMATINIB MESYLATE"
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}
],
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"patientonsetage": "90",
"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Squamous cell carcinoma",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Skin ulcer",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Skin mass",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Second primary malignancy",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SAIF MW, INAYAT F. NEW DRUG AND POSSIBLE NEW TOXICITY - SQUAMOUS CELL CARCINOMA FOLLOWING IMATINIB IN PATIENTS WITH GASTROINTESTINAL STROMAL TUMORS. ANTICANCER RESEARCH. 2016;36(11):6201-4",
"literaturereference_normalized": "new drug and possible new toxicity squamous cell carcinoma following imatinib in patients with gastrointestinal stromal tumors",
"qualification": "3",
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},
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"transmissiondate": "20170207"
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] |
{
"abstract": "BACKGROUND\nApproximately half of pulmonary embolism cases are diagnosed in an emergency context. The classic symptoms of pulmonary embolism are absent in intensive care unit patients who are under sedation and on mechanical ventilation. In this scenario, after the development of sudden, severe hypotension, pulmonary embolism must be considered and included in a differential diagnosis according to the cause of admission. Echocardiography may be of further help in a differential diagnosis of the cause of shock.\n\n\nMETHODS\nWe present a case of a 44-year-old Caucasian man who was admitted to the intensive care unit with a diagnosis of community-acquired pneumonia and respiratory failure and who required invasive mechanical ventilation. During admission, the patient developed sudden, severe hypotension that was refractory to treatment. An adequate diagnosis with transthoracic echocardiography was unachievable because of a poor echocardiographic window. However, the combined use of electrocardiography and transesophageal echocardiography established pulmonary embolism as a high-probability diagnosis based on findings of right ventricular pressure overload and right ventricular dysfunction. The unfavorable hemodynamic situation of the patient prevented his transfer to carry out other complementary tests that could confirm the diagnosis of pulmonary embolism. Fibrinolytic and anticoagulant therapies were administered immediately, and a favorable clinical outcome was achieved.\n\n\nCONCLUSIONS\nThis case highlights the fundamental role that echocardiography played in a patient in the intensive care unit who presented with shock secondary to pulmonary embolism with an unfavorable hemodynamic situation and in whom an unnecessary transfer to perform other complementary diagnostic tests was avoided. The combined use of electrocardiography and echocardiography provided a complete differential diagnosis, identifying the cause of shock and allowing the initiation of specific treatment without further delay. Knowledge of the echocardiographic results that are characteristic of pulmonary embolism can aid in the diagnosis.",
"affiliations": "Cardiac Imaging Laboratory, Department of Cardiology, Hospital Universitario de Canarias, Ofra s/n, La Cuesta, 38320, La Laguna, Tenerife, Spain.;Cardiac Imaging Laboratory, Department of Cardiology, Hospital Universitario de Canarias, Ofra s/n, La Cuesta, 38320, La Laguna, Tenerife, Spain.;Servicios Sanitarios del Área de Salud de El Hierro, Valle del Golfo Health Center, El Hierro, Spain.;Department of Critical Care, Hospital Universitario de Canarias, Tenerife, Spain.;Department of Critical Care, Hospital Universitario de Canarias, Tenerife, Spain.;Cardiac Imaging Laboratory, Department of Cardiology, Hospital Universitario de Canarias, Ofra s/n, La Cuesta, 38320, La Laguna, Tenerife, Spain.;Cardiac Imaging Laboratory, Department of Cardiology, Hospital Universitario de Canarias, Ofra s/n, La Cuesta, 38320, La Laguna, Tenerife, Spain. jlacalzada@gmail.com.",
"authors": "Miranda-Bacallado|Julio|J|;Izquierdo-Gómez|María Manuela|MM|;García-Niebla|Javier|J|;Jiménez|Juan José|JJ|;Iribarren|José Luis|JL|;Laynez-Cerdeña|Ignacio|I|;Lacalzada-Almeida|Juan|J|http://orcid.org/0000-0002-9863-3222",
"chemical_list": "D000925:Anticoagulants; D005343:Fibrinolytic Agents",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-019-1994-y",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 199410.1186/s13256-019-1994-yCase ReportRole of echocardiography in a patient with suspected acute pulmonary embolism: a case report Miranda-Bacallado Julio juliomiranda1990@gmail.com 1Izquierdo-Gómez María Manuela mariela_izquierdo@hotmail.com 1García-Niebla Javier jniebla72@hotmail.com 2Jiménez Juan José jjjimenezrivera@gmail.com 3Iribarren José Luis joseluis.iribarren@gmail.com 3Laynez-Cerdeña Ignacio imlaynez@ull.es 1http://orcid.org/0000-0002-9863-3222Lacalzada-Almeida Juan +34-922-678450jlacalzada@gmail.com 11 0000 0000 9826 9219grid.411220.4Cardiac Imaging Laboratory, Department of Cardiology, Hospital Universitario de Canarias, Ofra s/n, La Cuesta, 38320 La Laguna, Tenerife Spain 2 Servicios Sanitarios del Área de Salud de El Hierro, Valle del Golfo Health Center, El Hierro, Spain 3 0000 0000 9826 9219grid.411220.4Department of Critical Care, Hospital Universitario de Canarias, Tenerife, Spain 19 2 2019 19 2 2019 2019 13 371 10 2018 23 1 2019 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nApproximately half of pulmonary embolism cases are diagnosed in an emergency context. The classic symptoms of pulmonary embolism are absent in intensive care unit patients who are under sedation and on mechanical ventilation. In this scenario, after the development of sudden, severe hypotension, pulmonary embolism must be considered and included in a differential diagnosis according to the cause of admission. Echocardiography may be of further help in a differential diagnosis of the cause of shock.\n\nCase presentation\nWe present a case of a 44-year-old Caucasian man who was admitted to the intensive care unit with a diagnosis of community-acquired pneumonia and respiratory failure and who required invasive mechanical ventilation. During admission, the patient developed sudden, severe hypotension that was refractory to treatment. An adequate diagnosis with transthoracic echocardiography was unachievable because of a poor echocardiographic window. However, the combined use of electrocardiography and transesophageal echocardiography established pulmonary embolism as a high-probability diagnosis based on findings of right ventricular pressure overload and right ventricular dysfunction. The unfavorable hemodynamic situation of the patient prevented his transfer to carry out other complementary tests that could confirm the diagnosis of pulmonary embolism. Fibrinolytic and anticoagulant therapies were administered immediately, and a favorable clinical outcome was achieved.\n\nConclusion\nThis case highlights the fundamental role that echocardiography played in a patient in the intensive care unit who presented with shock secondary to pulmonary embolism with an unfavorable hemodynamic situation and in whom an unnecessary transfer to perform other complementary diagnostic tests was avoided. The combined use of electrocardiography and echocardiography provided a complete differential diagnosis, identifying the cause of shock and allowing the initiation of specific treatment without further delay. Knowledge of the echocardiographic results that are characteristic of pulmonary embolism can aid in the diagnosis.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s13256-019-1994-y) contains supplementary material, which is available to authorized users.\n\nKeywords\nPulmonary embolismEchocardiographyRight ventricular functionissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nApproximately half of pulmonary embolism (PE) cases are diagnosed in an emergency context [1–3]. The classic symptoms of PE are absent in intensive care unit (ICU) patients who are under sedation and on mechanical ventilation [4]. In this scenario, after the development of sudden, severe hypotension, PE must be considered and included as a differential diagnosis according to the cause of admission [5]. Our patient was admitted to the ICU with community-acquired pneumonia and was under sedation and mechanical ventilation and suddenly went into shock. In our patient, an adequate diagnosis with transthoracic echocardiography (TTE) was unachievable because of a poor echocardiographic window. Transesophageal echocardiography (TEE) played a pivotal role in our patient’s case, helping with the differential diagnosis of the cause of shock and resulting in a diagnosis of PE as the most prevalent etiology [6]. The robust echocardiographic findings in this case raised the suspicion of PE, avoiding an unnecessary transfer of the patient for other complementary diagnostic tests and justifying the initiation of specific therapy without delay.\n\nIn a hemodynamically unstable patient, the mobilization of the patient to perform major complementary tests is difficult to achieve. In this situation, an echocardiographic assessment was available and could be performed, and it played a fundamental role in the diagnosis.\n\nThe combined use of TTE and TEE, due to the poor transthoracic window in our patient, ruled out the most common causes of shock: pericardial tamponade, acute valvular dysfunction, severe global or regional left ventricular (LV) dysfunction, aortic dissection, or hypovolemia. The echocardiographic findings of a severely dilated and dysfunctional right ventricle (RV) were confirmed, and focus was placed on a suspected diagnosis of PE. This allowed an early intensive treatment with a favorable outcome for our patient. Knowledge of the characteristic PE echocardiographic findings allowed the diagnosis to be made.\n\nCase presentation\nA 44-year-old Caucasian man, a construction worker in an urban area, married and with two children, with no past medical history, previous treatment, or toxic habits, presented 1 week before entering the hospital with general weakness and respiratory difficulty that gradually increased in intensity, accompanied by cough without expectoration. He had also experienced recent fever (38.9 °C, 102.0 °F) and some episodes of vomiting and diarrhea. He was admitted to the ICU with a diagnosis of community-acquired pneumonia and respiratory failure. At the time of admission to the ICU, the patient was conscious, oriented, and collaborative, without presenting any neurological alteration. The patient was febrile (38 °C, 100.4 °F) and tachycardic (heart rate 110 beats/min), his blood pressure was 120/80 mmHg, and he was tachypneic (28 breaths/min), without intercostal print, with an oxygen saturation of 88% with a Ventimask (Flexicare Medical, Mountain Ash, UK) at 50%. Lung auscultation showed conserved vesicular murmur and basal and midfields bilateral crackles. His heart sounds were regular, rhythmic, and without murmurs. No heart failure data were recorded. We observed a soft and depressible abdomen with peristalsis present, without visceromegalies. The patient’s lower limbs were without edema and had symmetric palpable peripheral pulses. Empiric antibiotic treatment was started with ceftriaxone (2 g/24 h, 7 days), levofloxacin (500 mg/24 h, 7 days), and oseltamivir (150 mg/12 h, 5 days), and 24 h after the admission, the patient was diagnosed with influenza A(H1N1) pneumonia after the virus was isolated in the nasopharyngeal swab samples taken at admission by PCR (DNA isolation). In the patient’s medical history, he did not highlight any history of toxic habits; information on medication taken regularly or any drug allergies was not recorded.\n\nThe patient required mechanical ventilation, and his initial evaluation was favorable with stable hemodynamics. On day 12 of the admission, he developed acute severe hypotension (systolic blood pressure < 80 mmHg) with tachycardia (heart rate > 140 beats/min) and a markedly worsening respiratory status. Arterial acid-base balance at that time showed fraction of inspired oxygen 60%, pH 7.39, partial pressure of carbon dioxide 26.7 mmHg, partial pressure of oxygen 55.9 mmHg, bicarbonate 15.9 mmol/L, base excess − 8.1, lactic acid 0.9 mmol/L, and oxygen saturation 91.2%. The patient’s respiratory status failed to respond to high-dose vasopressors and ventilatory support. The laboratory findings at that time showed the following: red blood cells 3.4 × 106/mm3, hemoglobin 9.7 g/dl, mean corpuscular volume 96.5 fl (normal reference value 80–100), average corpuscular hemoglobin 28.5, leukocytes 14.8 × 103/mm3 (normal reference value 4.5–11.1 × 103), 74.9% neutrophils, 14.8% lymphocytes, international normalized ratio 1.29, basal glucose 155 mg/dl (normal reference value 65–110), blood urea nitrogen 33 mg/dl (normal reference value 5–20), creatinine 1.10 mg/dl, sodium 145 mEq/L, potassium 3.9 mEq/L, troponin I 0.022 ng/dl, (normal reference value < 0.034), D-dimer > 10,000 ng/ml (normal reference value < 500), and C-reactive protein > 90 mg/L (normal reference value 0–12).\n\nThe cultures of the bronchial secretion (sputum of the patient) and of urine and blood (direct puncture of a peripheral artery) were negative for both aerobic and anaerobic bacteria, as were urine antigens for Pneumococcus and Legionella. An anteroposterior chest radiograph showed right basal infiltrate (Fig. 1a). To determine the cause of this acute hemodynamic instability and facilitate patient management, TTE was performed for a differential diagnosis of hypovolemia, acute LV or RV dysfunction, cardiac tamponade, aortic dissection, severe valvular regurgitation, dynamic LV outflow tract obstruction, or PE. Poor-quality images were obtained, necessitating the completion of the study with TEE.Fig. 1 a Anteroposterior chest x-ray obtained in the intensive care unit showing basal pulmonary infiltrate. b Posteroanterior chest x-ray taken prior to discharge and showing disappearance of the pulmonary infiltrate\n\n\n\nTEE demonstrated a small and hyperdynamic LV and a severely dilated and dysfunctional RV. In the midesophageal four chambers view with TEE, the RV end-diastolic area to LV end-diastolic area ratio was 1.7 (normal reference value < 0.6), and the RV end-diastolic diameter to LV end-diastolic diameter ratio was 1.4 (normal reference value < 0.9). TEE also showed McConnell’s sign, normokinesia of the RV apical segment, and akinesia of the RV mid-free wall (Fig. 2a, Additional file 1) and a systolic flattening of the interventricular septum (Fig. 2b, Additional file 2), suggesting RV pressure overload. There was no evidence of a thrombus either on the right side of the heart or in the pulmonary arteries. These findings of acute RV failure due to pressure overload raised the possibility of a PE or RV myocardial infarction [1]. A 12-lead electrocardiogram showed T-wave inversion in leads V1 to V4 and an S1Q3T3 pattern without abnormalities in the ST segment (Fig. 2c). The combined use of electrocardiography and TEE in this clinical setting suggested a high probability of PE. The unfavorable hemodynamic situation of the patient prevented transfer to carry out other complementary tests that could confirm the diagnosis of PE. Fibrinolytic and anticoagulant therapies were administered immediately, achieving a favorable clinical outcome.Fig. 2 a A 45-degree TEE view showing a severely dilated right ventricle with normokinesia of the apical segment and akinesia of the remaining segments of the free wall. b Transgastric TEE view showing systolic flattening of the interventricular septum. c A 12-lead electrocardiogram shows T-wave inversion in leads V1 to V4 and an S1Q3T3 pattern without abnormalities in the ST segment. TEE Transesophageal echocardiography\n\n\n\n\nAdditional file 1: A 45-degree view of TEE showing severe systolic dysfunction and dilation of the RV, suggestive of pressure overload. TEE Transesophageal echocardiography, RV Right ventricle, LV Left ventricle. (AVI 531 kb)\n\n\n\n\n\nAdditional file 2: Transgastric view of TEE showing systolic flattening of the interventricular septum. TEE Transesophageal echocardiography, RV Right ventricle, IVST Interventricular septal thickness, LV Left ventricle. (AVI 666 kb)\n\n\n\n\nTwenty-four hours later, with the patient stable from a hemodynamic and respiratory point of view, computed tomography (CT) pulmonary angiography showed multiple filling defects in both the pulmonary artery and bilateral lobar arteries; this outcome is consistent with PE and peripheral pulmonary consolidations that were more extensive on the right side with hypodense zones compatible with areas of hypoperfusion (Fig. 3a). The diagnosis of PE was confirmed. The patient continued with anticoagulant and antibiotic treatment during admission, progressing favorably from both a hemodynamic and respiratory point of view. Mechanical ventilation was removed on the 27th day. After 11 days of admission, he showed acute renal failure secondary to the nephrotoxic effects of tobramycin, with subsequent normalization of renal function on the 31st day of admission. After completing approximately 2 weeks of rehabilitation, on the 45th day after admission, the patient was discharged without complications. He achieved normalization of the chest x-ray (Fig. 1b) and normalization of RV morphology (Fig. 3b, Additional file 3) and functionality (Fig. 3c). Three years and five months after discharge, the patient remained free of symptoms and was living a normal life.Fig. 3 a Axial CT slice showing multiple repletion defects in both the pulmonary artery and bilateral lobar arteries, along with peripheral pulmonary consolidations with hypodense zones compatible with areas of hypoperfusion. b Four-chamber apical view of TTE showing the right ventricle with normal diameter and contractility after PE treatment. c Normal (a) TAPSE and (b) TASV as an expression of functionality of the normal right ventricle after PE treatment. CT Computed tomography, TTE Transthoracic echocardiography, PE Pulmonary thromboembolism, TAPSE Tricuspid annular plane systolic excursion, TASV Tricuspid annular systolic velocity\n\n\n\n\nAdditional file 3: Four-chamber apical view of TTE showing a morphologically and functionally normal RV after PE treatment. TTE Transthoracic echocardiography, PE Pulmonary thromboembolism, RV Right ventricle, IVST Interventricular septal thickness, LV Left ventricle. (AVI 833 kb)\n\n\n\n\nDiscussion\nThis case report illustrates the fundamental role of echocardiography in the ICU for a patient admitted for community-acquired pneumonia with severe shock. The combined use of echocardiography, especially TEE in our patient, with an electrocardiogram, allowed for all possible causes of shock to be quickly ruled out at the patient’s bedside, avoiding unnecessary intrahospital transfers of an unstable patient. In addition, the echocardiographic findings suggestive of PE with repercussion on the RV were recognized, allowing for a suspected diagnosis to be made and for the initiation of fibrinolytic and anticoagulant treatment without further delay, with excellent outcomes in our patient. Although this case is not unique in the literature, it highlights the value of TEE over TTE in patients in the ICU, who, due to the clinical situation (mechanical ventilation, supine position, and so forth), usually have a poor transthoracic window.\n\nApproximately half of PE cases are diagnosed in an emergency setting [1–3]. Dyspnea, chest pain, and syncope are key symptoms that can lead to diagnosis, but these symptoms are absent in ICU patients who are under sedation and on mechanical ventilation [4]. In this scenario, after the development of sudden, severe hypotension, PE must be considered and included in a differential diagnosis according to the cause of admission [5]. TEE played a pivotal role in our patient due to the poor echocardiographic window, which is common in ICU patients. TEE was useful in the differential diagnosis of the cause of shock, ruling out pericardial tamponade, acute valvular dysfunction, severe global or regional LV dysfunction, aortic dissection, or hypovolemia, as recommended by the guidelines of the European Society of Cardiology [6], and resulting in a diagnosis of PE as the most prevalent etiology. Direct visualization of the thrombus is infrequent, and it was not observed in our patient. The echocardiographic diagnosis is based on indirect signs of the physiopathological consequences of increased pressure on the right side of the heart. In addition to TEE findings similar to those of our patient, clinicians may also observe an enlarged pulmonary artery diameter, tricuspid regurgitation that allows for an estimation of the pulmonary artery systolic pressure, an enlarged right atrium, and a dilated inferior vena cava. In the absence of these findings, PE is unlikely [7]. TTE has been established as a valuable tool for evaluating the different causes of hemodynamic instability. Furthermore, TEE has been shown to be of additional value in many instances for critically ill patients because of its ability to provide excellent visualization of cardiac structures. In this context, TTE has a diagnostic success rate of 50% and can occasionally lead to inadequate images that are not able to establish a diagnosis, compared with a 90% success rate for TEE [5]. TEE has 70% sensitivity and 81% specificity for the confirmation of PE [8]. The gold standard for the diagnosis of PE is pulmonary angiography and spiral CT. The PIOPED II trial showed a sensitivity of 83% and a specificity of 96% for multidetector computed tomographic (MDCT) angiography. That trial also highlighted that in patients with a low or intermediate clinical probability of PE as assessed by the Wells rule, a negative CT result had a high negative predictive value for PE (96% and 89%, respectively), whereas this value was only 60% in those with a high pretest probability. Conversely, the positive predictive value of a positive CT result was high (92–96%) in patients with an intermediate or high clinical probability, but much lower (58%) in patients with a low pretest likelihood of PE. Therefore, the PIOPED II trial concluded by warning clinicians to be cautious in cases of discordance between clinical suspicion of PE and MDCT outcome [9]. These techniques require the transport of an unstable patient, which causes a certain risk when performing crucial tests for diagnostic confirmation [5, 10]. In these cases, TEE is a very useful bedside technique for patients in an ICU environment. The recent guidelines of the European Society of Cardiology do not recommend diagnostic echocardiographic studies in patients with suspected (not high-risk) PE. However, signs of RV overload in patients with high-risk PE without another important alternative diagnosis warrant emergency treatment if CT or other confirmatory test results are not immediately available [6]. Thus, although it does not allow an initial PE diagnosis, TEE helps identify when PE is the cause of RV dilation (RV end-diastolic diameter/LV end-diastolic diameter ratio > 0.9) and exclude other causes, such as pericardial effusion or acute myocardial infarction [11]. Echocardiography, on the other hand, has the noninvasive ability to evaluate and monitor the RV and LV function. It also allows the serial determination of different measures of ventricular function, analyzing its response to medical interventions such as fluid and drug therapy. In the specific case of a patient with PE, it is useful for monitoring RV function and pulmonary artery systolic pressure when thrombolytics are administered [12]. In patients with massive PE, serial assessment of RV size and fractional area change, determination of RV systolic pressure, and inferior vena cava assessment can be performed using the American Society of Echocardiography RV guidelines for the normal ranges [13].\n\nConclusion\nOur patient’s case highlights the fundamental role of echocardiography in critically ill patients for whom the poor-quality imaging of TTE is addressed by TEE. In our patient, TEE allowed us to exclude other alternative diagnoses that were contemplated a priori at the bedside of a critically ill patient with severe respiratory and hemodynamic instability. The robust echocardiographic findings in our patient caused us to suspect PE, avoiding an unnecessary transfer of the patient to perform other complementary diagnostic tests such as CT pulmonary angiography and allowing the immediate initiation of specific therapeutics, leading to an excellent clinical outcome. CT pulmonary angiography could be performed later with a more grounded suspicion to justify the initiation of specific therapy. The subsequent TEE examination allowed us to evaluate the effectiveness of medical therapy and possible morphofunctional sequelae on the right side of the heart in the early stage. Therefore, in a patient in the ICU in shock, echocardiography plays a fundamental role in the differential diagnosis of the causes of shock, and knowledge of the echocardiographic findings of PE can prevent the diagnosis from going unnoticed.\n\nAbbreviations\nCTComputed tomography\n\nICUIntensive care unit\n\nLVLeft ventricular\n\nMDCTMultidetector computed tomography\n\nPEPulmonary embolism\n\nRVRight ventricular\n\nTEETransesophageal echocardiography\n\nTTETransthoracic echocardiography\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe authors declare the nonexistence of external financing of this article.\n\nAvailability of data and materials\nThe datasets obtained and analyzed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nJL conceived of the case report and its design. JM, MM, JG, JJ, and JL worked on acquisition of data and analysis. JL, JM, MM, and IL drafted the manuscript. JL, JM, and MM revised the manuscript critically. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis case report was reviewed and approved by the Clinical Research Ethics Committee of the University Hospital of the Canary Islands (Canary Islands, Tenerife, Spain).\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. McLean AS Echocardiography in shock management Crit Care 2016 20 275 10.1186/s13054-016-1401-7 27543137 \n2. Saric M Armour AC Arnaout MS Chaudhry FA Grimm RA Kronzon I Guidelines for the use of echocardiography in the evaluation of a cardiac source of embolism J Am Soc Echocardiogr 2016 29 1 42 10.1016/j.echo.2015.09.011 26765302 \n3. Fields JM Davis J Girson L Au A Potts J Morgan CJ Transthoracic echocardiography for diagnosing pulmonary embolism: a systematic review and meta-analysis J Am Soc Echocardiogr 2017 30 714 723 10.1016/j.echo.2017.03.004 28495379 \n4. Goldhaber SZ Pulmonary Embolism N Engl J Med 1998 339 93 104 10.1056/NEJM199807093390207 9654541 \n5. Subramanian B Talmor D Echocardiography for management of hypotension in the intensive care unit Crit Care Med 2007 35 8 Suppl S414 S430 17667467 \n6. Konstantinides SV Torbicki A Agnelli G Danchin N Fitzmaurice D Galiè N 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism Eur Heart J 2014 35 3033 3080 10.1093/eurheartj/ehu243 25173341 \n7. Pruszczyk P Torbicki A Kuch-Wocial A Szulc M Pacho R Diagnostic value of transoesophageal echocardiography in suspected haemodynamically significant pulmonary embolism Heart 2001 85 628 634 10.1136/heart.85.6.628 11359740 \n8. Kline JA Johns KL Colucciello SA Israel EG New diagnostic tests for pulmonary embolism Ann Emerg Med 2000 35 168 180 10.1016/S0196-0644(00)70137-5 10650235 \n9. Stein PD Fowler SE Goodman LR Gottschalk A Hales CA Hull RD Multidetector computed tomography for acute pulmonary embolism N Engl J Med 2006 354 2317 2327 10.1056/NEJMoa052367 16738268 \n10. Cheitlin MD Alpert JS Armstrong WF Aurigemma GP Beller GA Bierman FZ ACC AHA guidelines for the clinical application of echocardiography Circulation 1997 95 1686 1744 10.1161/01.CIR.95.6.1686 9118558 \n11. Torbicki A Perrier A Konstantinides S Agnelli G Galie N Pruszczyk P Guidelines on the diagnosis and management of acute pulmonary embolism Eur Heart J 2008 29 2276 2315 10.1093/eurheartj/ehn475 18757870 \n12. Porter TR Shillcutt SK Adams MS Desjardins G Glas KE Olson JJ Guidelines for the use of echocardiography as a monitor for therapeutic intervention in adults: a report from the American Society of Echocardiography J Am Soc Echocardiogr 2015 28 40 56 10.1016/j.echo.2014.09.009 25559474 \n13. Rudski LG Lai WW Afilalo J Hua L Handschumacher MD Chandrasekaran K Guidelines for the echocardiographic assessment of the right heart in adults: a report from the American Society of Echocardiography. Endorsed by the European Association of Echocardiography, a registered branch of the European Society of Cardiology, and the Canadian Society of Echocardiography J Am Soc Echocardiogr 2010 23 685 713 10.1016/j.echo.2010.05.010 20620859\n\n",
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"abstract": "We describe a gravid 37-year-old Chinese lady with known triple positive primary antiphospholipid syndrome with previous recurrent deep vein thrombosis and early spontaneous miscarriages. She was managed with low-molecular weight heparin, aspirin, hydroxychloroquine, prednisolone and monthly intravenous immunoglobulin. She presented with recurrent per-vaginal bleeding at 22 weeks of gestation and was found to have abruptio placentae. Anti-coagulation was held off. She subsequently delivered a stillborn at 24 weeks and anti-coagulation was restarted. Day 5 post-delivery, she developed HELLP, with hemolytic anaemia (Hb 10.1 g/dL, haptoglobin <30 g/L, LDH 2206 U/L), elevated transaminases (AST 1196 U/L, ALT 1130 U/L) and thrombocytopenia (platelet 28 × 10^9/L). There were also episodes of acute severe headache and abdominal pain assessed to be secondary to microvascular ischemia as CT did not reveal any thrombosis. Her blood pressure hovered persistently above systolic 180 mmHg, and required at least three anti-hypertensives. These were coupled with a new onset proteinuria of 2 to 3 g/day. There was no evidence of disseminated intravascular coagulation. She was assessed to have microangiopathic antiphospholipid syndrome and was started on plasmapheresis. On Day 10 post-partum, the patient complained of foul-smelling vaginal discharge and was found to have retained products of conception, which was immediately evacuated. Her course was followed by poly-microbial sepsis secondary to Enterococcus fecalis, Klebsiella Pneumoniae and Escherichia coli. The patient was further treated with imipenem and she completed eight exchanges of plasmapheresis followed by five days of intravenous immunoglobulins with good clinical and biochemical improvement.",
"affiliations": "Division of Rheumatology, Department of Medicine, National University Hospital, Singapore.;Division of Rheumatology, Department of Medicine, National University Hospital, Singapore.;Division of Rheumatology, Department of Medicine, National University Hospital, Singapore.",
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{
"abstract": "In our study of 596 men hospitalized in the last 3 years for deep venous thrombosis-pulmonary emboli (DVT-PE), we determined the prevalence of exogenous testosterone (T) use with subsequent development of DVT-PE. Of the 596 men, 110 were now dead, 97 had cancer thought to cause DVT-PE, 250 could not be contacted, leaving 139, of whom 7 had taken T before and at the time of their admissions, 1.2% of the total cohort, a conservative estimate of the prevalence of T-associated DVT-PE. In all, 5 of the 7 DVT-PE events occurred within 3 months of initiation of T, with mean and median intervals between initiation of T and hospitalization with DVT-PE 6.7 and 2 months. Of the 7 men treated with exogenous T, all 5 men who had evaluation of thrombophilia-hypofibrinolysis were found to have previously undiagnosed familial or acquired thrombophilia or hypofibrinolysis, suggesting a thrombotic interaction between exogenous T and thrombophilia-hypofibrinolysis.",
"affiliations": "1Jewish Hospital Cholesterol Center, Jewish Hospital of Cincinnati, Cincinnati, OH, USA.",
"authors": "Glueck|Charles J|CJ|;Richardson-Royer|Caitlin|C|;Schultz|Reiker|R|;Burger|Tim|T|;Bowe|Dedrick|D|;Padda|Jagjit|J|;Wang|Ping|P|",
"chemical_list": "D013739:Testosterone",
"country": "United States",
"delete": false,
"doi": "10.1177/1076029613499819",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1076-0296",
"issue": "20(3)",
"journal": "Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis",
"keywords": "blood coagulation factors; clinical epidemiology; clinical thrombophilia; deep venous thrombosis; endocrinology; hypercoagulability",
"medline_ta": "Clin Appl Thromb Hemost",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006760:Hospitalization; D006801:Humans; D008297:Male; D008875:Middle Aged; D011655:Pulmonary Embolism; D013739:Testosterone; D019851:Thrombophilia; D020246:Venous Thrombosis",
"nlm_unique_id": "9508125",
"other_id": null,
"pages": "244-9",
"pmc": null,
"pmid": "23925401",
"pubdate": "2014-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Testosterone therapy, thrombophilia-hypofibrinolysis, and hospitalization for deep venous thrombosis-pulmonary embolus: an exploratory, hypothesis-generating study.",
"title_normalized": "testosterone therapy thrombophilia hypofibrinolysis and hospitalization for deep venous thrombosis pulmonary embolus an exploratory hypothesis generating study"
} | [
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},
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"literaturereference": "GLUECK C, RICHARDSON-ROYER C, SCHULTZ R, ET AL. TESTOSTERONE THERAPY, THROMBOPHILIA-HYPOFIBRINOLYSIS, AND HOSPITALIZATION FOR DEEP VENOUS THROMBOSIS-PULMONARY EMBOLUS: AN EXPLORATORY, HYPOTHESIS-GENERATING STUDY. CLINICAL AND APPLIED THROMBOSIS/HEMOSTASIS. 2014;20(3):244-249.",
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{
"abstract": "In Europe, induction chemotherapy (ICT) followed by radiotherapy is preferred to conventional chemoradiotherapy to avoid total laryngectomy in patients with laryngeal/hypopharyngeal cancer. In comparison with conventional radiotherapy, bioradiotherapy with cetuximab significantly improves locoregional control rates (LCRs) and overall survival (OS) without any increase in unmanageable toxicity.\n\n\n\nPatients included had untreated non-metastatic stage III-IV laryngeal/hypopharyngeal invasive squamous cell carcinoma. Good responders after three cycles of docetaxel-cisplatin-5-fluorouracil (TPF)-ICT (docetaxel and cisplatin, 75 mg/m2 each on day 1, and 5-fluorouracil, 750 mg/m2/day on days 1-5) every 3 weeks were randomised to receive radiotherapy (70 Gy) with concurrent cisplatin (100 mg/m2/day on days 1, 22 and 43 of radiotherapy) or cetuximab (400 mg/m2 of loading dose, 250 mg/m2/week during radiotherapy). The primary end-point was larynx preservation. The secondary end-points were laryngo-oesophageal dysfunction-free survival (LEDFS), LCR and OS.\n\n\n\nA total of 153 patients were enrolled. Among 126 TPF-ICT responders, 116 were randomised to receive either cisplatin (n = 60) or cetuximab (n = 56). The median follow-up was 77.5 months. Five-year OS rates were 66.6% (95% confidence interval [CI]: 0.54-0.79) versus 66.9% (95% CI: 0.54-0.79) (p = 0.9), respectively. Five-year LCRs were 79.8% (95% CI: 69.5-90.0) versus 67.8% (95% CI: 55.1-80.5%) (p = 0.18). Five-year LEDFS was 62.2% (95% CI: 49.7-74.8%) versus 56.2% (95% CI: 43.0-69.4) (p = 0.38). Late grade III/IV salivary gland and laryngeal toxicity occurred in 10.3% versus 9.8% and 6.8% versus 11.8% of patients receiving cisplatin-radiotherapy versus cetuximab, respectively.\n\n\n\nNo significant difference in LEDFS was observed between the two arms. TPF-ICT followed by conventional chemoradiotherapy or cetuximab was feasible, and long-term toxicity was not statistically different between the two arms. LEDFS appears as a relevant end-point.",
"affiliations": "Centre Hospitalier Régional et Universitaire, Henry Kaplan Center, Clinique D'Oncologie et de Radiothérapie, Tours, France; Université François Rabelais de Tours, France; EA 7505, \"Education Ethique Santé\", EES, Tours, France. Electronic address: guillaume.janoray@yahoo.fr.;Centre Hospitalier Régional et Universitaire, Henry Kaplan Center, Clinique D'Oncologie et de Radiothérapie, Tours, France.;Clinique Sainte Catherine, Avignon, France.;Centre Hospitalier de Lorient, Lorient, France.;Institut de Cancérologie de Lorraine, Vandoeuvre Lès Nancy, France.;Centre François Baclesse, Caen, France.;Centre René Gauducheau, Nantes, France.;Centre Hospitalier Régional et Universitaire, Henry Kaplan Center, Clinique D'Oncologie et de Radiothérapie, Tours, France.;Centre Hospitalier Régional et Universitaire, Henry Kaplan Center, Clinique D'Oncologie et de Radiothérapie, Tours, France.;Centre Hospitalier Régional et Universitaire, Henry Kaplan Center, Clinique D'Oncologie et de Radiothérapie, Tours, France; Université François Rabelais de Tours, France.",
"authors": "Janoray|Guillaume|G|;Pointreau|Yoann|Y|;Alfonsi|Marc|M|;Sire|Christian|C|;Geoffrois|Lionel|L|;de Raucourt|Dominique|D|;Bardet|Etienne|E|;Calais|Marie-Hélène|MH|;Garaud|Pascal|P|;Calais|Gilles|G|",
"chemical_list": "D000068818:Cetuximab; D002945:Cisplatin",
"country": "England",
"delete": false,
"doi": "10.1016/j.ejca.2020.04.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-8049",
"issue": "133()",
"journal": "European journal of cancer (Oxford, England : 1990)",
"keywords": "Induction chemotherapy; Laryngo-oesophageal dysfunction-free survival; Larynx preservation; Quality of life; Radiation therapy",
"medline_ta": "Eur J Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D002294:Carcinoma, Squamous Cell; D000068818:Cetuximab; D059186:Chemoradiotherapy, Adjuvant; D002945:Cisplatin; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005602:France; D006801:Humans; D007012:Hypopharyngeal Neoplasms; D060828:Induction Chemotherapy; D007822:Laryngeal Neoplasms; D008297:Male; D008875:Middle Aged; D059351:Organ Sparing Treatments; D013997:Time Factors; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9005373",
"other_id": null,
"pages": "86-93",
"pmc": null,
"pmid": "32454417",
"pubdate": "2020-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Induction chemotherapy followed by cisplatin or cetuximab concomitant to radiotherapy for laryngeal/hypopharyngeal cancer: Long-term results of the TREMPLIN randomised GORTEC trial.",
"title_normalized": "induction chemotherapy followed by cisplatin or cetuximab concomitant to radiotherapy for laryngeal hypopharyngeal cancer long term results of the tremplin randomised gortec trial"
} | [
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"literaturereference_normalized": "induction chemotherapy followed by cisplatin or cetuximab concomitant to radiotherapy for laryngeal hypopharyngeal cancer long term results of the tremplin randomised gortec trial",
"qualification": "3",
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},
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] |
{
"abstract": "BACKGROUND\nGastroesophageal reflux disease (GERD) is a common complication in the spinal cord injury (SCI) population. Surgical treatment of GERD has a unique risk/benefit profile in this population.\n\n\nRESULTS\nThis 68-year-old male with chronic incomplete tetraplegia, dyslipidemia, and well-controlled diabetes mellitus underwent Roux-en-Y gastric bypass surgery (RYGBP) for intractable biliary reflux. Postoperatively, the patient had resolution of his symptoms but he also presented with significant weight loss and dumping syndrome. While he did have improvement in his dyslipidemia there was no change in his functional status.\n\n\nCONCLUSIONS\nRYGBP is an option for refractory GERD treatment in the SCI population but preoperative risk assessment and close monitoring postoperatively is essential.",
"affiliations": null,
"authors": "Caruso|Deborah|D|;Tower|Donald|D|;Goetz|Lance|L|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1179/2045772314Y.0000000260",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1079-0268",
"issue": "38(4)",
"journal": "The journal of spinal cord medicine",
"keywords": "Gastroesophageal reflux disease; Incomplete tetraplegia; Roux-en-Y gastric bypass surgery",
"medline_ta": "J Spinal Cord Med",
"mesh_terms": "D000368:Aged; D001655:Bile Reflux; D015390:Gastric Bypass; D006801:Humans; D008297:Male; D011782:Quadriplegia",
"nlm_unique_id": "9504452",
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"pages": "556-8",
"pmc": null,
"pmid": "25243335",
"pubdate": "2015-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23147521;14639569;22990271;19727973;16198710;23515976;23233009;10752870;6347313;12946831;16901370;16372614;21195675;16288128;22044980;17543776",
"title": "Roux-en-Y gastric bypass for intractable biliary reflux in an individual with incomplete tetraplegia.",
"title_normalized": "roux en y gastric bypass for intractable biliary reflux in an individual with incomplete tetraplegia"
} | [
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},
{
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{
"abstract": "Adult-onset Still's disease (AOSD) sometimes demonstrates hematologic disorder, whereas acquired amegakaryocytic thrombocytopenia (AAT) involvement is extremely rare. We herein report a 67-year-old woman with relapse of AOSD who concomitantly developed AAT. Thrombocytopenia along with high disease activity of AOSD was resistant to high-dose prednisolone, even in combination with methotrexate and tacrolimus. However, alternative treatment with cyclosporine after administering tocilizumab resulted in the improvement of thrombocytopenia, ultimately demonstrating that combination therapy based on suppressing the intractable disease activity of AOSD and subsequently adding a reliable immunosuppressant was required to achieve remission.",
"affiliations": "Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.;Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.;Department of Laboratory Medicine, Shinshu University Hospital, Japan.;Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.;Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.;Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan.",
"authors": "Ichikawa|Takanori|T|;Shimojima|Yasuhiro|Y|;Otuki|Toshiaki|T|;Ueno|Ken-Ichi|KI|;Kishida|Dai|D|;Sekijima|Yoshiki|Y|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D011239:Prednisolone; C502936:tocilizumab; D016559:Tacrolimus; D008727:Methotrexate",
"country": "Japan",
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"doi": "10.2169/internalmedicine.2929-19",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3139139910.2169/internalmedicine.2929-19Case ReportAcquired Amegakaryocytic Thrombocytopenia in Adult-onset Still's Disease: Successful Combination Therapy with Tocilizumab and Cyclosporine Ichikawa Takanori 1Shimojima Yasuhiro 1Otuki Toshiaki 2Ueno Ken-ichi 1Kishida Dai 1Sekijima Yoshiki 1\n1 Department of Medicine (Neurology and Rheumatology), Shinshu University School of Medicine, Japan\n2 Department of Laboratory Medicine, Shinshu University Hospital, JapanCorrespondence to Dr. Yasuhiro Shimojima, yshimoji@shinshu-u.ac.jp\n\n6 8 2019 1 12 2019 58 23 3473 3478 28 2 2019 25 6 2019 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).Adult-onset Still's disease (AOSD) sometimes demonstrates hematologic disorder, whereas acquired amegakaryocytic thrombocytopenia (AAT) involvement is extremely rare. We herein report a 67-year-old woman with relapse of AOSD who concomitantly developed AAT. Thrombocytopenia along with high disease activity of AOSD was resistant to high-dose prednisolone, even in combination with methotrexate and tacrolimus. However, alternative treatment with cyclosporine after administering tocilizumab resulted in the improvement of thrombocytopenia, ultimately demonstrating that combination therapy based on suppressing the intractable disease activity of AOSD and subsequently adding a reliable immunosuppressant was required to achieve remission. \n\nadult-onset Still's diseaseacquired amegakaryocytic thrombocytopeniathrombocytopeniatocilizumabcyclosporineserum ferritin\n==== Body\nIntroduction\nAdult-onset Still's disease (AOSD) is a systemic autoimmune inflammatory disease manifesting as spikes of a fever, polyarthritis, evanescent rash, pharyngitis, lymphadenopathy, and hepatosplenomegaly. Some complications related to AOSD appear in the active phase of this disease. In particular, macrophage activation syndrome (MAS), disseminated intravascular coagulation (DIC), and thrombotic thrombocytopenic purpura (TTP) can be life-threatening complications (1,2).\n\nThese hematologic abnormalities cause thrombocytopenia, which is demonstrated in approximately 15% of patients with acute AOSD (3) and can be a predictive factor of the prognosis (1,4). Even though immune thrombocytopenia (ITP) is also a representative autoimmune disorder showing thrombocytopenia and frequently found in certain autoimmune diseases, such as systemic lupus erythematosus (SLE) and antiphospholipid syndrome (5,6), ITP is rarely involved in AOSD, with only one case report describing its involvement in a case of systemic idiopathic juvenile arthritis (7).\n\nAcquired amegakaryocytic thrombocytopenia (AAT) is another rare hematologic disorder manifesting as severe thrombocytopenia with a marked reduction in or absence of megakaryocyte in the bone marrow tissue. The pathogenesis of AAT remains unclear, but immune-mediated interaction has been noted (8,9).\n\nWe herein report a patient who developed refractory AAT along with the deterioration of AOSD in whom the co-administration of tocilizumab (TCZ) with cyclosporine (CsA) resulted in a favorable outcome.\n\nCase Report\nA 67-year-old woman who had a 13-year history of AOSD was admitted to our hospital following appetite loss, general fatigue, and diffuse cutaneous rash together with thrombocytopenia. She had initially experienced a spiked fever, evanescent rash, lymphadenopathy, splenomegaly, and polyarthritis with explicit laboratory findings, including an increased number of leukocytes (13,760 /μL; normal, 3,300-8,600 /μL), neutrophils (11,500 /μL; normal, 1,170-5,780 /μL), and platelets (42.3×104/μL; normal, 15.8×104-34.8×104/μL) as well as elevated serum levels of C-reactive protein (CRP) (9.78 mg/dL; normal, <0.10 mg/dL) and ferritin (3,894 ng/mL; normal, 10-120 ng/mL). These findings established the diagnosis of AOSD according to the criteria proposed by Yamaguchi et al. (10).\n\nTacrolimus (TAC) and methotrexate (MTX) were sequentially administered with an increase in the prednisolone (PSL) dose, since she had experienced disease recurrence several times. However, she had shown no relapsing events within the latest 6 years while maintaining her regular medication (TAC, 1 mg daily; MTX, 10 mg weekly; PSL 8 mg daily).\n\nAt admission, a physical examination revealed a body temperature of 37.0℃, systemic erythematous eruption, and splenomegaly. Neither lymphadenopathy nor arthritis was shown. A laboratory examination showed normal finding for the renal function without any abnormalities on a urine test. The serum levels of total bilirubin, lactate dehydrogenase, and alkaline phosphatase were within the normal range, although slightly increased serum levels of aspartate transaminase (43 U/L; normal, 13-30 U/L) and alanine transaminase (51 U/L; normal, 7-23 U/L) were noted. The platelet count was 9.1×104/μL, whereas the leukocyte count was within the normal range (7,960 /μL) without any abnormal finding on a peripheral blood smear. The hemoglobin levels were also within the normal range (11.6 g/dL; normal, 11.6-14.8 g/dL), and no crushed erythrocytes were noted. Increased serum levels of CRP and ferritin were shown (12.79 mg/dL and 1,159 ng/mL, respectively). No positivity for rheumatoid factor or autoantibodies, including antinuclear antibody, anti-ds DNA antibody, anti-Sm antibody, anti-U1-RNP antibody, anti-SS-A/Ro antibody, anti-SS-B/La antibody, anti-phospholipid antibodies, and anti-neutrophil cytoplasmic antibodies specific for either myeloperoxidase or proteinase-3 were reported. Negative reactions to the platelet-associated IgG and heparin-induced thrombocytopenia platelet factor 4 antibody were also demonstrated. The serum levels of haptoglobin were within the normal range, and those of complement factors remained normal or high, as follows: C3 (94.0 mg/dL; normal, 86-160 mg/dL), C4 (19.8 mg/dL; normal, 17-45 mg/dL), and CH50 (60.1 U/mL; normal, 30-53 U/mL). Immune complex (C1q) was undetected in the serum. Normal plasma levels of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 activity were detected. Coagulation tests including prothrombin time, activated partial thromboplastin time, and fibrinogen had normal results. Serological tests for hepatitis C virus, human-immunodeficiency virus (HIV), parvovirus B19, and cytomegalovirus (CMV) were negative. The levels of procalcitonin and (1,3)-β-D-glucan were also within the normal range. Even though she had previously been diagnosed as an inactive hepatitis B virus (HBV) carrier, the levels of HBV DNA and HBV surface antigen were undetectable.\n\nA systemic survey with whole-body computed tomography revealed no findings suggestive of malignancy, infection, or other visceral abnormalities except for splenomegaly. Gastrointestinal endoscopy also revealed neither neoplastic nor ulcerative findings; in addition, the findings of Helicobacter pylori infection were negative.\n\nIntravenous infusion of methylprednisolone (mPSL) (1 g daily for 3 consecutive days) was started, and the PSL dose was increased to 60 mg (1 mg/kg), resulting in the short-term improvement of thrombocytopenia and decreased serum levels of ferritin (Fig. 1). Subsequently, TAC was increased to 2 mg daily, ultimately adjusting the blood trough concentration to 7.6 ng/mL. However, diffuse skin eruption and general fatigue persisted; furthermore, the number of platelets had again decreased approximately three weeks after the mPSL administration. TAC and MTX were stopped due to concerns of adverse drug reactions; nevertheless, the deterioration of thrombocytopenia persisted, along with increases in the serum levels of ferritin.\n\nFigure 1. The clinical course of the patient. MTX: methotrexate, TAC: tacrolimus, mPSL pulse: intravenous infusion of methylprednisolone (1 g daily for 3 days), PSL: prednisolone, IVIg: intravenous immunoglobulin infusion (0.4 g daily for 5 days), CsA: cyclosporine, TCZ: tocilizumab [560 mg (8 mg/kg) every 4 weeks], BM: bone marrow\n\nA bone marrow biopsy was therefore performed when the platelet count reached 6.3×104/μL. The pathological findings demonstrated moderate hypocellular marrow and an apparent decrease in megakaryocytes despite the maintenance of myeloid, lymphoid, and erythroid cell differentiation without proven hemophagocytosis or dysplasia (Fig. 2). The number of megakaryocytes was 0-1 per 10 microscopic fields at high-power magnification. In situ hybridization to Epstein-Barr virus (EBV)-encoding RNA was negative in the bone marrow specimen. Accordingly, she was found to have thrombocytopenia ascribable to AAT along with the deterioration of AOSD.\n\nFigure 2. The pathological finding of the bone marrow biopsy, showing ×40 and ×200 magnification images (A and B, respectively). The bone marrow specimen showed moderate hypocellular finding and a remarkable decrease in megakaryocyte, whereas normal findings were noted for myeloid, lymphoid, and erythroid cells differentiation without dysplasia or obvious phagocytosis.\n\nIntravenous immunoglobulin infusion (IVIg) (0.4 g daily for 5 days) was added because the readministration of mPSL was insufficient for improving the thrombocytopenia and high serum levels of ferritin; however, a reduction in the platelet counts was still demonstrated along with an increase in the serum ferritin levels (Fig. 1). Therefore, TCZ was intravenously administered at 560 mg (8 mg/kg) every 4 weeks. The platelet count increased after the first infusion of TCZ, and decreased serum levels of ferritin were also obtained. The administration of CsA, whose trough blood concentration was adjusted to 150-200 ng/mL, was additionally required because the platelet count was revealed to have again decreased. Consequently, she achieved and has maintained clinical remission.\n\nDiscussion\nComplication with a hematologic abnormality is often involved in the acute phase of AOSD (1,4,11). In the present patient, thrombocytopenia was concomitantly found when the deterioration of AOSD was demonstrated. Regarding the complications related to active AOSD, which play a major role in thrombocytopenia, MAS should be suspected and it is also implicated in the prognosis of AOSD patients (2,12-14). DIC and TTP have been also shown to be life-threatening hematologic disorders that can occur in the active phase of the disease (1-3). However, our patient showed no evidence of DIC or TTP according to the laboratory findings, nor was MAS observed based on the relevant diagnostic criteria (14,15).\n\nAAT has been defined as an independent thrombocytopenic disease that is differentiated from other causal disorders, such as ITP, aplastic anemia, and myelodysplastic syndrome, but its development can sometimes be induced by exposure to certain toxins and viruses, including HIV, CMV, EBV, and parvovirus B 19 (8,9,16). The present patient had no evidence of causal viral infections or toxic exposure, so the pathological findings of the bone marrow, in which a marked reduction in megakaryocytes was revealed despite the retention of other myeloid progenitor cells, had to be considered in order to exclude ITP and achieve a definitive diagnosis of AAT.\n\nAAT has been reported to occur as a consequence of some autoimmune diseases, including SLE, systemic sclerosis (SSc), and eosinophilic fasciitis (17-20). Regarding AOSD, only one case has been reported (21). Given the clinical findings of concomitant general fatigue, skin eruption, splenomegaly, and elevated serum levels of ferritin along with thrombocytopenia, the pathogenic mediators in acute AOSD might influence the development of AAT. Furthermore, thrombocytopenia is reportedly promoted along with increases in serum ferritin levels, which is strongly associated with the disease activity of AOSD (1,4,22), definitively demonstrating the correspondence between thrombocytopenia and the disease activity in AOSD.\n\nWhile neither the peripheral destruction of platelets nor splenomegaly has been considered a prevalent characteristic of AAT (9,23), the present patient showed splenomegaly associated with the disease activity of AOSD, suggesting that the peripheral destruction of platelets ascribable to splenomegaly might concomitantly exist together with AAT, although AAT is the underlying cause of thrombocytopenia.\n\nIn this patient it was necessary to suppress the disease activity of AOSD because thrombocytopenia had become exacerbated together with an increase in serum levels of ferritin, which is associated with the disease activity of AOSD. Relapse was induced despite the concomitant use of MTX and TAC, which have been found to exert therapeutic efficacy in cases of PSL-resistant AOSD (24-26). The trough blood concentration of TAC is usually maintained between 5 and 10 ng/mL, which are the ideal levels for achieving therapeutic efficacy without any adverse events (27-29); however, no favorable effect was obtained in the present patient despite adjusting the trough blood concentration to an appropriate level. Furthermore, although MTX and TAC administration was stopped because it has been suggested that the medications given prior to the onset of AAT should be withdrawn in order to ascertain whether or not they might be associated with the development of AAT (9), we ultimately realized that neither MTX nor TAC had influenced the occurrence of AAT.\n\nThe sustained symptoms related to active AOSD were successfully eliminated and serum ferritin levels reduced after administering TCZ, which is well-recognized as a potent biological agent conducive to a favorable outcome in multidrug-resistant AOSD (30,31). The platelet count decreased along with increasing serum ferritin levels, suggesting that the disease activity in AOSD influenced the reduction in the platelet count. However, additional treatment was subsequently required in order to maintain the amelioration of AAT even after initiating TCZ.\n\nSome immunosuppressive agents, such as corticosteroid, antithymocyte globulin, intravenous immunoglobulin, danazol, and cyclophosphamide, have been described as a useful empirical treatment for AAT; however, whether the therapeutic responses were invalid or transient in some patients has been a matter of concern (8,9,20). In contrast, CsA has predominantly demonstrated efficacy in patients with AAT related to several autoimmune disorders (8,20,21). In fact, the additional administration of CsA contributed to the recovery from thrombocytopenia in the present patient. CsA is a calcineurin inhibitor (CNI) that suppresses the activation of T cells by inhibiting the intracellular activating signal via cyclophilin A. Therefore, abrogating the activation of T cells might ultimately be effective in repressing the development of AAT. TAC is also a CNI, and its intracellular signaling regulation is performed via the 12-kDa FK506-binding protein (32). Considering the clinical process in the present patient, suppressing disease activity in AOSD might be fundamentally required to induce the efficacy of CNIs as the optimal therapy for AAT, as TAC failed to show any therapeutic efficacy after AOSD became exacerbated. TAC eventually had to be withdrawn due to concerns about related adverse reactions in the acute phase. However, TAC may also be a useful agent for AAT when the regulation of AOSD activity can be simultaneously achieved.\n\nRegarding the pathogenic mechanism of AAT, some in vitro investigations have shown immune-mediated interactions, notably the cell-mediated suppression of megakaryocyte colony formation (19,33,34). In addition, the depletion of T cells and macrophages has been shown to help improve the marrow megakaryocyte formation in AAT, suggesting that relevant immunocompetent cells might be implicated in the development of AAT. Indeed, both macrophages and effector T cells play crucial roles in the pathogenesis of AOSD (1,14,35), and the acceleration in an innate immune system affects the production of specific proinflammatory cytokines, such as interleukin (IL)-1β, IL-6, and IL-18, which are also associated with the disease activity (36-38). In particular, IL-6 has a pleiotropic effect of inducing both innate and acquired immunities (39). The activation of macrophages was found to be regulated by treatment with TCZ (40). Therefore, the combination therapy of TCZ with CsA might be essential for broadly regulating the immune system disorders that tend to develop AAT concomitantly with AOSD deterioration.\n\nAutoantibody against thrombopoietin receptor (c-Mpl) was identified as a causal mediator of AAT related to SLE and SSc (17,18,41), although the c-Mpl concentration was not evaluated in our case or in a previous report of AAT related to AOSD (21). Other humoral mediators affecting the suppression of marrow megakaryocyte might be involved, as suggested by previous reports (8,9,42). Despite such mediators not being examined, the present patient ultimately achieved remission thanks to combination therapy with TCZ and CsA; nevertheless, it may be necessary to clarify the overall pathogenic mechanism underlying the development of AAT related to AOSD in order to establish a definite diagnostic and advanced therapeutic strategy.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nGerfaud-Valentin M , Jamilloux Y , Iwaz J , Seve P \nAdult-onset Still's disease . Autoimmun Rev \n13 : 708 -722 , 2014 .24657513 \n2. \nEfthimiou P , Kadavath S , Mehta B \nLife-threatening complications of adult-onset Still's disease . Clin Rheumatol \n33 : 305 -314 , 2014 .24435354 \n3. \nAsanuma YF , Mimura T , Tsuboi H , et al \nNationwide epidemiological survey of 169 patients with adult Still's disease in Japan . 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Cell \n66 : 807 -815 , 1991 .1715244 \n33. \nGewirtz AM , Sacchetti MK , Bien R , Barry WE \nCell-mediated suppression of megakaryocytopoiesis in acquired amegakaryocytic thrombocytopenic purpura . Blood \n68 : 619 -626 , 1986 .3488773 \n34. \nBenedetti F , de Sabata D , Perona G \nT suppressor activated lymphocytes (CD8+/DR+) inhibit megakaryocyte progenitor cell differentiation in a case of acquired amegakaryocytic thrombocytopenic purpura . Stem Cells \n12 : 205 -213 , 1994 .8199563 \n35. \nChen DY , Lan JL , Lin FJ , Hsieh TY , Wen MC \nPredominance of Th1 cytokine in peripheral blood and pathological tissues of patients with active untreated adult onset Still's disease . Ann Rheum Dis \n63 : 1300 -1306 , 2004 .15361391 \n36. \nHu Q , Shi H , Zeng T , et al \nIncreased neutrophil extracellular traps activate NLRP3 and inflammatory macrophages in adult-onset Still's disease . Arthritis Res Ther \n21 : 9 , 2019 .30616678 \n37. \nChoi JH , Suh CH , Lee YM , et al \nSerum cytokine profiles in patients with adult onset Still's disease . J Rheumatol \n30 : 2422 -2427 , 2003 .14677188 \n38. \nChen DY , Lan JL , Lin FJ , Hsieh TY \nProinflammatory cytokine profiles in sera and pathological tissues of patients with active untreated adult onset Still's disease . J Rheumatol \n31 : 2189 -2198 , 2004 .15517632 \n39. \nHunter CA , Jones SA \nIL-6 as a keystone cytokine in health and disease . Nat Immunol \n16 : 448 -457 , 2015 .25898198 \n40. \nObeng JA , Amoruso A , Camaschella GL , Sola D , Brunelleschi S , Fresu LG \nModulation of human monocyte/macrophage activity by tocilizumab, abatacept and etanercept: an in vitro study . Eur J Pharmacol \n780 : 33 -37 , 2016 .26997366 \n41. \nKuwana M , Okazaki Y , Kajihara M , et al \nAutoantibody to c-Mpl (thrombopoietin receptor) in systemic lupus erythematosus: relationship to thrombocytopenia with megakaryocytic hypoplasia . Arthritis Rheum \n46 : 2148 -2159 , 2002 .12209520 \n42. \nHoffman R , Briddell RA , van Besien K , et al \nAcquired cyclic amegakaryocytic thrombocytopenia associated with an immunoglobulin blocking the action of granulocyte-macrophage colony-stimulating factor . N Engl J Med \n321 : 97 -102 , 1989 .2659998\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(23)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "acquired amegakaryocytic thrombocytopenia; adult-onset Still's disease; cyclosporine; serum ferritin; thrombocytopenia; tocilizumab",
"medline_ta": "Intern Med",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D001855:Bone Marrow Diseases; D003131:Combined Modality Therapy; D016572:Cyclosporine; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D008727:Methotrexate; D011239:Prednisolone; D011696:Purpura, Thrombocytopenic; D016706:Still's Disease, Adult-Onset; D016559:Tacrolimus",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "3473-3478",
"pmc": null,
"pmid": "31391399",
"pubdate": "2019-12-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25382730;9972972;24646465;7193425;15517632;28412707;25036233;2659998;17437176;26997366;29301129;14673984;16432869;18372362;11206351;19005182;2005777;14677188;30616678;24515813;24657513;16957888;14558048;3484642;14978695;29657144;23173570;1759171;25898198;8199563;30279267;3488773;26314788;24435354;1578458;12209520;12794833;11919310;19040301;1715244;15361391;27457756",
"title": "Acquired Amegakaryocytic Thrombocytopenia in Adult-onset Still's Disease: Successful Combination Therapy with Tocilizumab and Cyclosporine.",
"title_normalized": "acquired amegakaryocytic thrombocytopenia in adult onset still s disease successful combination therapy with tocilizumab and cyclosporine"
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"abstract": "The aim of this report is to present a case of cytomegalovirus (CMV) retinitis in an immunocompetent patient using lenalidomide.\nCase report with fundus photography, spectral-domain optical coherence tomography, and fluorescein angiography imaging.\nA 55-year-old male with history of multiple myeloma treated with lenalidomide presented with blurriness and floaters in his right eye and was found to have vitreous biopsy-confirmed CMV retinitis. The patient was treated with pars plana vitrectomy, oral valganciclovir, and intravitreal foscarnet. More than one year later, the patient was doing well with visual acuity of 20/25 and no recurrence of retinitis.\nThis represents the second report of CMV retinitis associated with lenalidomide therapy. It suggests that even immunocompetent patients can be affected by CMV retinitis in the context of lenalidomide treatment. It is critical that patients being treated with lenalidomide receive prompt evaluation if they develop ophthalmic symptoms.",
"affiliations": "Department of Ophthalmology, Baylor College of Medicine, 6565 Fannin Street, NC-205, Houston, TX 77030, USA.;Department of Ophthalmology, Baylor College of Medicine, 6565 Fannin Street, NC-205, Houston, TX 77030, USA.",
"authors": "Adams|Matthew K|MK|;Weng|Christina Y|CY|0000-0003-3135-1922",
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"fulltext": "\n==== Front\nCase Rep Ophthalmol MedCase Rep Ophthalmol MedCRIOPMCase Reports in Ophthalmological Medicine2090-67222090-6730Hindawi 10.1155/2019/3516394Case ReportCytomegalovirus Retinitis Associated with Lenalidomide Use for Multiple Myeloma in an Immunocompetent Patient Adams Matthew K. http://orcid.org/0000-0003-3135-1922Weng Christina Y. christina.weng@bcm.eduDepartment of Ophthalmology, Baylor College of Medicine, 6565 Fannin Street, NC-205, Houston, TX 77030, USAAcademic Editor: Alexander A. Bialasiewicz\n\n2019 25 2 2019 2019 35163947 1 2019 11 2 2019 Copyright © 2019 Matthew K. Adams and Christina Y. Weng.2019This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Purpose\n The aim of this report is to present a case of cytomegalovirus (CMV) retinitis in an immunocompetent patient using lenalidomide.\n\n Methods\n Case report with fundus photography, spectral-domain optical coherence tomography, and fluorescein angiography imaging.\n\n Results\n A 55-year-old male with history of multiple myeloma treated with lenalidomide presented with blurriness and floaters in his right eye and was found to have vitreous biopsy-confirmed CMV retinitis. The patient was treated with pars plana vitrectomy, oral valganciclovir, and intravitreal foscarnet. More than one year later, the patient was doing well with visual acuity of 20/25 and no recurrence of retinitis.\n\n Conclusion\n This represents the second report of CMV retinitis associated with lenalidomide therapy. It suggests that even immunocompetent patients can be affected by CMV retinitis in the context of lenalidomide treatment. It is critical that patients being treated with lenalidomide receive prompt evaluation if they develop ophthalmic symptoms.\n==== Body\n1. Introduction\nCytomegalovirus (CMV) infection typically occurs in immunocompromised patients and can present as a primary infection, reinfection, or reactivation. While generally asymptomatic in immunocompetent individuals, CMV can lead to serious pathology in those who are immunocompromised, such as transplant recipients, patients with immunodeficiency disorders, and those on immunosuppressive treatment [1].\n\nLenalidomide (Revlimid®; Celgene, Summit, NJ), an analogue of thalidomide, is an FDA-approved treatment for multiple myeloma, myelodysplastic syndrome, and mantle cell lymphoma. Its mechanism of action is complex and includes immunomodulation, antiangiogenic effects, and direct cytotoxic activity [2, 3]. While it is thought to have a more favorable side-effect profile than its parent drug, thalidomide, it still has potential serious adverse effects that include birth defects, neutropenia, and thrombocytopenia [4].\n\nCMV retinitis is most commonly seen in AIDS patients with a CD4+ count < 50 cells/µL; it is less commonly seen in patients with other causes of immunosuppression [5]. However, it has been reported once before in an immunocompetent multiple myeloma patient following lenalidomide therapy [6]. Here, we present the second reported case of CMV retinitis in a similar patient who was treated with lenalidomide; differences in management between the first reported case and ours are discussed.\n\n2. Case Report\nA 55-year-old male with multiple myeloma on his eighth cycle of chemotherapy with bortezomib, lenalidomide (recently decreased to 10 mg po daily from 25 mg po daily), and dexamethasone presented with a two-week history of worsening blurriness and floaters in his right eye. An outside provider noted panuveitis and retinal whitening on examination. Anterior chamber paracentesis was negative for CMV, HSV-1, HSV-2, VZV, and Toxoplasmosis. Oral valacyclovir and topical steroids and cycloplegics were started for presumed acute retinal necrosis, and the patient was referred to our institution for further diagnostic work-up and management. Of note, recent serum laboratory values revealed a normal white blood cell count (9.41 k/µL; range 4.5–11 k/µL) and neutrophilic profile (71.0%; range 39–69%) with negative CMV antigen and aerobic blood culture; lambda light chain immunoglobulins were significantly elevated (67.29 mg/L, range 5.7–26.3 mg/L) and alpha-2 globulin proteins were abnormally high on serum electrophoresis (0.93 g/dL, range 0.58–0.84 g/dL) as expected given his disease.\n\nBest-corrected visual acuity (BCVA) was 20/60 in the right eye, 20/20 in the left. Pupils and intraocular pressures were normal. Slit lamp examination of the right eye revealed mild anterior chamber flare without cell, mild cataract, and 3+ cell in the anterior vitreous. Dilated funduscopic examination revealed vitreous haze, diffuse vascular sheathing, and a poorly-defined area of inferotemporal retinal whitening without associated hemorrhage (Figure 1). The left eye was normal. Spectral-domain optical coherence tomography of the right eye showed no significant abnormalities aside from overlying hyperreflective vitreous debris (Figure 2). Fluorescein angiography demonstrated irregular vascular filling and blockage from vitreous debris (Figure 3).\n\nGiven the previous negative anterior chamber tap, worsening clinical exam, and high suspicion for infectious retinitis, the decision was made to proceed with a diagnostic vitrectomy. Diluted and undiluted vitreous biopsy were obtained via a 23-gauge pars plana vitrectomy. Intraoperatively, extensive retinal whitening and granular necrosis were observed along with diffuse vascular sheathing and perivascular inflammatory aggregates (Figure 4). Endolaser was placed 360 degrees prophylactically. The vitreous biopsy was sent for gram stain, cytology (to rule out malignant infiltration), fungal culture, Toxoplasmosis, AFB, VZV, EBV, CMV, HSV-1, HSV-2, and RPR testing.\n\nOn postoperative day 2, the vitreous PCR returned positive for CMV; all other tests were negative. The patient was switched from oral valacyclovir to valganciclovir 900 mg po twice daily. By postoperative day 3, the patient's visual acuity declined to 20/200 and there was an increase in anterior chamber cell. Hence, intravitreal foscarnet (2.4 mg/0.1 cc) was injected. At the postoperative week 1 visit, visual acuity had not improved, but the area of retinitis appeared less active (Figure 5). Repeat intravitreal foscarnet was given. Improvement continued over the first month with complete resolution of the patient's uveitis, vasculitis, and retinitis. By postoperative month 2, BCVA had improved to 20/63 without evidence of active disease. Five months after the vitreous biopsy, the patient remained without signs of intraocular infection with BCVA 20/50, mostly limited by cataract. Following cataract extraction one year later, his visual acuity was 20/25 with stable fundus findings (Figure 6).\n\n3. Discussion\nCytomegalovirus retinitis is thought to result from reactivation of a latent infection and is typically only seen in those with a compromised immune system. Multiple myeloma itself, although capable of causing an immunocompromised state by affecting cellular immunity, has never been reported to cause CMV retinitis [7]. Given that our patient was essentially immunocompetent (by definition of a normal white blood cell count and differential) along with the fact that lenalidomide-associated CMV retinitis has been previously reported, it is reasonable to assume that lenalidomide played a role in this patient's development of CMV retinitis. Notably, none of his other medications have been associated with this condition.\n\nThe first case of CMV retinitis following lenalidomide treatment was presented by Lim et al. in 2013 [6]. Similar to this case, CMV retinitis presented in their patient with multiple myeloma, on lenalidomide therapy, and in the absence of detectable systemic CMV titers. Lenalidomide can cause myelosuppression, but, like the previously-reported patient, our patient had a normal white blood cell count without neutropenia [4]. Our patient also received multiple blood draws during his treatment period and never had detectable CMV antigen. This lends itself to the likelihood that lenalidomide crosses the blood-retinal barrier to alter local intraocular immunity which can lead to CMV reactivation [8]. While no consensus exists, there is some evidence to support that the drug can modulate the blood-retinal barrier which typically protects the eye from bloodstream pathogens [9].\n\nSome differences between the diagnostic work-up and management of these two cases exist. Unlike the case presented by Lim and colleagues, our patient first received an anterior chamber paracentesis which was negative. Vitreous sample was obtained surgically via pars plana vitrectomy as opposed to a vitreous tap. Although both approaches were successful in identifying a causative organism, our approach allowed for concurrent removal of vitreous debris and placement of prophylactic endolaser to the necrotic retina. This may prevent future retinal detachment, a devastating sequela of CMV retinitis that occurs in upwards of 30% of patients [10]. Our patient was treated only with oral valganciclovir versus intravenous ganciclovir. Both patients did well with a good visual outcome and no recurrence. We continued our patient on a maintenance dose of oral valganciclovir 900 mg po daily for the duration of his lenalidomide therapy.\n\nThis case represents the second report of CMV retinitis associated with lenalidomide, a relatively new drug that received FDA approval in 2013. Lenalidomide is a derivative of thalidomide and works by modulating the substrate specificity of the CRL4CRBNE3 ubiquitin ligase which leads to subsequent proteasomal degradation of certain transcription factors that kills multiple myeloma cells. It is more appropriate to consider lenalidomide an immunomodulator rather than an immunosuppressant because its use actually stimulates certain immunogenic cell lines (IL-2 production in T lymphocytes, natural killer cells). Its use in diseases like myelodysplastic syndromes and mantle cell lymphoma is growing, and it is possible that cases such as this one will be seen more frequently in upcoming years. Although CMV retinitis often carries a poor visual prognosis, its course can be halted with early diagnosis and treatment. Because CMV retinitis classically affects AIDS patients, providers may fail to consider this diagnosis in the types of patients treated with lenalidomide. However, it seems that even immunocompetent HIV-negative patients can be affected by CMV retinitis in the context of lenalidomide treatment. Thus, it is critical that patients being treated with lenalidomide receive prompt evaluation if they develop ophthalmic symptoms.\n\nAdditional Points\n\nSummary Statement. A relatively immunocompetent patient with multiple myeloma being treated with lenalidomide presented with cytomegalovirus (CMV) retinitis. This report supports an association between lenalidomide and CMV retinitis and offers a different management approach from the one previously reported in a similar case.\n\nDisclosure\nNo grant support or research funding was received in relation to this study. The authors alone are responsible for the content and writing of the manuscript.\n\nConflicts of Interest\nThe authors report no relevant conflicts of interest.\n\nFigure 1 Color fundus photograph of the right eye shows vitreous haze, vascular sheathing, and granular retinal whitening in the inferotemporal periphery (inset).\n\nFigure 2 Spectral-domain OCT of the right eye demonstrates vitreous debris overlying a well-preserved foveal contour.\n\nFigure 3 Fluorescein angiography of the right eye reveals irregular filling defects and blockage from overlying vitreous debris; of note, the inferotemporal area of retinal whitening is not captured in this image.\n\nFigure 4 Intraoperative image of fundus reveals diffuse vascular sheathing with perivascular inflammatory aggregates and an area of granular retinal necrosis and whitening (arrows) involving the inferotemporal periphery.\n\nFigure 5 Fundus photograph from postoperative week 1 demonstrates improving vasculitis and retinitis.\n\nFigure 6 Fundus photograph more than one year following initial presentation shows resolution of retinitis with laser scars in the periphery.\n==== Refs\n1 Sissons J. G. P. Carmichael A. J. Clinical aspects and management of cytomegalovirus infection Infection 2002 44 2 78 83 2-s2.0-0036068175 10.1053/jinf.2001.0949 12076065 \n2 Arora M. Gowda S. Tuscano J. A comprehensive review of lenalidomide in B-cell non-Hodgkin lymphoma Therapeutic Advances in Hematology 2016 7 4 209 221 10.1177/2040620716652861 27493711 \n3 Kotla V. Goel S. Nischal S. Mechanism of action of lenalidomide in hematological malignancies Journal of Hematology & Oncology 2009 2 12, article 36 10.1186/1756-8722-2-36 2-s2.0-69949096727 \n4 Zeldis J. Knight R. Jacques C. Lenalidomide in multiple myeloma: current role and future directions Expert Opinion on Pharmacotherapy 2011 11 5 829 842 10.1517/14656566.2011.557566 2-s2.0-79951621844 \n5 Kuo I. C. Kempen J. H. Dunn J. P. Vogelsang G. Jabs D. A. Clinical characteristics and outcomes of cytomegalovirus retinitis in persons without human immunodeficiency virus infection American Journal of Ophthalmology 2004 138 3 338 346 2-s2.0-4444349784 10.1016/j.ajo.2004.04.015 15364214 \n6 Lim H. Y. Francis D. Yeoh J. Lim L. L. Cytomegalovirus retinitis after treatment with lenalidomide for multiple myeloma Retinal Cases and Brief Reports 2013 7 2 172 175 2-s2.0-84878059734 10.1097/ICB.0b013e31827aee62 25390816 \n7 Nucci M. Anaissie E. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents Clinical Infectious Diseases 2009 49 8 1211 1225 2-s2.0-70349898336 10.1086/605664 19769539 \n8 Zhang M. Xin H. Atherton S. S. Murine cytomegalovirus (MCMV) spreads to and replicates in the retina after endotoxin-induced disruption of the blood-retinal barrier of immunosuppressed BALB/c mice Journal of NeuroVirology 2005 11 4 365 375 10.1080/13550280591002432 2-s2.0-27144440156 16162479 \n9 Cox M. C. Mannino G. Lionetto L. Naso V. Simmaco M. Spiriti M. A. A. Lenalidomide for aggressive B-cell lymphoma involving the central nervous system? American Journal of Hematology 2011 86 11 957 957 2-s2.0-80054023067 10.1002/ajh.22148 21990093 \n10 Holland G. N. AIDS and ophthalmology: the first quarter century American Journal of Ophthalmology 2008 145 3 397 408 10.1016/j.ajo.2007.12.001 2-s2.0-39149102154 18282490\n\n",
"fulltext_license": "CC BY",
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"issue": "2019()",
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"medline_ta": "Case Rep Ophthalmol Med",
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"references": "12076065;15364214;16162479;18282490;19674465;19769539;20210686;21990093;25390816;27493711",
"title": "Cytomegalovirus Retinitis Associated with Lenalidomide Use for Multiple Myeloma in an Immunocompetent Patient.",
"title_normalized": "cytomegalovirus retinitis associated with lenalidomide use for multiple myeloma in an immunocompetent patient"
} | [
{
"companynumb": "US-CELGENEUS-USA-20190404707",
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"literaturereference": "ADAMS M. CYTOMEGALOVIRUS RETINITIS ASSOCIATED WITH LENALIDOMIDE USE FOR MULTIPLE MYELOMA IN AN IMMUNOCOMPETENT PATIENT. ADAMS K M, WENG Y C? CYTOMEGALOVIRUS RETINITIS ASSOCIATED WITH LENALIDOMIDE USE FOR MULTIPLE MYELOMA IN AN IMMUNOCOMPETENT PATIENT: A CASE REPORTS IN OPHTHALMOLOGICAL MEDICINE? 2019, (25/FEBRUARY/2019).. 2019 FEB 25?2019:.",
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{
"abstract": "OBJECTIVE\nTreatment of patients with unresectable liver metastases is challenging. Regional therapies to the liver have been developed that maximize treatment of the localized disease process without systemic toxic adverse effects. We discuss the procedural aspects of liver chemosaturation with percutaneous hepatic perfusion (CS-PHP).\n\n\nMETHODS\nWe present as an illustration of this technique a case report of the treatment of unresectable metastatic leiomyosarcoma of the liver.\n\n\nRESULTS\nA randomized phase III trial for unresectable liver metastases from melanoma was recently completed comparing CS-PHP with melphalan vs. best alternative care (BAC). When compared with BAC, CS-PHP was associated with a significant improvement in hepatic progression-free survival (8.0 months CS-PHP vs. 1.6 months BAC, p < 0.0001) and overall progression-free survival (6.7 months CS-PHP vs. 1.6 months BAC, p < 0.0001), respectively. On the basis of these results, and given our experience as one of the treating institutions for this phase III trial, we appealed for compassionate use of CS-PHP in a patient with isolated bilobar unresectable hepatic metastases from leiomyosarcoma. Four target lesions were identified and monitored to assess treatment response. A total of 4 CS-PHP procedures were performed, with a 25 % reduction in size of the largest lesion observed and 16 month hepatic progression-free survival. Toxicity was mild (neutropenia) and manageable on an outpatient basis.\n\n\nCONCLUSIONS\nCS-PHP offers several advantages for unresectable hepatic sarcoma metastases. CS-PHP is minimally invasive and repeatable, and it has a predictable and manageable systemic toxicity profile. For appropriately selected patients, CS-PHP can delay tumor progression and could potentially improve survival.",
"affiliations": "Department of Cutaneous and Sarcoma Oncology, Moffitt Cancer Center, 12902 Magnolia Drive, SRB4, 24012, Tampa, FL 33612, USA. Jeremiah.Deneve@Moffitt.org",
"authors": "Deneve|Jeremiah L|JL|;Choi|Junsung|J|;Gonzalez|Ricardo J|RJ|;Conley|Anthony P|AP|;Stewart|Steven|S|;Han|Dale|D|;Werner|Philip|P|;Chaudhry|Tariq A|TA|;Zager|Jonathan S|JS|",
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"country": "United States",
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"issue": "35(6)",
"journal": "Cardiovascular and interventional radiology",
"keywords": null,
"medline_ta": "Cardiovasc Intervent Radiol",
"mesh_terms": "D000279:Administration, Cutaneous; D000368:Aged; D000792:Angiography; D001706:Biopsy; D010478:Chemotherapy, Cancer, Regional Perfusion; D004621:Embolization, Therapeutic; D005260:Female; D006801:Humans; D007890:Leiomyosarcoma; D008113:Liver Neoplasms; D049268:Positron-Emission Tomography; D012811:Sigmoid Neoplasms; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "8003538",
"other_id": null,
"pages": "1480-7",
"pmc": null,
"pmid": "22699779",
"pubdate": "2012-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Chemosaturation with percutaneous hepatic perfusion for unresectable isolated hepatic metastases from sarcoma.",
"title_normalized": "chemosaturation with percutaneous hepatic perfusion for unresectable isolated hepatic metastases from sarcoma"
} | [
{
"companynumb": "DE-APOPHARMA USA, INC.-2016AP015208",
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"literaturereference": "JEREMIAH L., DENEVE, J.L.,CHOI, J., GONZALEZ, R.J., CONLEY, A.P.,STEWART, S., HAN, D., WERNER, P., CHAUDHRY, T.A., ZAGER, J.S.. CHEMOSATURATION WITH PERCUTANEOUS HEPATIC PERFUSION FOR UNRESECTABLE ISOLATED HEPATIC METASTASES FROM SARCOMA. CARDIOVASCULAR AND INTERVENTIONAL RADIOLOGY, DOI 10.1007/S00270-012-0425-X. 2012;N/A:N/A ONLINE",
"literaturereference_normalized": "chemosaturation with percutaneous hepatic perfusion for unresectable isolated hepatic metastases from sarcoma",
"qualification": "1",
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},
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}
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{
"abstract": "A 44-year-old man with hepatitis B virus (HBV)-related cirrhosis underwent living donor liver transplantation at our institute. Induction of immunosuppression was achieved with basiliximab, due to deranged renal function, and maintained with prednisolone, tacrolimus and mycophenolate mofetil. The intraoperative and immediate postoperative periods were fairly uneventful. A duplex scan, taken during the third week post-transplantation due to sudden rise in liver enzymes, revealed multifocal hypoechoic lesions in the graft liver with normal Doppler parameters. Multidetecor computed tomography (MDCT) showed multiple hypodense vessel-sparing lesions in the graft liver. Cultures from the aspirate grew filamentous fungi identified as Basidiobolus ranarum species. Despite multiple broad spectrum antifungal infusions including liposomal amphotericin, itraconazole, caspofungin and posaconazole, serial sonography showed the hepatic lesions increasing in size, and involving segments V, VI and VII. The patient developed severe liver dysfunction ultimately progressing to sepsis, multiorgan dysfunction and death.",
"affiliations": "Department of Gastrointestinal Surgery, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India.;Department of Gastrointestinal Surgery, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India.;Department of Gastrointestinal Surgery, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India.;Department of Anaesthesiology and Critical Care, Amrita Institute of Medical Sciences and Research Centre, Cochin, Kerala, India.",
"authors": "Sethi|Pulkit|P|;Balakrishnan|Dinesh|D|;Surendran|Sudhindran|S|;Mohamed|Zubair Umer|ZU|",
"chemical_list": "D000935:Antifungal Agents",
"country": "England",
"delete": false,
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"issn_linking": "1757-790X",
"issue": "2016()",
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"mesh_terms": "D000328:Adult; D000935:Antifungal Agents; D020091:Entomophthorales; D017809:Fatal Outcome; D006801:Humans; D008107:Liver Diseases; D016031:Liver Transplantation; D008297:Male; D020096:Zygomycosis",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
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"pmid": "26873918",
"pubdate": "2016-02-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12664879;10451160;15245532;15004122;22441651",
"title": "Fulminant zygomycosis of graft liver following liver transplantation.",
"title_normalized": "fulminant zygomycosis of graft liver following liver transplantation"
} | [
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"abstract": "The neuroleptic malignant syndrome (NMS) of extrapyramidal signs and hyperthermia is an uncommon complication of therapy with the major tranquilizers. Other manifestations are pallor, diaphoresis, blood pressure fluctuation, tachycardia, and tachypneic hypoventilation, which may necessitate respirator support. Death often occurs, but full recovery can result with prompt recognition and proper management. In a patient with Parkinson disease and a chronic psychiatric disorder treated with haloperidol, typical features of NMS appeared upon cessation of dopaminergic antiparkinsonian drugs. Manifestations of NMS are attributed to dopamine receptor blockade in the striatum, increasing thermogenesis, and in the hypothalamus, impairing heat dissipation.",
"affiliations": null,
"authors": "Henderson|V W|VW|;Wooten|G F|GF|",
"chemical_list": "D014150:Antipsychotic Agents; D011954:Receptors, Dopamine; D008094:Lithium; D003402:Creatine Kinase; D006220:Haloperidol",
"country": "United States",
"delete": false,
"doi": "10.1212/wnl.31.2.132",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3878",
"issue": "31(2)",
"journal": "Neurology",
"keywords": null,
"medline_ta": "Neurology",
"mesh_terms": "D014150:Antipsychotic Agents; D001480:Basal Ganglia Diseases; D001833:Body Temperature Regulation; D003402:Creatine Kinase; D005334:Fever; D006220:Haloperidol; D006801:Humans; D007031:Hypothalamus; D008094:Lithium; D008297:Male; D008875:Middle Aged; D011954:Receptors, Dopamine; D013577:Syndrome",
"nlm_unique_id": "0401060",
"other_id": null,
"pages": "132-7",
"pmc": null,
"pmid": "6110195",
"pubdate": "1981-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Neuroleptic malignant syndrome: a pathogenetic role for dopamine receptor blockade?",
"title_normalized": "neuroleptic malignant syndrome a pathogenetic role for dopamine receptor blockade"
} | [
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{
"abstract": "OBJECTIVE\nPill-induced esophagitis has been recognized in adults, but rarely in children. The aim of this article is to discuss endoscopic features, drugs implicated, prevention and treatment in pill-induced esophagitis in children.\n\n\nMETHODS\nOver a period of 4 years, 26 patients presented at our clinic with drug-induced esophageal ulcerations. All patients were diagnosed by means of endoscopy and treated with proton-pump inhibitors and prokinetics. The mean age of the children was 10.76 years.\n\n\nRESULTS\nThe ulcers were frequently located at the mid-esophagus. Odynophagea, retrosternal pain and dysphagia were the most common presenting symptoms. All children took pills (non-steroidal anti-inflammatory drugs, antibiotics - Doxycycline and ferrous sulfate) with little water and at bed time. The mean elapse between the drug intake and endoscopy was 4.96 days. The symptoms resolved within a maximum of one week of antireflux therapy.\n\n\nCONCLUSIONS\nIn pediatric cases treated by tablets or capsules, the possibility of medication-induced esophagitis should always be considered. The drug-induced esophagitis should be suspected in all patients presenting with chest pain and dysphagia. Physicians must warn the patients to take the pills and capsules with enough water and in the upright position.",
"affiliations": "Pediatrics Clinics II. Emergency Hospital for Children, Cluj-Napoca, Romania.;Department of Pediatrics II, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.;Pediatrics Clinics II. Emergency Hospital for Children, Cluj-Napoca, Romania.;Pediatrics Clinics II. Emergency Hospital for Children, Cluj-Napoca, Romania.;Department of Bioinformatics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.;Department of Immunology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.;Department of Pediatrics II, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania.",
"authors": "Bordea|Madalina Adriana|MA|;Pirvan|Alexandru|A|;Sarban|Costica|C|;Margescu|Camelia|C|;Leucuta|Daniel|D|;Samasca|Gabriel|G|;Miu|Nicolae|N|",
"chemical_list": null,
"country": "Romania",
"delete": false,
"doi": "10.15386/cjm.2014.8872.871.mab1",
"fulltext": "\n==== Front\nClujul MedClujul MedCMClujul Medical1222-21192066-8872Iuliu Hatieganu University of Medicine and Pharmacy 10.15386/cjm.2014.8872.871.mab1cm-87-15Original ResearchPediatricsPill –Induced Erosive Esophagitis in Children BORDEA MADALINA ADRIANA 1PIRVAN ALEXANDRU 2SARBAN COSTICA 1MARGESCU CAMELIA 1LEUCUTA DANIEL 3SAMASCA GABRIEL 4MIU NICOLAE 21 Pediatrics Clinics II. Emergency Hospital for Children, Cluj-Napoca, Romania2 Department of Pediatrics II, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania3 Department of Bioinformatics, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania4 Department of Immunology, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, RomaniaAddress for correspondence: Gabriel.Samasca@umfcluj.ro2014 30 1 2014 87 1 15 18 05 12 2013 23 1 2014 24 1 2014 2014This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International LicenseAims\nPill-induced esophagitis has been recognized in adults, but rarely in children. The aim of this article is to discuss endoscopic features, drugs implicated, prevention and treatment in pill-induced esophagitis in children.\n\nPatients and methods\nOver a period of 4 years, 26 patients presented at our clinic with drug-induced esophageal ulcerations. All patients were diagnosed by means of endoscopy and treated with proton-pump inhibitors and prokinetics. The mean age of the children was 10.76 years.\n\nResults\nThe ulcers were frequently located at the mid-esophagus. Odynophagea, retrosternal pain and dysphagia were the most common presenting symptoms. All children took pills (non-steroidal anti-inflammatory drugs, antibiotics – Doxycycline and ferrous sulfate) with little water and at bed time. The mean elapse between the drug intake and endoscopy was 4.96 days. The symptoms resolved within a maximum of one week of antireflux therapy.\n\nConclusions\nIn pediatric cases treated by tablets or capsules, the possibility of medication-induced esophagitis should always be considered. The drug-induced esophagitis should be suspected in all patients presenting with chest pain and dysphagia. Physicians must warn the patients to take the pills and capsules with enough water and in the upright position.\n\nchildrendrug-induced esophagitisendoscopic featuresmanagement\n==== Body\nIntroduction\nEsophagitis is the most frequent esophageal disorder in children. Around 90 % of drug-induced esophagitis occur after use of non-steroidal anti-inflammatory drugs, antibiotics – doxycycline and ferrous sulfate [1,2,3,4,5]. Retrosternal pain, odynophagia and dysphagia are the most frequently reported symptoms.\n\nThe diagnosis is established by upper gastrointestinal endoscopy, which is also recognized as the method of choice. Double contrast studies detect also superficial ulcers and subtle mucosal changes. History alone may also be sufficient to establish a clinical diagnosis of esophagitis. Ulcers occur often at the level of the aortic arch and occasionally at the distal esophagus or very rarely at the proximal esophagus. Histopathological changes are nonspecific and constitute necrosis and inflammatory exudate with lymphocytes and eosinophils predominance.\n\nThe clinical course is usually uneventful and severe complications are rare in children. Severe complications (including mortality) have been associated with iron and potassium. Usually, the disease is self-limiting. Symptoms frequently disappear within 7 days of symptomatic treatment and discontinuation of injurious drugs. It can be prevented by avoiding drug intake at bed time and ingestion of an adequate liquid amount.\n\nThe aim of this article is to increase the awareness of physicians and endoscopists on drug-induced esophageal ulcerations in children and to discuss endoscopic features, drugs implicated, prevention and treatment.\n\nPatients and methods\nIn a retrospective analysis of 532 upper gastrointestinal (UGI) endoscopies performed by our endoscopists over a period of 4 years, 26 patients had drug-induced esophageal ulcerations. There were 16 girls (61.5%) and 10 (38.5%) boys with a mean age of 10.76 years. We mention that we have our patients’ written consent regarding their inclusion in this study. Five patients were excluded from our study because the parents did not provide an informed consent.\n\nThe excluding 5 patients were not different from the studied population with regard to age, gender ratio and presence of symptoms. Odynophagia, retrosternal pain and dysphagia are the most frequently reported symptoms. Endoscopy was performed with a pediatric videoscope after a mean elapse of 4.96 days, utilizing 10% xylocaine spray for local anesthesia to all 26 patients. The number of ulcers and the distance from the incisors teeth were estimated also. After endoscopic diagnosis, children were asked to bring the drugs correlated with the development of the current symptoms. The patients were also asked about the timing of drug intake and the amount of concurrent fluid ingested. The patients were managed with proton-pump inhibitors and prokinetic agents such as metoclopramide or macrolide agents and when feasible, the injurious pills were withdrawn. All children were requested to give a feedback on their response after a week of treatment initiation.\n\nAcid suppression with a proton pump inhibitor (PPI) is standard treatment for erosive esophagitis in adults and increasingly is becoming first–line therapy for children aged 1–17 years. Currently three PPIs are approved by the US FOOD and Drug Administration for the treatment of erosive esophagitis in children: esomeprazole (1–17 years), omeprazole (2–16 years) and lansoprazole (1–17 years).\n\nFindings from direct comparative studies in adults show that esomeprazole more effectively heals erosive esophagitis in adults than omeprazole or lansoprazole. Patients were assigned randomly to esomeprazole (Nexium) 5 or 10 mg (children >8kg and <20 kg) or 10 or 20 mg (children >20 kg) once daily. For children aged <6 years or for those who had difficulty swallowing the capsules; capsule contents could be mixed with one tablespoon of apple sauce.\n\nResults\nOver a 4 years period 532 UGI-endoscopies were performed. The majority (466) were due to gastroesophageal reflux disease and peptic esophagitis. Drug-induced esophageal ulcers were found in 26 patients with different gender distribution (10 males and 16 females) (Figure 1). The age ranged between 8 and 15 (mean 10.76) years. All patients presented with odynophagia. Other symptoms are as shown in [Table 1]. Anti-steroidal anti-inflammatory drugs (Ibuprofen), antibiotics (Doxycycline) and ferrous sulfate were the only drugs incriminated in all patients (Figure 2). The drugs were prescribed for fever in 13 patients (Ibuprofen), acne in 7 children (Doxycycline) and anemia-iron deficiency (ferrous sulfate) in 6 patients. The elapse between drug ingestion and endoscopy was 4.96 days. The ulcers were found at 20 cm (mean distance) from the incisors teeth. In 3 patients ulcers occur at the distal esophagus and in one patient at the proximal esophagus. The surrounding mucosa appeared normal. The ulcers were variable in size, depth and number. The number ranged from one to six. Repeat endoscopy four weeks after treatment revealed healed ulcers in the majority of children.\n\nAll patients, except one, adhered to follow-up. Initial improvement occurred as early as 24 hours after treatment initiation in some children. After one week, most of the patients reported a complete resolution of symptoms. Eight patients developed complications (stenosis) and required a long time fallow–up. One patient had no post treatment endoscopy (Figure 3).\n\nDiscussion\nThe prevalence of drug-induced esophageal ulcerations in this analysis was 4.88. Several drugs including antibiotics, anti-steroidal anti-inflammatory drugs, potassium chloride, quinidine, ascorbic acid and iron preparation may induce ulcerative esophagitis in children.\n\nThe drugs used by our patients were anti-steroidal anti-inflammatory drugs, doxycycline and ferrous sulfate. The risk factor was drug intake at bedtime with little fluid in all children. During recumbent position and sleep, salivation and swallowing are reduced and esophageal transit time is prolonged, which causes drug retention in the esophagus. Pre-existing esophageal disease and external esophageal compression, due to left atrial enlargement, precipitate also drug-induced esophageal ulceration, but none of our children had a history of a pre-existing esophageal or cardiac disorder [6].\n\nDrug retention and the acidic property of a drug such as doxycycline and ferrous sulfate, may explain its injurious esophageal mucosal effect [7,8]. Esophagitis associated with anti-steroidal anti-inflammatory drugs is linked with a mucosa altered protective function due to decreased prostaglandine synthesis [9].\n\nThe ulcers were located mainly at the midesophagus. This is in accordance with other reports where the mid-esophagus was found to be the commonest site [3,10]. In 3 patients ulcers occurred at the distal esophagus and in one patient at the proximal esophagus, an uncommon position. The ulcers number and size were variable. They were small and/or large, single or multiple, mostly facing each other with apparently normal surrounding mucosa. Extensive ulcers involving a large portion or the entire esophagus reported in adults are atypical for drug-induced esophageal injury in children. We have not encountered such a severe and extensive esophageal injury.\n\nThe main presenting symptoms of our patients were odynophagia, retrosternal pain and dysphagia. This is in agreement with other reports, where retrosternal pain, odynophagia and dysphagia are the most frequently reported symptoms also [5,11]. Heartburn ranged as the fourth commonest symptom.\n\nEndoscopy is the method of choice for confirming the clinical diagnosis. Double contrast barium swallow is also accurate and may detect even subtle mucosal changes, but a single contrast study may give wrong negative results in children. Complications (stenosis) were encountered in this analysis in 8 patients. Complications have been reported in association with anti-steroidal anti-inflammatory drugs. This is also in agreement with other reports. Drug-induced esophagitis is usually a self-limiting disease and symptoms resolve within 7 to 10 days.\n\nWe agree with other authors, who have considered injurious drug withdrawal as the main step of management. However, we feel anti-steroidal anti-inflammatory drugs, doxycycline or ferrous sulfate therapy can be continued when required with emphasis on patients and their parents education in regard of the timing of medication and the amount of fluid required. Many patients became asymptomatic within the first week of treatment with proton-pump inhibitors and prokinetics. Only eight children required a long time fallow-up.\n\nThe benefit of commonly used medications including antacids, sucralfate, H 2 -receptors antagonists and proton-pump inhibitors for treatment of drug-induced esophageal injuries is real. The symptoms improved soon after initiation of treatment and ulcer healing was confirmed by endoscopy.\n\nConclusions\nIn the current study, anti-steroidal anti-inflammatory drugs, doxycycline and ferrous sulfate were responsible for all drug-induced esophageal ulcerations. The presence of odynophagea and retrosternal pain should raise the suspicion and necessitate exploration of drugs history and endoscopy to confirm the diagnosis. Withdrawal of medicine is the main step of management when feasible. Children and their parents’ education and the use of alternative drugs in patients at risk are important to prevent drug-induced esophageal ulcerations. Proton-pump inhibitors and prokinetics are also an important step of management in children.\n\nFigure 1 Gender Distribution\n\nFigure 2 Drugs Distribution\n\nFigure 3 Evolution\n\nTable I Clinical symptoms\n\nSYMPTOM\tProcentual values (%)\t\nretrosternal pain\t42\t\ndysphagia\t25\t\nheartburn\t12\t\nvomiting\t10\t\nnausea\t6\t\nother\t5\n==== Refs\nReferences\n1 Shelat VG Seah M Lim KH Doxycycline induced acute erosive oesophagitis and presenting as acute dysphagia J Assoc Physicians India 2011 59 57 59 21751670 \n2 Pociello Almiñana N Vilar Escrigas P Luaces Cubells C Doxycycline-induced esophagitis: report of two cases An Pediatr (Barc) 2005 62 171 173 15701316 \n3 Kadayifci A Gulsen MT Koruk M Savas MC Doxycycline-induced pill esophagitis Dis Esophagus 2004 17 168 171 15230733 \n4 Yamamoto T Mishina Y Ebato T Prevalence of erosive esophagitis among Japanese patients taking low-dose aspirin J Gastroenterol Hepatol 2010 25 792 794 20074160 \n5 Areia M Gradiz R Souto P Iron-induced esophageal ulceration Endoscopy 2007 39 Suppl 1 E326 18273777 \n6 Jaspersen D Drug-induced oesophageal disorders: pathogenesis, incidence, prevention and management Drug Saf 2000 22 237 249 10738847 \n7 Isler M Doxycycline-induced esophageal ulceration Mil Med 2001 166 203 222 11263018 \n8 Cerezo A Costán G Gonzále A Severe esophagitis due to overdose of iron tablets Gastroenterol Hepatol 2008 31 551 552 18928764 \n9 Kuramoto T Umegaki E Nouda S Preventive effect of irsogladine or omeprazole on non-steroidal anti-inflammatory drug-induced esophagitis, peptic ulcers, and small intestinal lesions in humans, a prospective randomized controlled study BMC Gastroenterol 2013 13 85 23672202 \n10 Zografos GN Georgiadou D Thomas D Kaltsas G Digalakis M Drug-induced esophagitis Dis Esophagus 2009 22 633 637 19392845 \n11 Kato S Komatsu K Harada Y Medication-induced esophagitis in children Gastroenterol Jpn 1990 25 485 488 2210223\n\n",
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"abstract": "OBJECTIVE\nAromatic antiepileptic drugs are frequently implicated for cutaneous adverse drug reactions (cADRs); there are case-reports of even severe reactions like drug reaction eosinophilia and systemic symptoms (DRESS) and Stevens Johnson syndrome (SJS)-toxic epidermal necrolysis with Levetiracetam (LEV). Certain human leukocyte antigen (HLA)-alleles have strong association with cADRs due to specific drugs - HLA-B*15:02 and HLA-A*31:01 in Carbamazepine (CBZ)-related SJS in Han-Chinese and European populations, respectively. Here, the spectrum of cADRs to LEV was studied, and HLA-typing in patients with cADRs due to LEV and some who were LEV-tolerant was performed, in an attempt to find an association between HLA and such reactions.\n\n\nMETHODS\n589 patients taking LEV were screened for skin reactions, and eight patients with LEV-related cADRs and 25 LEV-tolerant controls were recruited - all 33 of North Indian ethnicity, their HLA-A, B, DRB1 genotyping done. Statistical analysis was done to compare carrier-rates and allele-frequencies of HLA-alleles between cases and controls (and healthy population, where necessary) for alleles occurring more than two times in either group.\n\n\nRESULTS\nOut of 589 patients on LEV screened, there were 8 cases of cADR: 5 with maculopapular exanthema (MPE), 2 of SJS, and 1 with DRESS. Although HLA-A*33:01 was seen to occur more in MPE cases as compared to tolerant controls, the difference was not statistically significant (odds ratio [OR] 6.00, 95% confidence interval [CI] 0.30-116.6; p = 0.31). HLA A*11:01 and 24:02 were found to occur more in LEV-tolerant controls than in cases (OR 0.23 [95% CI 0.02-2.36, p = 0.33] and 1.00 [95% CI 0.09-11.02, p = 1.00] respectively).\n\n\nCONCLUSIONS\nCutaneous reactions to LEV are very unusual, and their association with HLA in North-Indian population was not statistically significant.",
"affiliations": "Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.;Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.;Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India.;Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.;Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India.;Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, India.;Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.;Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.",
"authors": "Ramanujam|Bhargavi|B|;Ihtisham|Kavish|K|;Kaur|Gurvinder|G|;Srivastava|Shivani|S|;Mehra|Narinder Kumar|NK|;Khanna|Neena|N|;Singh|Mahip|M|;Tripathi|Manjari|M|",
"chemical_list": null,
"country": "Korea (South)",
"delete": false,
"doi": "10.14581/jer.16016",
"fulltext": "\n==== Front\nJ Epilepsy ResJ Epilepsy ResJournal of Epilepsy Research2233-62492233-6257Korean Epilepsy Society 10.14581/jer.16016er-6-2-89Original ArticleSpectrum of Cutaneous Adverse Reactions to Levetiracetam and Human Leukocyte Antigen Typing in North-Indian Patients Ramanujam Bhargavi 1Ihtisham Kavish 1Kaur Gurvinder 2Srivastava Shivani 1Mehra Narinder Kumar 2Khanna Neena 3Singh Mahip 1Tripathi Manjari 11 Department of Neurology, All India Institute of Medical Sciences, New Delhi, \nIndia2 Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, \nIndia3 Department of Dermatology and Venereology, All India Institute of Medical Sciences, New Delhi, \nIndiaCorresponding author: Manjari Tripathi, Department of Neurology, Neurosciences Centre, All India Institute of Medical Sciences, New Delhi, India, Tel. +91-11-26594494/26588248, Fax. +91-26588248/26588166, E-mail; manjari.tripathi1@gmail.com12 2016 31 12 2016 6 2 89 94 04 5 2016 05 6 2016 Copyright © 2016 Korean Epilepsy Society2016This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Background and Purpose\nAromatic antiepileptic drugs are frequently implicated for cutaneous adverse drug reactions (cADRs); there are case-reports of even severe reactions like drug reaction eosinophilia and systemic symptoms (DRESS) and Stevens Johnson syndrome (SJS)-toxic epidermal necrolysis with Levetiracetam (LEV). Certain human leukocyte antigen (HLA)-alleles have strong association with cADRs due to specific drugs - HLA-B*15:02 and HLA-A*31:01 in Carbamazepine (CBZ)-related SJS in Han-Chinese and European populations, respectively. Here, the spectrum of cADRs to LEV was studied, and HLA-typing in patients with cADRs due to LEV and some who were LEV-tolerant was performed, in an attempt to find an association between HLA and such reactions.\n\nMethods\n589 patients taking LEV were screened for skin reactions, and eight patients with LEV-related cADRs and 25 LEV-tolerant controls were recruited - all 33 of North Indian ethnicity, their HLA-A, B, DRB1 genotyping done. Statistical analysis was done to compare carrier-rates and allele-frequencies of HLA-alleles between cases and controls (and healthy population, where necessary) for alleles occurring more than two times in either group.\n\nResults\nOut of 589 patients on LEV screened, there were 8 cases of cADR: 5 with maculopapular exanthema (MPE), 2 of SJS, and 1 with DRESS. Although HLA-A*33:01 was seen to occur more in MPE cases as compared to tolerant controls, the difference was not statistically significant (odds ratio [OR] 6.00, 95% confidence interval [CI] 0.30–116.6; p = 0.31). HLA A*11:01 and 24:02 were found to occur more in LEV-tolerant controls than in cases (OR 0.23 [95% CI 0.02–2.36, p = 0.33] and 1.00 [95% CI 0.09–11.02, p = 1.00] respectively).\n\nConclusions\nCutaneous reactions to LEV are very unusual, and their association with HLA in North-Indian population was not statistically significant.\n\nLevetiracetamMaculo-papular exanthemStevens-Johnson syndromeToxic Epidermal NecrolysisHuman leukocyte antigen (HLA)\n==== Body\nIntroduction\nCutaneous adverse drug reactions (cADRs) are commonly associated with antiepileptic drugs (AEDs) particularly the aromatic Carbamazepine (CBZ), Phenytoin (PHT), Phenobarbitone (PB), and Lamotrigine (LTG). They range from minor maculopapular exanthem (MPE) to severe life-threatening reactions like Drug reaction eosinophilia and systemic symptoms (DRESS), Stevens Johnson Syndrome (SJS) and Toxic epidermal Necrolysis (TEN), and manifest within a few hours to weeks of the AED being initiated. In a study by Sharma et al, out of 500 patients with cADRs with all drugs, anticonvulsants - PHT, CBZ and PB were implicated in 41.6% of patients with maculopapular rashes and 43.8% of life-threatening reactions - TEN and SJS.1 Although non-aromatic AEDs like Topiramate (TPM) and LEV are thought to be safer, there are several reports of even severe cADRs like SJS, DRESS due to LEV.2–4 In 2011, the United States Food and Drug Administration (US-FDA) included serious cADRs as potential safety risk from LEV in both paediatric and adult population.5\n\nCutaneous reactions to certain drugs including anticonvulsants have shown to have strong association with specific human leukocyte antigen (HLA) alleles - HLA-B*15:02 with CBZ-related SJS/TEN in the Han-Chinese, HLA-A*31:01 in European people.6,7 CBZ has been also found to be the causative drug in many other populations. Therefore, it is now recommended that HLA screening for HLA-B*15:02 be done in the susceptible ethnic groups prior to initiation of the potentially offending drugs. Most of the studies with HLA typing in cADRs due to AEDs have been in CBZ-induced cases or those related to PHT or LTG, probably because of their much more frequent occurrence. In our study, we screened patients on LEV and performed HLA-typing of North Indian patients with a skin reaction to it, in an attempt to find a possible HLA-association with LEV-induced cADR in this population.\n\nMethods\nPatient enrolment\nFive hundred and eighty-nine consecutive patients of epilepsy on LEV, presenting to the Neurology Outpatient Clinic or Emergency Department of the All India Institute of Medical Sciences (AIIMS) hospital between February 2013 and March 2015 were screened. All those developing skin rash, mucosal ulcers or both, within three months of initiation of LEV were recruited. These patients were all from the North Indian states of Bihar, Uttar Pradesh, Delhi, Haryana or Punjab. Dermatologist’s opinion was taken to confirm the cutaneous drug reaction and to classify the same. Twenty-five patients, also from one of the above-mentioned North-Indian states, who had no skin reactions to LEV even after six months of taking the drug were enrolled as controls. A written informed consent was taken from all subjects, and the study was approved by the Institutional Ethics Committee. History, general physical, neurological and dermatological examination findings were recorded in a proforma.\n\nHLA genotyping\n5 mL blood sample was drawn from all recruited subjects; De-oxy-ribonucleic acid (DNA) was extracted and checked for quality and quantity on 0.8% Agarose gel and spectrophotometer. HLA-A, B and DRB1 allele typing was done by Luminex based SSO technology (Lab type SSO HLA-B, A and DRB1 kits).\n\nStatistical analysis\nTwo-tailed Fisher’s exact test was done to determine statistical significance of the difference in carrier-rates between cases of MPE and controls for alleles occurring more than two times in either group. Also, odds ratio (OR) and allele frequency (AF) - number of times the allele is present in the sample divided by twice sample-size, expressed as a percentage - were calculated for these alleles.\n\nIf the AF was higher among tolerant controls than cases, the two-tailed Fisher’s exact test was done to find statistical significance in the difference of carrier-rates and AFs in the former group and in a healthy North Indian population.\n\nResults\nOut of the 589 patients on LEV, 107 were on monotherapy and 482 on polytherapy. In all, eight patients developed cADR to LEV and were recruited as cases; of these, five were on LEV monotherapy and three on polytherapy. Mean age of the cases was 25.23 (range 14–45 years), there were six females and two males; their clinical features are tabulated (Table 1). Of the 25 controls, 13 were female and 12 were male; mean age was 26.68 (range 13–54 years), and twelve were on LEV alone, rest were also on other AEDs. None of the recruited subjects had a history of cADR to any drug previously.\n\nHLA-A*11:01, 24:02, 33:01, 33:02, 68:01, 26:01, 01:01, 02:01 HLA B*7:02, 35:01, 40:01, 40:02, 40:06 15:01, 44:02 and HLA DRB1*15:01, 15:02 07:01, 13:01, 14:01, 10:01 were the alleles that occurred more than twice in the MPE cases and/or the control-groups; their AF and OR are presented in Table 2.8,9 When the Fisher exact test was applied to carrier rates and AFs between the groups, the differences were not statistically significant (Table 2), The AF’s of HLA-A*11:01 was higher in tolerant controls (26% versus 10% in MPE cases and 12.5% in healthy population), and HLA-A*33:01 was higher among MPE cases (20% versus 2% and 0.05% in tolerant controls and healthy population respectively). HLA-DRB1*13:01, 07:01 and 15:01 were also found to be more in tolerant controls than MPE cases (OR 2.66 [95% CI 0.34–20.50, p = 0.56]; OR 2.66 [95% CI 0.34–19.06, p = 0.36]; OR 0.27 [95% CI 0.02–2.77 p = 0.62]).\n\nHowever, the differences in occurrence-rates of alleles between MPE cases and tolerant controls were not statistically significant. Notably, one case of SJS was positive for HLA-B*15:02 in our study, and had been on CBZ for over a year before that without any cutaneous reactions. The four digit alleles of all the 33 subjects have been tabulated (Table 3).\n\nDiscussion\nCutaneous drug reactions due to LEV are rare, and only case reports and small series are published (Table 4).2–4,10–15 In a systematic review of ten randomised controlled trials by Mbizvo et al, adverse effect profile of LEV in patients of drug-resistant epilepsy was studied, and rash due to LEV was reported in only two studies. It was noted that only symptoms affecting more than 5 or 10% of participants of the groups were published in these ten trials.16 In the study by Cheung et al, out of 55 patients of cADR due to various AEDs identified over 16.5 years, there was only one patient with rashes due to LEV, though one of the reasons maybe that being a newly introduced AED it may not have been prescribed much in the initial few years.17 Out of 589 patients screened in our study over two years, there were only eight cases of cADRs - this explains the small sample-size of cases. Two of the patients with skin reactions had SJS - though severe cutaneous drug reactions like SJS/TEN and DRESS are much less common than MPE. Both our SJS patients were on LEV monotherapy at onset of the symptoms therefore likelihood of the reaction being LEV-induced is high; most case-reports of these life-threatening cADRs with LEV are of patients on other drugs also, including AEDs.\n\nAssociation of HLA alleles has been studied mainly in aromatic AEDs, as they are the cause of most cADRs, in particular CBZ, and certain HLA alleles predispose patients of some ethnicities to specific cADRs due to AEDs. In the European and the Chinese populations, presence of the allele HLA-A*31:01 appears to predispose to CBZ-induced DRESS, as found in an international study and meta-analysis.18 HLA B*15:02 is associated with SJS and TEN due to CBZ intake in Han Chinese population, but not with MPE.6 Evidence from another meta-analysis of nine case-control studies by Li X et al shows significant association between HLA-A*15:02 and PHT and LTG-induced SJS/TEN.19 A pilot-study showed that the same allele may be associated with OXC-induced mild cutaneous reactions.20 It was shown in a prospective study of 252 patients, 5 developed cADRs to OXC. Out of these 5 patients, 1 was positive for HLA-B*15:02.21 In our study we have noted seen that HLA-A*33:01, though not statistically significant, is present in cases of MPE compared to controls (OR = 6). The p-values were not significant (0.31), when differences in AF or carrier rates were considered for calculation, and the confidence intervals may have been wide, due to the small sample size of cases.\n\nStudies have shown HLA-B* 15:02 to be associated with SJS in Indians as well. Mehta et al found 6 out of 8 CBZ-induced SJS patients from the western state of Gujarat HLA B* 15:02 positive, but none among 10 healthy controls. Other studies were on North and South Indian origin patients in which also a significant association was found between the presence of this allele and SJS due to CBZ.22,23 However, one of our SJS patients was positive for HLA-B* 15:02. Interestingly, she had been on CBZ for over a year without any skin or mucosal reactions, and recovered as soon as her LEV was stopped. Since she had tested positive for this allele, she was shifted to Valproate from CBZ. None of the MPE cases came out to be positive for 15:02. The fact that India has a racially diverse population may be an explanation. Also there are probably other factors, like interaction of the HLA molecule with specific T-cell receptors also contributing to a cADR. HLA-A*31:01 was shown to be linked to all types of cutaneous reactions (MPE, DRESS and SJS) in the European population in a genome-wide association based study and Hu et al had four OXC-induced MPE cases positive for HLA-B*15:02 out of nine, significant when compared with population controls.7,20 A significant association of HLA-A*24:02 with LTG induced MPE was found in study of 21 Korean patients.24\n\nPossible protective effects of the presence of HLA-B*40:01 and HLA-B*58:01 have also been demonstrated on the basis of significantly higher rates of occurrence among AED-tolerant controls.17 We found HLA-A*11:01 positivity in 11 out of the 25 LEV-tolerant controls as against 3 out of eight cases, the AF being 26% and 10% respectively; the AF among healthy controls from the same North Indian states was 12.5%, which may suggest that the presence of this allele may be protective, though not statistically significant.8 A limitation of our study is that we did not simultaneously recruit healthy population controls. However, we have quoted published AF values from the same population for the alleles found in our cases and controls (Table 2). These studies, by Rajalingam et al and Rani et al had HLA-typing of 52 and 90 healthy North-Indian subjects respectively.8,9\n\nAnother very recent study in the Chinese population, with nine cases of mild rashes due to LEV has also shown no significant association between HLA alleles and LEV-induced cutaneous rashes.25\n\nCutaneous reactions to LEV, though quite unusual, have a wide spectrum of phenotypes including severe reactions like SJS/TEN and DRESS. HLA-A*33:01 was higher among MPE cases as compared to tolerant controls whereas HLA-A*11:01 was higher in tolerant controls than MPE cases, although neither association was statistically significant. We did not find any significant association between HLA alleles and LEV induced cutaneous drug rashes but a larger sample-size of cases in a multicentre study may be required in order to confirm the findings.\n\nAcknowledgement\nThis work was supported by Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India. Project code: BT/PR3436/MED/30/651/2011.\n\nConflict of Interest\n\nNone of the authors has any conflict of interest to disclose.\n\nTable 1 Clinical characteristics of cases with LEV-induced cADR\n\n\tAge (years)/Gender\tDiagnosis\tPhenotype\tDose at which cADR occurred\tLatency to cADR (days)\tConcurrent Drug\t\nCase 1\t38/M\tLRE-Right parietal lobe NCC\tMPE\t500 mg twice a day\t15\tNil\t\nCase 2\t45/F\tLRE-left frontal lobe NCC\tMPE\t1,000 mg twice a day\t13\tNil\t\nCase 3\t14/F\tLRE-left frontal FCD\tMPE\t250 mg twice a day\t7\tCBZ taken without cADR for 1year\t\nCase 4\t18/F\tJME\tSJS\t250 mg twice a day\t10\tNil\t\nCase 5\t24/M\tJME\tSJS\t500 mg twice a day\t7 days\tNil\t\nCase 6\t22/F\tJME\tDRESS\t750 mg twice a day\t15days\tOXC, LTG\t\nCase 7\t24/F\tLRE-Post stroke\tMPE\t500 mg twice a day\t15days\tClopidogrel, Losartan.\t\nCase 8\t22/F\tIdiopathic generalized epilepsy\tMPE\t1,000 mg twice a day\t5days\tNil\t\nLEV, levetiracetam; cADR, cutaneous adverse drug reaction; LRE, localization-related epilepsy; NCC, Neurocysticercosis; MPE, maculopapular exanthem; SJS, Stevens Johnson syndrome; FCD, focal cortical dysplasia; CBZ, Carbamazepine; JME, juvenile myoclonic epilepsy; DRESS, drug reaction eosinophilia and systemic symptoms; OXC, Oxcarbazepine; LTG, lamotrigine.\n\nTable 2 Allele frequencies and odds ratios of alleles occurring more than twice in MPE cases and/or control-groups\n\nAlleles\tAllele frequency (%)\tOdds ratio\t95% CI\tFisher exact test-p-values\tAllele frequency in normal population (%)\t\n\n\t\n\t\nCases\tControls\tCases vs. Controls\t\nHLA-A*11:01\t10\t26\t0.23\t0.02–2.36\t0.33\t12.5*\t\nHLA-A*33:01\t20\t2\t6.00\t0.30–116.6\t0.31\t0.50†\t\nHLA-A*33:03\t20\t6\t1.83\t0.15–22.36\t0.53\t8.65*\t\nHLA-A*24:01\t10\t6\t1.83\t0.15–22.36\t0.53\t11.1†\t\nHLA-A*24:02\t10\t10\t1.00\t0.09–11.02\t1.00\t19.2*\t\nHLA-A*68:01\t10\t6\t1.83\t0.15–22.36\t0.53\t1.92*\t\nHLA-A*26:01\t10\t4\t2.87\t0.20–39.68\t0.43\t1.92*\t\nHLA-A*01:01\t0\t6\t0.58\t0.02–13.05\t1.00\t11.5*\t\nHLA-A*02:01\t0\t8\t0.43\t0.02–9.34\t1.00\t5.77*\t\nHLA-B*07:02\t30\t10\t6.00\t0.78–46.14\t0.10\t3.84*\t\nHLA-B*15:01\t0\t8\t0.43\t0.02–9.34\t1.00\t1.92*\t\nHLA-B*44:02\t30\t10\t6.00\t0.78–46.14\t0.10\t1.92*\t\nHLA-B*35:01\t10\t6\t1.83\t0.15–22.36\t0.53\t7.69*\t\nHLA-B*40:01\t10\t6\t1.83\t0.15–22.36\t0.53\t0.96*\t\nHLA-B*40:02\t0\t10\t0.33\t0.01–7.11\t0.55\t1.10†\t\nHLA-B*40:06\t0\t4\t0.85\t0.03–20.45\t1.00\t15.4*\t\nHLA-B*50:01\t0\t8\t0.43\t0.02–9.34\t1.00\t1.92*\t\nHLA-DRB1*15:01\t10\t22\t0.27\t0.02–2.77\t0.62\t14.8*\t\nHLA-DRB1*15:02\t0\t6\t0.58\t0.02–13.05\t1.00\t7.4*\t\nHLA-DRB1*07:01\t30\t20\t2.66\t0.37–19.06\t0.36\t9.25*\t\nHLA-DRB1*13:01\t20\t10\t2.66\t0.34–20.50\t0.56\t1.85*\t\nHLA-DRB1*10:01\t10\t8\t1.31\t0.11–15.03\t1.00\t3.7*\t\nHLA-DRB1*14:01\t0\t4\t0.85\t0.03–20.45\t1.00\t0.92*\t\nHLA-DRB1*04:01\t10\t4\t2.87\t0.20–39.68\t0.43\t0.92*\t\nMPE, maculopapular exanthem; HLA, human leukocyte antigen.\n\n* Ref.8;\n\n† Ref.9.\n\nTable 3 4-digit HLA allele of all 33 subjects\n\n\tHLA-A (Allele 1)\tHLA-A (Allele 2)\tHLA-B (Allele 1)\tHLA-B (Allele 2)\tHLA-DRB1 (Allele 1)\tHLA-DRB1 (Allele 2)\t\nCase 1\t33:01\t68:01\t35:03\t40:01\t13:01\t14:04\t\nCase 2\t03:02\t26:01\t07:02\t07:02\t07:01\t10:01\t\nCase 3\t24:02\t33:01\t07:02\t44:02\t13:01\t15:01\t\nCase 4\t02:03\t02:11\t15:02\t40:06\t15:01\t15:02\t\nCase 5\t11:01\t68:01\t07:02\t15:01\t15:01\t15:01\t\nCase 6\t11:01\t68:01\t13:16\t52:01\t04:01\t14:01\t\nCase 7\t11:01\t24:01\t44:02\t44:02\t07:01\t07:01\t\nCase 8\t32:01\t33:03\t18:01\t35:01\t04:01\t11:01\t\nCtrl 1\t01:01\t24:01\t35:01\t52:01\t12:02\t15:02\t\nCtrl 2\t11:01\t11:01\t35:03\t44:02\t13:15\t14:19\t\nCtrl 3\t02:11\t11:01\t40:02\t41:01\t11:01\t14:01\t\nCtrl 4\t02:05\t11:01\t07:02\t44:02\t15:01\t15:02\t\nCtrl 5\t26:01\t31:01\t44:02\t51:01\t15:01\t15:01\t\nCtrl 6\t02:01\t33:01\t13:01\t15:01\t04:06\t13:01\t\nCtrl 7\t11:01\t24:02\t18:01\t52:01\t15:01\t15:01\t\nCtrl 8\t11:01\t11:01\t15:01\t40:02\t04:08\t07:08\t\nCtrl 9\t11:01\t24:02\t15:01\t40:06\t10:01\t12:01\t\nCtrl 10\t24:02\t24:07\t15:02\t40:06\t15:01\t15:02\t\nCtrl 11\t32:01\t33:03\t07:02\t40:02\t13:01\t15:01\t\nCtrl 12\t11:01\t24:02\t15:01\t40:02\t10:01\t12:01\t\nCtrl 13\t11:01\t68:01\t07:02\t40:02\t04:01\t07:01\t\nCtrl 14\t24:02\t26:01\t07:02\t44:02\t07:01\t15:01\t\nCtrl 15\t03:01\t03:01\t50:01\t57:01\t03:01\t07:01\t\nCtrl 16\t02:01\t11:01\t13:01\t50:01\t10:01\t13:01\t\nCtrl 17\t24:01\t68:01\t07:02\t50:01\t07:01\t07:01\t\nCtrl 18\t03:01\t24:01\t35:01\t40:01\t07:01\t11:01\t\nCtrl 19\t03:01\t33:03\t35:01\t44:02\t04:01\t07:01\t\nCtrl 20\t30:01\t68:01\t51:01\t53:01\t13:01\t14:01\t\nCtrl 21\t01:01\t02:01\t37:01\t53:01\t10:01\t13:01\t\nCtrl 22\t01:01\t24:06\t52:01\t57:01\t03:01\t07:01\t\nCtrl 23\t11:01\t33:03\t40:01\t52:01\t14:07\t15:01\t\nCtrl 24\t02:01\t03:01\t40:01\t52:01\t07:01\t15:01\t\nCtrl 25\t01:02\t11:01\t50:01\t57:01\t03:01\t15:01\t\nHLA, human leukocyte antigen.\n\nTable 4 Case series and reports of cutaneous adverse effects related to LEV\n\nSerial number\tCase detail\tType of cADR\tReference number\t\n1\tNeonate with perinatal asphyxia, pneumothorax\tErythematous rash and reaction anaphylactic\t10\t\n2\t33 year old lady with drug-refractory epilepsy\tAngioedema\t11\t\n3\t55 year old man with intracranial haemorrhage\tDRESS\t12\t\n4\t2 cases of 20 and 29 year old women with epilepsy\tTEN\t4\t\n5\t2.25 year old female after surgery for congenital heart disease and cardiorespiratory arrest\tSJS\t2\t\n6\t18 year old man\tDRESS\t3\t\n7\t64 year old man with basal ganglia mass\tMorbilliform rash\t13\t\n8\t5 Cases\tHair loss\t14\t\n9\t2 cases with epilepsy-19 year old woman, 29 year old man\tMPE, Morbilliform rash\t15\t\nLEV, levetiracetam; cADR, cutaneous adverse drug reaction; SJS, Stevens Johnson syndrome; DRESS, drug reaction eosinophilia and systemic symptoms; TEN, toxic epidermal necrolysis; MPE, maculopapular exanthem.\n==== Refs\nReferences\n1 Sharma VK Sethuraman G Kumar B Cutaneous adverse drug reactions: clinical pattern and causative agents--a 6 year series from Chandigarh, India J Postgrad Med 2001 47 95 9 11832597 \n2 Zou LP Ding CH Song ZJ Li XF Stevens-Johnson syndrome induced by levetiracetam Seizure 2012 21 823 5 23036769 \n3 Hall DJ Fromm JS Drug reaction with eosinophilia and systemic syndrome in a patient taking phenytoin and levetiracetam: a case report J Med Case Rep 2013 7 2 23286229 \n4 Duong TA Haddad C Valeyrie-Allanore L Sbidian E Chosidow O Wolkenstein P Levetiracetam: a possible new inducer of toxic epidermal necrolysis and Stevens-Johnson syndrome in 2 cases JAMA Dermatol 2013 149 113 5 23324778 \n5 FDA Approved Labeling text dated 16 Dec 2011 Reference ID: 3060029, www.fda.gov/downloads/Drugs/DrugSafety/UCM152832.pdf \n6 Chung WH Hung SI Hong HS Medical genetics: a marker for Stevens-Johnson syndrome Nature 2004 428 486 15057820 \n7 McCormack M Alfirevic A Bourgeois S HLA-A* 3101 and carbamazepine-induced hypersensitivity reactions in Europeans N Engl J Med 2011 364 1134 43 21428769 \n8 Rajalingam R Krausa P Shilling HG Distinctive KIR and HLA diversity in a panel of north Indian Hindus Immunogenetics 2002 53 1009 19 11904677 \n9 Rani R Marcos C Lazaro AM Zhang Y Stastny P Molecular diversity of HLA-A, -B and -C alleles in a North Indian population as determined by PCR-SSOP Int J Immunogenet 2007 34 201 8 17504510 \n10 Koklu E Ariguloglu EA Koklu S Levetiracetam-Induced anaphylaxis in a neonate Pediatr Neurol 2014 50 192 4 24262344 \n11 Alkhotani A McLachlan RS Levetiracetam induced angioedema in a patient with previous anticonvulsant hypersensitivity reaction to phenytoin and lamotrigine Seizure 2012 21 407 8 22524985 \n12 Eleni K Dress syndrome induced by levetiracetam J Eur Acad Dermatol Venereol 2015 29 377 8 24397826 \n13 Jones RT Evans W Mersfelder TL Kavanaugh K Rare red rashes: a case report of levetiracetam-Induced cutaneous reaction and review of the literature Am J Ther J 2016 23 e944 6 \n14 Zou X Hong Z Zhou D Hair loss with levetiracetam in five patients with epilepsy Seizure 2014 23 158 60 24315496 \n15 Bhoi Sk Kalita J Misra Uk Skin rash following levetiracetam Seizure 2016 37 45 7 26987035 \n16 Mbizvo GK Dixon P Hutton JL Marson AG The adverse effect profile of levetiracetam in epilepsy: a more detailed look Int J Neurosci 2014 124 627 34 24256446 \n17 Cheung YK Cheng SH Chan EJ Lo SV Ng MH Kwan P HLA-B alleles associated with severe cutaneous reactions to antiepileptic drugs in Han Chinese Epilepsia 2013 54 1307 14 23692434 \n18 Genin E Chen DP Hung SI HLA-A*31:01 and different types of carbamazepine-induced severe cutaneous adverse reactions: an international study and meta-analysis Pharmacogenomics J 2014 14 281 8 24322785 \n19 Li X Yu K Mei S HLA-B*15:02 increases the risk of phenytoin or lamotrigine induced Stevens-Johnson Syndrome/toxic epidermal necrolysis: evidence from a meta-analysis of nine case-control studies Drug Res (Stuttg) 2015 65 107 11 24871931 \n20 Hu FY Wu XT An DM Yan B Stefan H Zhou D Pilot-association study of oxcarbazepine-induced mild cutaneous reaction with HLA B*1502 allele in Chinese Han population Seizure 2011 20 160 2 21169036 \n21 He N Min FL Shi YW Cutaneous reactions induced by oxcarbazepine in Southern Han Chinese: incidence, features, risk factors and relation to HLA-B alleles Seizure 2012 21 614 8 22818943 \n22 Aggarwal R Sharma M Modi M Garg VK Salaria M HLA-B* 1502 is associated with carbamazepine induced Stevens–Johnson syndrome in North Indian population Human Immunol 2014 75 1120 2 25305458 \n23 Khor AH Lim KS Tan CT Wong SM Ng CC HLA-B*15:02 association with carbamazepine-induced Stevens-Johnson syndrome and toxic epidermal necrolysis in an Indian population: a pooled-data analysis and meta-analysis Epilepsia 2014 55 e120 4 25266342 \n24 Wang XQ Lv B Wang HF Lamotrigine induced DIHS/DRESS: Manifestations, treatment, and outcome in 57 patients Clin Neurol Neurosurg 2015 138 1 7 26209753 \n25 Hu FY Wang W Ren JC An DM Chen JN Zhou D Levetiracetam-induced cutaneous adverse drug reactions were not associated with HLA genes in a small sample of Chinese patients with epilepsy Epilepsy Res 2016 124 12 5 27162008\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "6(2)",
"journal": "Journal of epilepsy research",
"keywords": "Human leukocyte antigen (HLA); Levetiracetam; Maculo-papular exanthem; Stevens-Johnson syndrome; Toxic Epidermal Necrolysis",
"medline_ta": "J Epilepsy Res",
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"nlm_unique_id": "101577886",
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"pages": "87-92",
"pmc": null,
"pmid": "28101480",
"pubdate": "2016-12",
"publication_types": "D016428:Journal Article",
"references": "23286229;24871931;23324778;25259954;24397826;22818943;15057820;24262344;21169036;25266342;23036769;24256446;24322785;21428769;11904677;17504510;22524985;24315496;27162008;23692434;11832597;25305458;26987035;26209753",
"title": "Spectrum of Cutaneous Adverse Reactions to Levetiracetam and Human Leukocyte Antigen Typing in North-Indian Patients.",
"title_normalized": "spectrum of cutaneous adverse reactions to levetiracetam and human leukocyte antigen typing in north indian patients"
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"literaturereference": "RAMANUJAM B, IHTISHAM K, KAUR G, SRIVASTAVA S, MEHRA NK, KHANNA N, SINGH M, TRIPATHI M. SPECTRUM OF CUTANEOUS ADVERSE REACTIONS TO LEVETIRACETAM AND HUMAN LEUKOCYTE ANTIGEN TYPING IN NORTH-INDIAN PATIENTS. J EPILEPSY RES. 2016 DEC 31;6(2):87-92.",
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"abstract": "Schizophrenia and related psychoses are characterized by high recurrence rates and a serious impact on social functions. Many patients with these conditions, therefore, require prophylactic treatment during the postpartum period. Antipsychotic medication is the main treatment strategy for these disorders. Compared with single use of antipsychotics, data on the safety of combined antipsychotics on the breastfed infants are very limited. The current report presents adverse events in an infant exposed to a combination of risperidone and haloperidol through breast milk.",
"affiliations": "Department of Psychiatry, Meram Faculty of Medicine, Necmettin Erbakan University, Konya, Turkey.",
"authors": "Uguz|Faruk|F|",
"chemical_list": "D014150:Antipsychotic Agents; D006220:Haloperidol; D018967:Risperidone",
"country": "United States",
"delete": false,
"doi": "10.1089/bfm.2019.0093",
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"issue": "14(9)",
"journal": "Breastfeeding medicine : the official journal of the Academy of Breastfeeding Medicine",
"keywords": "antipsychotics; haloperidol; lactation; risperidone",
"medline_ta": "Breastfeed Med",
"mesh_terms": "D014150:Antipsychotic Agents; D000074341:Dietary Exposure; D004359:Drug Therapy, Combination; D005260:Female; D006220:Haloperidol; D006801:Humans; D007231:Infant, Newborn; D008895:Milk, Human; D011247:Pregnancy; D018967:Risperidone; D012559:Schizophrenia; D055815:Young Adult",
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"pubdate": "2019-11",
"publication_types": "D002363:Case Reports",
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"title": "Adverse Events in a Breastfed Infant Exposed to Risperidone and Haloperidol.",
"title_normalized": "adverse events in a breastfed infant exposed to risperidone and haloperidol"
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{
"abstract": "We present the case of a young boy who was born to a human immunodeficiency virus (HIV)-positive mother and originally found to be uninfected. Evidence-based guidelines were followed regarding the mother's prenatal and infant's postnatal care, including the avoidance of breast milk. HIV DNA polymerase chain reaction qualitative tests were obtained at birth, 6 weeks and 4 months, and were all negative. He also received 6 weeks of prophylactic zidovudine. Despite these measures, his health began to decline at 17 months of age and antibody and serology tests performed at this time confirmed HIV infection. Guidelines no longer recommend routine antibody testing at 18 months of age to confirm the absence of infection in exposed infants with a record of negative virology in the first year of life. Based on this case and others we propose that this test be added back to the national guidelines for the early detection and prompt treatment of HIV infection in infants born to HIV-positive mothers.",
"affiliations": "University of Queensland School of Medicine and Ochsner Clinical School, New Orleans, LA, USA mora.puertolaslopez@uq.net.au.;Our Lady of the Lake Children's Hospital, Baton Rouge, LA, USA.;University of Queensland School of Medicine and Ochsner Clinical School, New Orleans, LA, USA.",
"authors": "Puertolas|Mora V|MV|;Bolton|Michael T|MT|;Steele|Russell W|RW|",
"chemical_list": "D019380:Anti-HIV Agents; D015215:Zidovudine",
"country": "United States",
"delete": false,
"doi": "10.1177/0009922815601032",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0009-9228",
"issue": "55(7)",
"journal": "Clinical pediatrics",
"keywords": "HIV PCR; HIV in infants; acquired HIV; congenital HIV; perinatal HIV",
"medline_ta": "Clin Pediatr (Phila)",
"mesh_terms": "D019380:Anti-HIV Agents; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D015658:HIV Infections; D006801:Humans; D007223:Infant; D018445:Infectious Disease Transmission, Vertical; D008297:Male; D016133:Polymerase Chain Reaction; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D015215:Zidovudine",
"nlm_unique_id": "0372606",
"other_id": null,
"pages": "673-6",
"pmc": null,
"pmid": "26294760",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late ELISA Testing in Infants Born to HIV-Positive Mothers.",
"title_normalized": "late elisa testing in infants born to hiv positive mothers"
} | [
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},
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"medicinalproduct": "ZIDOVUDINE."
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},
{
"reactionmeddrapt": "Lymphadenopathy",
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},
{
"reactionmeddrapt": "Viral load increased",
"reactionmeddraversionpt": "19.1",
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},
{
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},
{
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},
{
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},
{
"reactionmeddrapt": "Decreased appetite",
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},
{
"reactionmeddrapt": "Rhinorrhoea",
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},
{
"reactionmeddrapt": "Oral candidiasis",
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],
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},
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"literaturereference": "PUERTOLAS MV, BOLTON MT, STEELE RW. LATE ELISA TESTING IN INFANTS BORN TO HIV-POSITIVE MOTHERS. CLINICAL PEDIATRICS. 2016;55 (7):673-676",
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}
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{
"abstract": "The rejection rate in cord blood transplants for chronic Epstein-Bar virus-associated T or natural killer cell lymphoproliferative diseases using our standard reduced-intensity conditioning \"LPAM140 regimen,\" which includes fludarabine, melphalan (LPAM), etoposide, and antithymocyte globulin, has been high. To ensure better engraftment, we increased the LPAM dose to 210 mg/m2 (\"LPAM210 regimen\"). Patient data (n = 22; LPAM140, n = 7; LPAM210, n = 15) were analyzed retrospectively. The engraftment rate after the LPAM210 regimen (100.0%) was significantly higher than that after the LPAM140 regimen (57.1%; P = .002). Fludarabine combined with melphalan (210 mg/m2 ) had a favorable impact on engraftment.",
"affiliations": "Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan.;Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan.;Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan.;Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan.;Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan.;Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan.;Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan.;Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan.;Department of Hematology/Oncology, Osaka Women's and Children's Hospital, Osaka, Japan.",
"authors": "Mayumi|Azusa|A|0000-0002-2091-2619;Sawada|Akihisa|A|;Sato|Maho|M|;Shimizu|Mariko|M|;Ioi|Aya|A|;Higuchi|Kohei|K|;Yasui|Masahiro|M|;Kawa|Keisei|K|;Inoue|Masami|M|",
"chemical_list": "D000961:Antilymphocyte Serum; D005047:Etoposide; D014740:Vidarabine; C024352:fludarabine; D008558:Melphalan",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.28536",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "67(9)",
"journal": "Pediatric blood & cancer",
"keywords": "chronic Epstein-Barr virus-associated T or natural killer cell lymphoproliferative diseases; chronic active Epstein-Barr virus infection; cord blood transplantation; engraftment; reduced-intensity conditioning",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000961:Antilymphocyte Serum; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D003131:Combined Modality Therapy; D036101:Cord Blood Stem Cell Transplantation; D020031:Epstein-Barr Virus Infections; D005047:Etoposide; D005260:Female; D005500:Follow-Up Studies; D006086:Graft vs Host Disease; D004854:Herpesvirus 4, Human; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D007694:Killer Cells, Natural; D008232:Lymphoproliferative Disorders; D008297:Male; D008558:Melphalan; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate; D013601:T-Lymphocytes; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014740:Vidarabine; D055815:Young Adult",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e28536",
"pmc": null,
"pmid": "32564520",
"pubdate": "2020-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Impact of melphalan dose during reduced-intensity conditioning on engraftment of cord blood transplantation for chronic Epstein-Barr virus-associated T or NK cell lymphoproliferative diseases.",
"title_normalized": "impact of melphalan dose during reduced intensity conditioning on engraftment of cord blood transplantation for chronic epstein barr virus associated t or nk cell lymphoproliferative diseases"
} | [
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"medicinalproduct": "METHOTREXATE."
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"activesubstancename": "FLUDARABINE PHOSPHATE"
},
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"medicinalproduct": "FLUDARABINE"
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{
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"medicinalproduct": "MELPHALAN."
}
],
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"reaction": [
{
"reactionmeddrapt": "Thrombotic microangiopathy",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute graft versus host disease",
"reactionmeddraversionpt": "23.1",
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}
],
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},
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"literaturereference": "MAYUMI A, SAWADA A, SATO M, SHIMIZU M, IOI A, HIGUCHI K ET AL.. IMPACT OF MELPHALAN DOSE DURING REDUCED?INTENSITY CONDITIONING ON ENGRAFTMENT OF CORD BLOOD TRANSPLANTATION FOR CHRONIC EPSTEIN?BARR VIRUS?ASSOCIATED T OR NK CELL LYMPHOPROLIFERATIVE DISEASES. PEDIATRIC BLOOD AND CANCER. 2020",
"literaturereference_normalized": "impact of melphalan dose during reduced intensity conditioning on engraftment of cord blood transplantation for chronic epstein barr virus associated t or nk cell lymphoproliferative diseases",
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},
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"sendertype": "2"
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"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20201103"
}
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{
"abstract": "Nevirapine (NVP)-based antiretroviral therapy continues to be used in some human immunodeficiency virus (HIV)-infected patients. Rilpivirine (RPV) could be used as an alternative to NVP. We studied the efficacy of RPV-based regimens as switch therapy.\nA randomized controlled noninferiority trial was conducted in HIV-infected patients who received NVP-based regimens and had undetectable plasma viral loads (VLs). Patients were randomized to a continuation arm (NVP was continued) or a switch arm (NVP was switched to RPV). Tenofovir disoproxil fumarate (TDF) plus lamivudine or emtricitabine were the backbone of the regimens. The primary endpoint was an HIV VL <40 copies/mL at week 48.\nA total of 106 patients were enrolled, 55 patients were in the continuation arm and 51 patients were in the switch arm. The mean (standard deviation) age was 49.1 (9.2) years and 51.9% were females. The median (interquartile range) baseline CD4 count was 561 (443-732) cells/mm3. At week 48, 52 patients (94.6%) in the continuation arm and 50 patients (98.0%) in the switch arm had an HIV VL <40 copies/mL, with an efficacy difference of 3.5% (95% confidence interval [CI], -13.0 to 5.6; P = .619). Decreases in total cholesterol and triglyceride were observed in the switch arm (-17.1 mg/dL, 95% CI = -29.7 to -4.4, P = .008 and -36.0 mg/dL, 95% CI = -71.0 to -1.1, P = .044, respectively).\nSwitching from NVP to RPV can maintain virological suppression and decrease total cholesterol and triglyceride at week 48. In patients virologically suppressed with NVP-based regimens, RPV-based regimens can be a switch option.",
"affiliations": "Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, Thailand.;Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.",
"authors": "Petchkum|Porkaew|P|;Sungkanuparph|Somnuek|S|;Kiertiburanakul|Sasisopin|S|;Phuphuakrat|Angsana|A|0000-0003-2474-1850",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofz155",
"fulltext": "\n==== Front\nOpen Forum Infect DisOpen Forum Infect DisofidOpen Forum Infectious Diseases2328-8957Oxford University Press US 10.1093/ofid/ofz155ofz155Major ArticleEfficacy of Rilpivirine-Based Regimens as Switch Therapy From Nevirapine-Based Regimens in Human Immunodeficiency Virus-Infected Patients With Virological Suppression: A Randomized Controlled Trial Petchkum Porkaew 1Sungkanuparph Somnuek 2Kiertiburanakul Sasisopin 1http://orcid.org/0000-0003-2474-1850Phuphuakrat Angsana 11 Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand2 Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Samut Prakan, ThailandCorrespondence: A. Phuphuakrat, MD, PhD, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, 270 Rama VI Rd., Bangkok 10400, Thailand (angsana.phu@mahidol.ac.th).4 2019 25 3 2019 25 3 2019 6 4 ofz15530 1 2019 21 3 2019 © The Author(s) 2019. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2019This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nNevirapine (NVP)-based antiretroviral therapy continues to be used in some human immunodeficiency virus (HIV)-infected patients. Rilpivirine (RPV) could be used as an alternative to NVP. We studied the efficacy of RPV-based regimens as switch therapy.\n\nMethods\nA randomized controlled noninferiority trial was conducted in HIV-infected patients who received NVP-based regimens and had undetectable plasma viral loads (VLs). Patients were randomized to a continuation arm (NVP was continued) or a switch arm (NVP was switched to RPV). Tenofovir disoproxil fumarate (TDF) plus lamivudine or emtricitabine were the backbone of the regimens. The primary endpoint was an HIV VL <40 copies/mL at week 48.\n\nResults\nA total of 106 patients were enrolled, 55 patients were in the continuation arm and 51 patients were in the switch arm. The mean (standard deviation) age was 49.1 (9.2) years and 51.9% were females. The median (interquartile range) baseline CD4 count was 561 (443–732) cells/mm3. At week 48, 52 patients (94.6%) in the continuation arm and 50 patients (98.0%) in the switch arm had an HIV VL <40 copies/mL, with an efficacy difference of 3.5% (95% confidence interval [CI], −13.0 to 5.6; P = .619). Decreases in total cholesterol and triglyceride were observed in the switch arm (−17.1 mg/dL, 95% CI = −29.7 to −4.4, P = .008 and −36.0 mg/dL, 95% CI = −71.0 to −1.1, P = .044, respectively).\n\nConclusions\nSwitching from NVP to RPV can maintain virological suppression and decrease total cholesterol and triglyceride at week 48. In patients virologically suppressed with NVP-based regimens, RPV-based regimens can be a switch option.\n\nefficacyHIVrandomized controlled trialrilpivirineswitch therapyFaculty of Medicine Ramathibodi HospitalMahidol UniversityThai AIDS SocietyThailand Research FundRTA6080009\n==== Body\nIn resource-limited settings, 2 nucleoside reverse-transcriptase inhibitors (NRTIs) in combination with efavirenz (EFV) is the preferred agent for initial treatment of human immunodeficiency virus (HIV)-1-infected patients [1]. However, some patients remain on nevirapine (NVP)-based antiretroviral therapy (ART), despite its twice-daily dosing, because the treatment was initiated before EFV availability and/or the presence of drug-related adverse effects due to EFV in the past [2].\n\nRilpivirine (RPV) is a second-generation nonnucleoside reverse-transcriptase inhibitor (NNRTI), given at a daily dose of 25 mg, which can be coformulated with 2 NRTIs [3]. Rilpivirine has noninferior efficacy compared with EFV in treatment-naive HIV-infected patients, especially in the groups of patients with either an HIV ribonucleic acid (RNA) <100 000 or 100 000–500 000 copies/mL, along with a favorable safety and tolerability profile [4, 5]. The ART regimen tenofovir/emtricitabine (FTC)/RPV is categorized as the recommended initial regimen for certain HIV-infected patients with pretreatment HIV RNA viral loads (VLs) <100 000 copies/mL and a CD4 count >200 cells/mm3 in both the United States and the European guidelines [3, 6]. However, in resource-limited settings, HIV VL is scarcely carried out before initiation of therapy, and many patients presented with late-stage HIV disease despite ART scale-up [7]. Consequently, RPV has seldom been used in treatment-naive HIV-infected patients in resource-limited settings.\n\n Previous studies showed that RPV combined with 2 NRTIs, as a switch therapy in virologically suppressed HIV-infected patients, was a safe and efficacious option [8, 9]. A small, prospective, single-arm study of switching from tenofovir disoproxil fumarate (TDF)/FTC + NVP to a TDF/FTC/RPV single-tablet regimen in virologically suppressed, HIV-1-infected subjects demonstrated that all 32 patients remained virologically suppressed at weeks 12 and 24 [10]. A randomized controlled study in Rwandans revealed that a switch from NVP plus any 2 NRTIs to coformulated TDF/FTC/RPV was virologic effective, with few adverse events at week 24 [11].\n\nDue to cost constraints, a fixed drug combination of TDF/FTC/RPV is not available in some resource-limited countries. However, RPV is available as a separate tablet to be combined with TDF/FTC or TDF plus lamivudine (3TC) as once-daily regimens. We aimed to investigate the efficacy and adverse events of ART switching from NVP to RPV, plus either TDF/FTC or TDF + 3TC in virologically suppressed HIV-infected patients. The primary endpoint was an HIV VL <40 copies/mL at week 48. The secondary endpoints were the changes in CD4 cell counts and lipid profiles from baseline at week 48.\n\nMETHODS\nStudy Design and Participants\nA single-center, randomized, controlled, noninferiority trial to study 48-week treatment outcomes of RPV as a switch therapy was conducted at Ramathibodi Hospital, a 1300-bed university hospital in Bangkok, Thailand, from December 2016 to October 2017. Human immunodeficiency virus-1-infected adults over 18 years old were enrolled from the infectious disease clinic. Inclusion criteria were patients who had a recent plasma HIV-1 RNA VL within 6 months of the screening <40 copies/mL and had been treated with TDF/FTC + NVP or TDF + 3TC + NVP for at least 6 months. Exclusion criteria included patients with a history of any documented HIV drug resistance, patients who used drugs that interact with RPV (eg, proton pump inhibitors, histamine H2-receptor antagonists, rifampin, and anticonvulsants), women during pregnancy or breastfeeding, patients with an estimated glomerular filtration rate (eGFR) of <60 mL/min per 1.73 m2 (by the Chronic Kidney Disease Epidemiology Collaboration [CKD-EPI]) [12], and patients who had depressive or psychiatric disorders.\n\nThe study was reviewed and ethically approved by the Committee of Human Rights Related to Research Involving Human Subjects, Faculty of Medicine Ramathibodi Hospital, Mahidol University (MURA2016/642). All participants provided written informed consent before enrollment. The trial was registered at ClinicalTrials.gov under registration number NCT03664440.\n\nProcedures\nEligible patients who were on the regimens TDF + 3TC + NVP or TDF/FTC + NVP were blocks of 4 randomly assigned (1:1) by computer-generated random numbers, to continue their regimens of NVP 200 mg twice daily plus the previous backbone NRTIs or to switch from NVP to RPV 25 mg once-daily plus the previous backbone NRTIs. Patients were advised to take RPV with a meal. Patient visits were scheduled at baseline, weeks 12, 24, 36, and 48. The laboratory assessment was performed at baseline, weeks 24 and 48. Laboratory tests included complete blood count, CD4 percentage, CD4 cell count, chemistry panel (eg, alanine aminotransferase [ALT], creatinine, fasting sugar, and lipid panel), and urinalysis. The HIV RNA VL was performed using the Amplicor HIV-1 Monitor Test, version 1.5 (Roche, Basel, Switzerland). We assessed safety and tolerability by self-adverse event reporting, history taking, and physical examination. Adherence counseling and routine standard of care were performed at each study visit to patients enrolled in the program (Figure 1). Depression was accessed by using Patient Health Questionnaire-2 at weeks 0, 24, and 48 [13].\n\nFigure 1. Study screening, enrollment, and follow-up through week 48. 3TC, lamivudine; AE, adverse events; eGFR, estimated glomerular filtration rate; FTC, emtricitabine; NVP, nevirapine; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate.\n\nOutcomes\nThe primary outcome was assessed at week 48. The proportion of patients with virological suppression (HIV VL <40 copies/mL) after switching treatment regimens from NVP-based regimens to RPV-based regimens (switch arm) were compared with those continuing the NVP-based regimens (continuation arm). The secondary outcomes were to evaluate changes in CD4 cell counts, lipid levels (including triglycerides level, total cholesterol level, low-density lipoprotein cholesterol level [LDL-C], and high-density lipoprotein cholesterol level [HDL-C]), and adverse events between the 2 groups during the study.\n\nThe definition of virological suppression was an HIV RNA VL <40 copies/mL. Virological failure was defined as the inability to maintain a suppression level of an HIV VL <200 copies/mL [3]. Adverse events were defined as any undesirable experience associated with the use of antiretroviral drugs include rash, gastrointestinal symptoms (nausea, vomiting, and epigastric pain), neurological symptoms, and psychiatric events [3, 5]. Serious adverse events included death, hospitalization, disability, or permanent impairment of body structure, physical activities, and quality of life [14].\n\nStatistical Analyses\nThe sample size was calculated from the proportional response rate from the previous trial [11] using n4Studies program, version 1.4.0 [15]. A population of 53 in each group was required to establish the noninferiority of the switching group compared with the continuing group and allowing for a dropout rate of approximately 10% at 0.9 power and a 0.05 significance level. Baseline participant characteristics were compared using t test and Mann-Whitney U test for continuous variables and χ2 or Fisher’s exact tests for categorical variables. The primary analysis was based on intention-to-treat (ITT) populations (all who received a study drug). We did an additional analysis on per-protocol populations (as ITT but excluding dead patients or patients that discontinued study drug for any reason), with a prespecified noninferior margin of 12%. The noninferiority margin was chosen in accordance with the US Food and Drug Administration guidelines for HIV drug development, with the margin ranging from 10% to 12% [16]. Secondary outcomes were compared using Mann-Whitney U test for nonparametric continuous variables and multilevel mixed-effects linear regression for repeated measurements of continuous variables. All statistical analyses were performed using Stata statistical software, version 14.0.\n\nRESULTS\nParticipants and Baseline Characteristics\nDuring the study period, 109 HIV-infected individuals were screened for study enrollment with 106 enrolled and randomized. Three individuals were excluded: 1 had an eGFR <60 mL/min per 1.73 m2, 1 withdrew consent, and 1 suffered from a psychiatric disorder. A total of 106 patients were enrolled: 55 and 51 patients were randomly assigned to the continuation arm and the switch arm, respectively. Of all patients, 55 (51.9%) were females. The mean age was 49.1 (standard deviation [SD] = 9.2) years. The median baseline CD4 cell count was 561 (interquartile range [IQR], 443–732) cells/mm3. Pretreatment HIV VL was performed in 40 patients (36.7%). The median pretreatment HIV VL was 105 600 (IQR, 17 345–252 378) copies/mL. The median nadir CD4 cell count was 157.5 (IQR, 39–305) cells/mm3. Of all patients, 57 (53.8%) had a history of opportunistic infection, and the most common opportunistic infection was tuberculosis. The mean duration of ART was 10.9 (SD = 4.1) years. Baseline characteristics including age, gender, CD4 percentage, CD4 cell count, and ART duration were comparable between the 2 groups (P > .05) (Table 1).\n\nTable 1. Baseline Characteristics\n\nCharacteristics\tContinuation Arm\tSwitch Arm\t\nP Value\t\n\t(Group A)\t(Group B)\t\t\n\tN = 55\tN = 51\t\t\nFemale sex, n (%)\t29 (52.7)\t26 (47.3)\t.857\t\nMean age, years (SD)\t50.0 (9.6)\t48.2 (8.9)\t.325\t\nMean body weight, kilograms (SD)\t58.4 (10.6)\t58.8 (9.9)\t.849\t\nRoute of HIV transmission, (%)\t\t\t.123\t\n Heterosexual\t52 (94.6)\t42 (82.4)\t\t\n Homosexual\t3 (5.5)\t8 (15.7)\t\t\n Intravenous drug user\t0 (0.0)\t1 (2.0)\t\t\nMean duration of ART, years (SD)\t10.84 (4.3)\t10.96 (4.0)\t.877\t\nPrior NRTI and NNRTI use, n (%)\t\t\t.662\t\n Stavudine\t26 (47.3)\t23 (45.1)\t\t\n Zidovudine\t19 (34.6)\t22 (43.1)\t\t\n Efavirenz\t7 (12.7)\t5 (9.2)\t\t\n Reason for efavirenz discontinuation\t\t\t.332\t\n CNS adverse effects\t3 (42.9)\t4 (80.0)\t\t\n Rash\t2 (28.6)\t1 (20.0)\t\t\n Gynecomastia\t2 (28.6)\t0 (0.0)\t\t\nUnderlying diseases, n (%)\t\t\t.053\t\n No underlying diseases\t35 (63.6)\t41 (80.4)\t\t\n Diabetes mellitus\t2 (3.6)\t0 (0.0)\t\t\n Hypertension\t11 (20.0)\t2 (3.9)\t\t\n Dyslipidemia \t2 (3.6)\t4 (7.8)\t\t\n Othersa\t5 (9.1)\t4 (7.8)\t\t\nMedian CD4 cell count at entry, cells/mm3 (IQR)\t552 (434–733)\t563 (457–727)\t.912b\t\nMedian CD4 at entry, % (IQR)\t27 (22–33)\t27 (22–32)\t.995b\t\nMedian nadir CD4 cell count, cell/mm3 (IQR)\t190 (40–368)\t145 (30–297)\t.479\t\nMedian pretreatment HIV VL, copies/mL (IQR)\t125 000 (21 200–31 200)\t81 900 (15 000–211 000)\t.303b\t\nHistory of opportunistic infection, n (%)\t31 (56.4)\t26 (51.0)\t.579\t\nTuberculosis\t19 (34.6)\t14 (27.5)\t.431\t\nPneumocystis pneumonia\t4 (7.3)\t6 (11.8)\t.429\t\nCryptococcal infection\t1 (1.8)\t1 (2.0)\t.957\t\nHerpes virus infection\t4 (7.3)\t3 (5.9)\t.773\t\nCMV infection\t1 (1.8)\t2 (3.9)\t.514\t\nHistoplasmosis\t1 (1.8)\t0 (0.0)\t.333\t\nToxoplasmosis\t1 (1.8)\t0 (0.0)\t.333\t\nHBsAg positive\t3 (5.5)\t5 (5.9)\t.924\t\nAnti-HCV IgG positive\t2 (3.6)\t1 (2.0)\t.603\t\nMean fasting plasma glucose, mg/dL (SD)\t92.7 (9.7)\t94.7 (11.6)\t.302\t\nMean lipid levels, mg/dL (SD)\t\t\t\t\n Total cholesterol\t198.7 (36.5)\t198.6 (25.0)\t.930\t\n HDL-C\t50.4 (15.8)\t52.9 (11.7)\t.389\t\n LDL-C\t114.9 (34.1)\t116.9 (25.7)\t.716\t\n Triglycerides\t155.8 (98.3)\t128.1 (82.0)\t.130\t\nTotal cholesterol/HDL-C ratio, (SD)\t4.2 (1.2)\t4.0 (1.0)\t.238\t\nMean alanine aminotransferase, U/L (SD)\t40.4 (25.8)\t44.8 (27.1)\t.057\t\nMean serum creatinine, mg/dL (SD)\t0.9 (0.2)\t0.9 (0.2)\t.810\t\nMean eGFR, mL/min per 1.73 m2 (SD)\t91.8 (18.6)\t92.6 (16.0)\t.912\t\nAbbreviations: ART, antiretroviral therapy; CMV, cytomegalovirus; CNS, central nervous system; eGFR, estimated glomerular filtration rate; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HDL-C, high-density lipoprotein cholesterol level; HIV, human immunodeficiency virus; IgG, immunoglobulin G; IQR, interquartile range; LDL-C, low-density lipoprotein cholesterol level; NNRTI, nonnucleoside reverse-transcriptase inhibitor; NRTI, nucleos(t)ide reverse-transcriptase inhibitor; SD, standard deviation; VL, viral load.\n\n\naThyroid disease, anal cancer, liver cirrhosis, chronic kidney disease, cardiovascular disease.\n\n\nbMann-Whitney U test.\n\nThere were 2 deaths in the continuation arm, from hematologic malignancy and dilated cardiomyopathy, which occurred at weeks 12 and 20 after enrollment, respectively. One patient in the switch arm developed nausea and vomiting, which occurred at week 8 of enrollment. She discontinued RPV and chose to resume TDF/FTC + NVP. At week 48, 53 patients in the continuation arm and 50 patients in the switch arm remained in the study (Figure 1).\n\nEfficacy\nAt week 48, by ITT analysis, 52 patients (94.6%) in the continuation arm and 50 patients (98.0%) in the switch arm achieved the primary outcome of an HIV VL <40 copies/mL. The difference in the proportions was 3.5% (95% confidence interval [CI], −13.0 to 5.6; P = .619), thus meeting the prespecified noninferiority criterion. By per-protocol analysis, the difference in the proportions was 1.9% (95% CI, −9.9 to +5.4; P > .999) (Figure 2). During the study, one patient had an HIV VL of 593 copies/mL at week 24 under RPV therapy. This patient reported poor compliance to the ART regimen at approximately 3 weeks after enrollment because of family matters. After assessment and discussion on the adherence issue with the patient, HIV VL was followed at week 32 and week 48 in which the level was <40 copies/mL. Another patient in the continuation arm had an HIV VL of 42 copies/mL at week 48. He reported low compliance to the ART regimen at week 40 after enrollment because of a change of his work and financial problems.\n\nFigure 2. Proportion of patients with virological suppression (A), and median CD4 cell counts (B) at week 48. CI, confidence interval; ITT-analysis, intention to treat analysis; IQR, interquartile range; PP-analysis, per protocol analysis.\n\nFor the secondary outcomes, by ITT analysis, the median CD4 cell count at week 48 was 520 (424–720) cells/mm3 in the continuation arm and 547 (417–708) cells/mm3 in the switch arm (P = .911) (Figure 2). Significant decreases in the means total cholesterol and triglyceride were observed in the switch arm (−17.1 mg/dL, 95% CI = −29.7 to −4.4, P = .008 and −36.0 mg/dL, 95% CI = −71.0 to −1.1, P = .044, respectively). In the continuation arm, significant increases in the means HDL-C and LDL-C were observed (5.2 mg/dL, 95% CI = 2.5 to 7.9, P < .001 and 8.5 mg/dL, 95% CI = 1.6 to 15.4, P = .015, respectively). However, there were no significant changes in means of the total cholesterol to HDL-C ratio, alanine aminotransferase, serum creatinine, eGFR, or fasting plasma glucose in both arms (Figure 3 and Table 2).\n\nFigure 3. Changes in levels of lipid profiles from baseline through week 48: (A) total cholesterol, (B) triglyceride, (C) high-density lipoprotein cholesterol (HDL-C), (D) low-density lipoprotein cholesterol (LDL-C), and (E) total cholesterol/HDL-C ratio. \n\nTable 2. Mean Change in Blood Chemistry Parameters From Baseline\n\nBlood Chemistry Parameters\tChangea (95% CI)\t\tChangea (95% CI)\t\t\t\n\tContinuation Arm at Week 24\tContinuation Arm at Week 48\tSwitch Arm at Week 0\tSwitch Arm at Week 24\tSwitch Arm at Week 48\t\nTotal cholesterol, mg/dL \t0.06 (−8.76 to 8.89)\t7.25 (−0.87 to 15.38)\t−0.52 (−12.21 to 11.17)\t−15.85b (−29.57 to −2.14)\t−17.05c (−29.69 to −4.40)\t\nTriglyceride, mg/dL\t−9.83 (−33.68 to 14.01)\t−12.25 (−40.93 to 16.43)\t−30.17 (−64.89 to 4.54)\t−40.45b (−72.82 to −8.08)\t−36.02b (−71.02 to −1.12)\t\nHDL-cholesterol, mg/dL\t0.13 (−2.70 to 2.97)\t5.16c (2.46 to 7.86)\t1.55 (−4.16 to 7.27)\t2.80 (−14.98 to 20.57)\t−0.37 (−6.10 to 5.36)\t\nLDL-cholesterol, mg/dL\t7.62b (0.86 to 14.38)\t8.52b (1.63 to 15.41)\t3.83 (−8.47 to 16.13)\t7.20 (−5.45 to 19.83)\t0.53 (−11.80 to 12.86)\t\nTC/HDL-C ratio, mg/dL\t0.01 (−0.20 to 0.22)\t−0.22 (−0.47 to 0.03)\t−0.12 (−0.56 to 0.32)\t0.00 (−0.47 to 0.47)\t−0.31 (−0.75 to 0.13)\t\nAlanine aminotransferase, U/L\t2.91 (−0.86 to 6.68)\t−2.13 (−7.60 to 3.35)\t3.06 (−7.14 to 13.30)\t−3.53 (−12.68 to 5.62)\t−3.67 (−13.27 to 5.93)\t\nSerum creatinine, mg/dL\t−0.01 (−0.03 to 0.02)\t−0.01 (−0.04 to 0.02)\t0.00 (−0.07 to 0.08)\t0.51 (−0.42 to 1.43)\t0.03 (−0.05 to 0.10)\t\neGFR, mL/min per 1.73 m2\t0.13 (−2.30 to 2.56)\t2.25 (−1.24 to 5.73)\t0.33 (−6.25 to 6.92)\t−2.50 (−9.14 to 4.15)\t0.10 (−6.95 to 7.15)\t\nFasting plasma glucose, mg/dL\t−1.56 (−3.61 to 0.50)\t−0.40 (−2.76 to 1.95)\t2.00 (−2.06 to 6.06)\t7.69 (−3.21 to 18.59)\t2.47 (−1.82 to 6.75)\t\nAbbreviations: CI, confidence interval; eGFR, estimated glomerular filtration rate; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol level.\n\n\n a Multilevel mixed-effects linear regression, reference is blood chemistry levels at baseline of continuation arm\n\n\nb\nP < .05\n\n\nc\nP < .01\n\nThree patients (5.9%) in the switch arm reported adverse events. Two patients developed nausea, vomiting, and abdominal discomfort. One patient discontinued RPV and chose to resume TDF/FTC + NVP, whereas the symptoms improved after week 10 in another patient in which RPV was continued. Another patient complained of numbness in both hands at week 3, but the symptom later subsided, and RPV was continued. No patient developed a rash or central nervous system adverse effects. None of the patients in the switch arm complained of RPV-associated food constraints or reported serious adverse events. In the continuation arm, 2 deaths (3.6%) occurred from hematologic malignancy and dilated cardiomyopathy. There was no statistically significant difference in adverse events between both arms (P = .670).\n\nDISCUSSION\nOur study demonstrated that in HIV-infected patients virologically suppressed with NVP-based regimens, the switch to once-daily RPV-based regimens was not inferior to the continuation of TDF + 3TC + NVP or TDF/FTC + NVP after 48 weeks, with a few adverse events. Our results agreed with the previous study in Rwanda, which showed that switching from an NVP-based regimen to coformulated TDF/FTC/RPV was noninferior to a continuation of NVP-base regimens at week 24. However, the switching strategies were different between that study and our study. The NRTI backbones before switching to TDF/FTC/RPV in the Rwandan study included TDF (63%), azidothymidine (35%), and abacavir (1%) combined with 3TC [11]. In our study, 70% used TDF + 3TC and 30% used TDF/FTC as backbones. The NRTI backbones were fixed, and only RPV was switched from NVP. Despite FTC and 3TC being closely structurally related NRTIs, in vitro study showed differing resistance profiles when administered in combination with TDF and either EFV or ritonavir-boosted protease inhibitors [17]. The prevalence of the M184V/I resistance mutation was significantly lower in patients who received FTC and TDF than in those who received 3TC and TDF [17, 18]. In an observational study using data from the AIDS Therapy Evaluation in the Netherlands (ATHENA), the nationwide HIV cohort revealed that the use of FTC instead of 3TC as part of combination ART was associated with better virological responses [19]. Therefore, by reducing the effect of different NRTIs in the backbone, our study demonstrated the efficacy of RPV per se in the switch regimens.\n\nIn our study, patients had been on ART for approximately 10 years and had good baseline CD4 at study entry. However, they had low nadir CD4, and more than half of the patients had a history of opportunistic infections. The median of known pretreatment HIV VL was more than >100 000 copies/mL. These demonstrated the efficacy of the RPV switch regimens in populations with a history of opportunistic infection, high baseline pretreatment VL, and/or low nadir CD4. We also showed the durability of the switch regimens through week 48.\n\nOther than efficacy, the switch to RPV-based regimens in our study demonstrated a beneficial effect on total cholesterol and triglyceride. The switch trial in Rwanda also showed a trend toward a reduction in total cholesterol and HDL-C in the RPV switch arm compared with the NVP continuation arm, but no significant differences were detected in other fasting lipid measurements at week 24 [11]. A prospective, open-label, controlled trial in the Netherlands showed significant decreases in total cholesterol, HDL-C, and LDL-C over 24 weeks after switching from NVP to RPV [20]. Previous studies comparing RPV to EFV showed improvement of lipid profiles in the RPV switch arm [4, 5, 21]. Nevirapine was demonstrated to have less atherogenic lipid profiles compared with EFV [22]. Our results agreed with the previous study, which demonstrated (1) small increases in HDL-C and (2) non-HDL-C in patients taking an NVP-containing ART [22]. Without significant changes of LDL-C and the total cholesterol to HDL-C ratio after ART switching, this suggested that RPV might be suitable for switching in patients with risk factors of cardiovascular diseases.\n\nAlthough the switch to RPV in treatment-experienced patients did not show higher virological failure [8, 11, 21], this switching strategy had some concerns on pharmacokinetics. Rilpivirine should always be taken with a meal to enhance its bioavailability. Administration of RPV under fasting conditions lowered the oral bioavailability when compared with the administration with a normal-fat and high-fat breakfast [23]. Rilpivirine is predominantly metabolized by cytochrome P450 3A4 (CYP3A4), sharing this metabolic pathway with the first-generation NNRTIs and CYP3A4 inducers NVP and EFV [24]. In a previous prospective study, RPV concentrations were therapeutic at day 7 after NVP to RPV switching in most subjects [25]. Substituting NVP for RPV did not have clinically relevant pharmacokinetic effects by cytochrome P450 interactions [25]. In our study, substituting NVP for RPV can maintain virological suppression. Only 1 patient who had a compliance problem had a virological rebound.\n\nThe strengths of our study included the following: the study was a randomized control trial, and RPV was the only drug in the regimens that was switched. Therefore, the efficacy of RPV per se as a switch therapy can be demonstrated. Moreover, the duration of the study was 48 weeks, which showed the durability of the switch regimens. However, there were some limitations. This study was a single-center study, and the study was not blinded to investigators and participants.\n\nCONCLUSIONS\nIn conclusion, our findings show that in virologically suppressed HIV-infected patients with NVP-based regimens, switching to once-daily RPV-based regimens can maintain virological suppression and decrease total cholesterol and triglyceride. A few adverse events were observed with this switching strategy. Further study on long-term efficacy and durability of this switching strategy should be pursued.\n\nAcknowledgments\nWe thank the participants and their families for their support during the trial. We are grateful to Dr. Rapeepong Suphanchaimat for help with data analysis.\n\n\nAuthor contributions. A. P. contributed to conceptualization; P. P. contributed to data curation; P. P. and A. P. contributed to formal analysis; P. P., S. S., and A. P. acquired funding; P. P., S. S., S. K., and A. P. conducted investigations; A. P. contributed to project administration; P. P., wrote the original draft; and S. S., S. K., and A. P. reviewed and edited the manuscript.\n\n\nFinancial support. This study was funded by grants from the Faculty of Medicine Ramathibodi Hospital, Mahidol University, the Thai AIDS Society, and the Thailand Research Fund (RTA6080009).\n\n\nPotential conflicts of interest. All authors: no reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. \n\nPresented in a part: HIV Drug Therapy Congress 2018, October 28–31, 2018, Glasgow, United Kingdom.\n==== Refs\nReferences\n1. \nThe Bureau of AIDS, TB and STI, Department of Disease Control, Thailand . Thailand national guidelines on HIV/AIDS treatment and prevention . 2017 Available at: http://www.thaiaidssociety.org/index.php?option=com_content&view=article&id=79&Itemid=86. Accessed 5 March 2019 .\n2. \nFord N , Shubber Z , Pozniak A , et al \nComparative safety and neuropsychiatric adverse events associated with efavirenz use in first-line antiretroviral therapy: A systematic review and meta-analysis of randomized trials . J Acquir Immune Defic Syndr 2015 ; 69 :422 –9 .25850607 \n3. \nPanel on Antiretroviral Guidelines for Adults and Adolescents . Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents . Department of Health and Human Services \n2018 Available at: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Accessed 2 March 2019 .\n4. \nCohen CJ , Andrade-Villanueva J , Clotet B , et al \nRilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, non-inferiority trial . Lancet 2011 ; 378 :229 –37 .21763935 \n5. \nMolina JM , Cahn P , Grinsztejn B , et al \nRilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): A phase 3 randomised double-blind active-controlled trial . Lancet 2011 ; 378 :238 –46 .21763936 \n6. \nEACS: European AIDS Clinical Society . EACS Guidelines Version 9.1 - October 2018 . European AIDS Clinical Society (EACS) ; 2018 Available at: http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html. Accessed 2 March 2019 .\n7. \nKiertiburanakul S , Boettiger D , Lee MP , et al \nTrends of CD4 cell count levels at the initiation of antiretroviral therapy over time and factors associated with late initiation of antiretroviral therapy among Asian HIV-positive patients . J Int AIDS Soc 2014 ; 17 :18804 .24598459 \n8. \nMills AM , Cohen C , Dejesus E , et al \nEfficacy and safety 48 weeks after switching from efavirenz to rilpivirine using emtricitabine/tenofovir disoproxil fumarate-based single-tablet regimens . HIV Clin Trials 2013 ; 14 :216 –23 .24144898 \n9. \nPalella FJ Jr, Fisher M , Tebas P , et al \nSimplification to rilpivirine/emtricitabine/tenofovir disoproxil fumarate from ritonavir-boosted protease inhibitor antiretroviral therapy in a randomized trial of HIV-1 RNA-suppressed participants . AIDS 2014 ; 28 :335 –44 .24670520 \n10. \nAllavena C , Dailly E , Reliquet V , et al \nSwitching from tenofovir/emtricitabine and nevirapine to a tenofovir/emtricitabine/rilpivirine single-tablet regimen in virologically suppressed, HIV-1-infected subjects . 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PLoS One 2015 ; 10 :e0128131 .26107265 \n19. \nRokx C , Fibriani A , van de Vijver DA , et al \nIncreased virological failure in naive HIV-1-infected patients taking lamivudine compared with emtricitabine in combination with tenofovir and efavirenz or nevirapine in the Dutch nationwide ATHENA cohort . Clin Infect Dis 2015 ; 60 :143 –53 .25273080 \n20. \nRokx C , Blonk M , Verbon A , et al \nThe efficacy, pharmacokinetics, safety and cardiovascular risks of switching nevirapine to rilpivirine in HIV-1 patients: the RPV switch study . J Int AIDS Soc 2014 ; 17 :19789 .25397533 \n21. \nThamrongwonglert P , Chetchotisakd P , Anunnatsiri S , Mootsikapun P \nImprovement of lipid profiles when switching from efavirenz to rilpivirine in HIV-infected patients with dyslipidemia . HIV Clin Trials 2016 ; 17 :12 –6 .26739573 \n22. \nvan Leth F , Phanuphak P , Stroes E , et al \nNevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral-therapy-naive patients infected with HIV-1 . PLoS Med 2004 ; 1 :e19 .15526045 \n23. \nCrauwels HM , van Heeswijk RP , Buelens A , et al \nImpact of food and different meal types on the pharmacokinetics of rilpivirine . J Clin Pharmacol 2013 ; 53 :834 –40 .23720136 \n24. \nUsach I , Melis V , Peris JE \nNon-nucleoside reverse transcriptase inhibitors: a review on pharmacokinetics, pharmacodynamics, safety and tolerability . J Int AIDS Soc 2013 ; 16 :1 –14 .24008177 \n25. \nRokx C , Blonk M , Verbon A , et al \nThe efficacy, pharmacokinetics, and safety of a nevirapine to rilpivirine switch in virologically suppressed HIV-1-infected patients . J Acquir Immune Defic Syndr 2015 ; 68 :36 –9 .25247434\n\n",
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"issue": "6(4)",
"journal": "Open forum infectious diseases",
"keywords": "HIV; efficacy; randomized controlled trial; rilpivirine; switch therapy",
"medline_ta": "Open Forum Infect Dis",
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"pmid": "31041351",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article",
"references": "10075613;14583691;15526045;21763935;21763936;22371439;23720136;24008177;24144898;24598459;24670520;24907142;25247434;25273080;25397533;25850607;26107265;26739573;27704000",
"title": "Efficacy of Rilpivirine-Based Regimens as Switch Therapy From Nevirapine-Based Regimens in Human Immunodeficiency Virus-Infected Patients With Virological Suppression: A Randomized Controlled Trial.",
"title_normalized": "efficacy of rilpivirine based regimens as switch therapy from nevirapine based regimens in human immunodeficiency virus infected patients with virological suppression a randomized controlled trial"
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"abstract": "Viral retinitis due to cytomegalovirus (CMV) infection is rare in patients with acute leukemia who did not receive hematopoietic stem cell transplantation. We report a case of CMV retinitis that developed in a 49-year-old patient with acute lymphoblastic leukemia. The patient was treated with salvage chemotherapy using a hyper-CVAD regimen and did not receive hematopoietic stem cell transplantation. The incidence of CMV retinitis in this subgroup of patients is not described in literature. He had a very complicated course during chemotherapy but was successfully treated, with preservation of visual acuity, and to date he is in complete remission. Interestingly, prior to CMV retinitis, the patient had been diagnosed with and treated for candida retinitis. This case shows the importance of eye examination and care in patients diagnosed with hematological malignancies.",
"affiliations": "Department of Hematology and Medical Oncology, Al Amal Hospital, Hamad Medical Corporation, Doha, Qatar.",
"authors": "Taha|Ruba|R|;Al Hijji|Ibrahim|I|;El Omri|Halima|H|;Al-Laftah|Fareed|F|;Negm|Riham|R|;Yassin|Mohammed|M|;El Ayoubi|Hanadi|H|",
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"fulltext": "\n==== Front\nCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 2074020310.1159/000318230cro0003-0234Published: July 2010Two Ocular Infections during Conventional Chemotherapy in a Patient with Acute Lymphoblastic Leukemia: A Case Report Taha Ruba a*Al Hijji Ibrahim aEl Omri Halima aAl-Laftah Fareed bNegm Riham aYassin Mohammed aEl Ayoubi Hanadi aaDepartment of Hematology and Medical Oncology, Al Amal Hospital, Hamad Medical Corporation, Doha, QatarbDepartment of Ophthalmology, Hamad Medical Corporation, Doha, Qatar*Dr. Ruba Taha, Department of Hematology and Bone Marrow TransplantAl Amal Hospital, Hamad Medical Corporation HMCPO Box 3050, Doha (Qatar), Tel. +974 439 7895, Fax +974 4397857, E-Mail rubataha@yahoo.com, rtaha@hmc.org.qaApr-Aug 2010 10 7 2010 10 7 2010 3 2 234 239 Copyright © 2010 by S. Karger AG, Basel2010This is an Open Access article distributed under the terms of the Creative Commons Attribution-Noncommercial-No-Derivative-Works License (http://creativecommons.org/licenses/by-nc-nd/3.0/). Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Viral retinitis due to cytomegalovirus (CMV) infection is rare in patients with acute leukemia who did not receive hematopoietic stem cell transplantation. We report a case of CMV retinitis that developed in a 49-year-old patient with acute lymphoblastic leukemia. The patient was treated with salvage chemotherapy using a hyper-CVAD regimen and did not receive hematopoietic stem cell transplantation. The incidence of CMV retinitis in this subgroup of patients is not described in literature. He had a very complicated course during chemotherapy but was successfully treated, with preservation of visual acuity, and to date he is in complete remission. Interestingly, prior to CMV retinitis, the patient had been diagnosed with and treated for candida retinitis. This case shows the importance of eye examination and care in patients diagnosed with hematological malignancies.\n\nKey Words\nCytomegalovirus retinitisAcute lymphoblastic leukemiaChemotherapyHyper-CVADCandida\n==== Body\nIntroduction\nCytomegalovirus (CMV) or human herpesvirus 5 is a well-known cause of opportunistic infection in immunocompromised patients; the infection is especially known in patients with acquired immunodeficiency syndrome (AIDS), organ transplantations and hematological malignancies. It is particularly serious after solid organ transplantation or allogenic hematopoietic stem cell transplantation (HSCT). Without prophylaxis, 8-39% of solid organ transplantation and 20-35% of allogenic HSCT recipients develop CMV infection [1]. In the eye, CMV presents as a necrotizing retinitis with a characteristic ophthalmoscopic appearance; it is usually unilateral, but if left untreated, it may progress to the contralateral eye and result in complete visual loss. CMV retinitis usually occurs as a result of hematogenous spread of the virus to the retina after systemic reactivation of a latent infection and usually in patients with severe deficiency of cell-mediated immunity. CMV retinitis has rarely been described in medical literature in settings of acute leukemia without autologus or allogenic HSCT. Here we present a case report of a patient with acute lymphoblastic leukemia who developed 2 different ocular infections during treatment: fungal retinitis in the right eye during induction chemotherapy and CMV retinitis during consolidation chemotherapy.\n\nCase Report\nA 49-year-old gentleman from Iraq, a known carrier of the β-thalassemia trait, presented on March 2007 with fever and symptomatic anemia. Complete blood count (CBC) showed pancytopenia, white blood cell (WBC) count was 3.2 × 103/μl, hemoglobin (Hb) 5.8 g/dl, mean corpuscular volume (MCV) 60.7 fl, platelets (PLT) 46 × 103/μl, neutrophils 1.0 × 103/μl and lymphocyte count 2.1 × 103/μl. Peripheral smear was unremarkable apart from microcytic hypochromic anemia and absolute neutropenia. Bone marrow aspiration and biopsy showed hypercellular marrow with 95% of nucleated cells being blasts of lymphoid features. Immunophenotyping confirmed the diagnosis of B-cell common acute lymphoblastic leukemia (ALL). Karyotype was normal. Molecular studies were not available. Cerebrospinal fluid was not involved. Coagulation, kidney and liver functions were normal. Autoimmune screen was negative. Serologies for hepatitis B, C and human immunodeficiency virus (HIV) were negative. Viral serology was positive for CMV IgG 2,000 IU/ml and toxoplasma IgG 7.5 IU/ml. Chest X-ray and abdominal ultrasound were normal. Echocardiography was normal and the ejection fraction was 55% (55-70). We started induction chemotherapy using the German ALL protocol (prednisolone, cyclophosphamide, vincristine, doxorubicin, L-asparaginase) through a Hickman line. During induction, the patient developed severe mucositis grade IV and prolonged neutropenia less than 0.2 × 103/μl for which he was receiving multiple blood and PLT transfusions. He also had febrile neutropenia which was treated empirically with intravenous meropenem and vancomycin. His blood culture grew Candida albicans; therefore, caspofungin was added and the central line was removed. After 2 weeks on these antimicrobials, the patient still had a fever. A workup to exclude secondary candida foci was done, included echocardiography, which showed no vegetations, and imaging of the chest and abdomen which was normal. A retinal examination was performed by the ophthalmologist and showed left-sided focal retinitis superotemporal to the macula sparing visual acuity, most likely secondary to candida infection. There were no satellite lesions and no vitritis (fig. 1). Caspofungin was replaced with intravenous amphotericin B for a better ocular penetration and 2 weeks later the retinitis healed leaving a scar (fig. 2). The patient achieved hematological remission; however, he developed severe hepatic impairment and progressed to fulminant hepatic failure. Liver biopsy suggested a drug-induced etiology and confirmed absence of fungal deposits. He received maximum supportive care till complete normalization of the liver function. L-asparaginase was presumed the most likely agent to have caused the hepatic toxicity; therefore, we shifted the patient to a hyper-CVAD regimen (course A: dexamethasone, vincristine, doxorubicin alternating with course B: high-dose methotrexate and high-dose cytarabine). After the 4th course of hyper-CVAD the patient reported a decrease in vision in the opposite eye (left side) with floaters. His visual acuity reduced from normal to 6/24 in the left eye (best corrected) and remained normal in the right eye. There was no afferent pupillary defect. Fundus showed active hemorrhagic retinitis suggestive of CMV infection more in the left eye (fig. 3). The plasma CMV polymerase chain reaction (PCR) was 15 copies and continued to rise till 138 copies. The patient was started on intravenous ganciclovir 5 mg/kg b.i.d. for 3 weeks followed by maintenance with oral valganciclovir 900 mg b.i.d. for 2 months. His visual acuity improved to 6/9 in the left eye and retinitis resolved (fig. 4). During the 5th course of hyper-CVAD (October 2007), the patient had a sudden headache and progressed rapidly to coma. Computer tomography of the brain showed a large subdural hemorrhage with midline shift. Urgent surgical evacuation was done. This resulted in the patient regaining full consciousness. However, he sustained residual right-sided spastic hemiparesis and started an intensive rehabilitation program including speech therapy, physiotherapy and occupational therapy.\n\nMaintenance chemotherapy was started on February 2008 with 6-mercaptopurine 60 mg/m2 daily and methotrexate 20 mg/m2 weekly. At the 24-month follow-up (February 2010), CBC was normal with WBC 6.6 × 103/μl, absolute neutrophil count (ANC) 4.3 × 103/μl, Hb 11.9 g/dl and PLT 315 × 103/μl. The patient was in complete remission with fair neurological recovery and stable visual acuity.\n\nDiscussion\nThe retinal involvement in acute leukemia may be of different causes like direct leukemic infiltrates, or secondary to vitreous and retinal hemorrhage caused by anemia, thrombocytopenia or hyperviscosity [2, 3]. Patients with acute leukemia are also susceptible to opportunistic – particularly viral, protozoal and fungal – infections that may involve the retina, especially during the periods of neutropenia, [3]. Candida infection is among the common infections in this subset of patients; when it involves the retina, it typically appears as focal, deep white lesions that can be singular or multiple. It may extend into the vitreous and cause vitritis and endophthalmitis. The rate of developing chorioretinitis in patients with candidemia has reduced markedly since the 1990's due to the early identification of candidemia in blood cultures coupled with a trend of early empiric antifungal therapy. The risk of ocular involvement is increased with Candida albicans compared with other candida species, as well as in multiple positive blood cultures or in the immunosuppressed states [4]. Cytomegalovirus infection is also among the common viral infections in the immunocompromised hosts. However, the prevalence of CMV antigenemia and disease in patients with hematological malignancies who are not transplant recipients or HIV infected is largely unknown and is thought to be low [5,6,7,8]. One retrospective cohort by Han [9] looked into the incidence of CMV antigenemia in more than 2,000 patients with hematological malignancies who did not undergo autologous or allogenic stem cell transplantation. They were tested during the antineoplastic treatment. The antigenemia rate was 13.6% in lymphoid malignancies and 3.9% in myeloid malignancies. This suggests that CMV reactivation occurs primarily in situations of severe lymphoid disease. Another retrospective case series by Ng et al. [10] looked into the rate of CMV reactivation according to the type of therapy prior to CMV antigenemia in patients with hematological malignancies without HSCT. The series showed that the highest event rate was for alemtuzumab therapy 50%, 9.7% for the hyper-CVAD regimen, 4.6% for fludarabine-based regimens, 4.2% for autologous stem cell transplantation, and less than 1% for other conventional chemotherapy regimens. The lung and gastrointestinal tract were the main organs affected with CMV disease in this series.\n\nThe diagnosis of CMV end organ disease is most definitively made by the detection of CMV DNA or RNA in tissues by in situ hybridization. However, in cases of retinitis, retinal biopsy is not often recommended because of the high risk of retinal detachment. Accordingly, examining the intraocular fluid by PCR technique is the most specific mode for diagnosis [11]. The value of virus detection using blood culture or blood PCR may, on the other hand, have a strong correlation to the development of CMV retinitis as suggested by many studies in patients with AIDS [12, 13]. In our case, CMV retinitis was suggested by the typical ophthalmoscopic appearance of CMV hemorrhagic retinitis along with the concomitant rising of plasma CMV DNA by PCR and the remarkable improvement of retinal examination after resolution of the leucopenia and starting ganciclovir. Intraocular fluid sampling was not done because the patient was severely thrombocytopenic and had high a bleeding tendency in spite of PLT transfusions.\n\nPossible factors that predisposed our patient for developing CMV retinitis are: the immunosuppression secondary to the disease itself and to the myeloablative chemotherapy of ALL that caused prolonged leukopenia. In addition, the high dose of steroids in the hyper-CVAD regimen aggravated the myelosuppression even more. The CMV infection in our patient may have developed due to the reactivation of the virus since the patient was seropositive for CMV before starting chemotherapy, or it may have been a new transmission from blood transfusions. The patient was HIV negative, so CD4 count was not done initially or during the chemotherapy, but it was definitely very low during the treatment since total WBC count was 0.1-0.4 × 103/μl. CD4 count was done after bone marrow recovery and was normal.\n\nConclusion\nCMV retinitis is rare in patients with acute leukemia receiving conventional chemotherapy without HSCT, yet it can occur, particularly when the treatment includes a large dose of steroids like in the hyper-CVAD protocol. Moreover, ocular infections in this subgroup of patients can be asymptomatic. Therefore, an eye examination by an ophthalmologist, even in the absence of ocular symptoms, is of importance during the treatment of these patients.\n\nFig. 1 Color photograph of the right fundus showing focal hemorrhagic retinitis superotemporal to macula (candida retinitis).\n\nFig. 2 Color photograph of the right fundus 2 weeks after starting intravenous amphotericin B: focal retinitis healed leaving a scar.\n\nFig. 3 Color photo of the left fundus showing white fluffy lesions in the temporal macula surrounding retinal vessels associated with hemorrhage (CMV retinitis).\n\nFig. 4 Right and left fundi show healed retinal scars corresponding to the site of the previous retinitis (right fungal retinitis and bilateral CMV retinits).\n==== Refs\nReferences\n1 Nichols WG Boeckh MJ Recent advances in the therapy and prevention of CMV Infections J Clin Virol 2000 16 25 40 10680738 \n2 Reddy SC Jackson N Menon BS Ocular involvement in leukemia – a study of 288 cases Ophthalmologica 2003 217 441 445 14573980 \n3 Sharma T Grewal J Gupta S Murray PI Ophthalmic manifestations of acute leukaemias: the ophthalmologist's role Eye 2004 18 663 672 15002029 \n4 Shah CP McKey J Spirn MJ Maguire J Ocular candidiasis: a review Br J Ophthalmol 2008 92 466 468 18369061 \n5 Nguyen Q Estey E Raad I Rolston K Kantarjian H Jacobson K Konoplev S Ghosh S Luna M Tarrand J Whimbey E Cytomegalovirus pneumonia in adults with leukemia: an emerging problem Clin Infect Dis 2001 32 539 545 11181115 \n6 Offidani M Corvatta L Olivieri A Rupoli S Frayfer J Mele A Manso E Montanari M Centurioni R Leoni P Infectious complications after autologous peripheral blood progenitor cell transplantation followed by G-CSF Bone Marrow Transplant 1999 24 1079 1087 10578158 \n7 Eddleston M Peacock S Juniper M Warrell DA Severe cytomegalovirus infection in immunocompetent patients Clin Infect Dis 1997 24 52 56 8994755 \n8 Kanno M Chandrasekar PH Bentley G Vander Heide RS Alangaden GJ Disseminated cytomegalovirus disease in hosts without acquired immunodeficiency syndrome and without an organ transplant Clin Infect Dis 2001 32 313 316 11170926 \n9 Han XY Epidemiologic analysis of reactivated cytomegalovirus antigenemia in patients with cancer J Clin Microbiol 2007 45 1126 1132 17287334 \n10 Ng AP Worth L Chen L Seymour JF Prince HM Slavin M Thursky K Cytomegalovirus DNAemia and disease: incidence, natural history and management in settings other than allogenic stem cell transplantation Haematologica 2005 90 1672 1679 16330442 \n11 Derzko-Dzulynsky LA Berger AR Berinstein NL Cytomegalovirus retinitis and low-grade non-Hodgkin's lymphoma: case report and review of the literature Am J Hematol 1998 57 228 232 9495375 \n12 Hansen KK Ricksten A Hofmann B Detection of cytomegalovirus DNA in serum correlates with clinical cytomegalovirus retinitis in AIDS J Infect Dis 1994 170 1271 1274 7963725 \n13 Rasmussen L Morris S Zipeto D Quantitation of human cytomegalovirus DNA from peripheral blood cells of human immunodeficiency virus-infected patients could predict cytomegalovirus retinitis J Infect Dis 1995 171 177 182 7798658\n\n",
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"abstract": "Goodpasture Syndrome (GS) is an autoimmune disease caused by the development of auto-antibodies against the Glomerular Basement Membrane (GBM). Linear deposit of immunoglobulins G on the GBM detected by immunofluorescence analysis of renal biopsies is a GS pathognomonic finding. GS is commonly monophasic and its incidence is 1.6 case per million per year.\n\n\n\nThis report describes and discusses the case of a 40-year-old woman who one year after allograft kidney transplant, presented with acute pulmonary and renal symptoms of GS, leading to acute graft dysfunction, without circulating anti-GBM antibody detection in laboratory assays. She received a living donor kidney transplant 4 years after the first diagnosis of GS without circulating anti-GBM antibodies, when considered in remission.\n\n\n\nIn both episodes, the diagnosis of GS was based exclusively on the kidney biopsy that showed rapidly progressing glomerulonephritis with deposition of immunoglobulins G on the GBM. Although rare, the management of patients with GS without circulating anti-GBM antibodies is difficult due to the lack of standardized follow-up guidelines to reduce the risk of GS recurrence after kidney transplantation.",
"affiliations": "Department of Hematology, CHU Rennes, Rennes, France.;Department of Pathology, CHU Rennes, Rennes, France.;Department of Nephrology, CHU Rennes, Rennes, France.;Department of Nephrology, CHU Rennes, Rennes, France.",
"authors": "Thibaud|V|V|0000-0003-1648-6167;Rioux-Leclercq|N|N|;Vigneau|C|C|;Morice|S|S|",
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"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 119710.1186/s12882-018-1197-6Case ReportRecurrence of Goodpasture syndrome without circulating anti-glomerular basement membrane antibodies after kidney transplant, a case report http://orcid.org/0000-0003-1648-6167Thibaud V. 1Rioux-Leclercq N. 2Vigneau C. 3Morice S. 31 0000 0001 2175 0984grid.411154.4Department of Hematology, CHU Rennes, Rennes, France 2 0000 0001 2175 0984grid.411154.4Department of Pathology, CHU Rennes, Rennes, France 3 0000 0001 2175 0984grid.411154.4Department of Nephrology, CHU Rennes, Rennes, France 8 1 2019 8 1 2019 2019 20 621 8 2018 26 12 2018 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nGoodpasture Syndrome (GS) is an autoimmune disease caused by the development of auto-antibodies against the Glomerular Basement Membrane (GBM). Linear deposit of immunoglobulins G on the GBM detected by immunofluorescence analysis of renal biopsies is a GS pathognomonic finding. GS is commonly monophasic and its incidence is 1.6 case per million per year.\n\nCase presentation\nThis report describes and discusses the case of a 40-year-old woman who one year after allograft kidney transplant, presented with acute pulmonary and renal symptoms of GS, leading to acute graft dysfunction, without circulating anti-GBM antibody detection in laboratory assays. She received a living donor kidney transplant 4 years after the first diagnosis of GS without circulating anti-GBM antibodies, when considered in remission.\n\nConclusions\nIn both episodes, the diagnosis of GS was based exclusively on the kidney biopsy that showed rapidly progressing glomerulonephritis with deposition of immunoglobulins G on the GBM. Although rare, the management of patients with GS without circulating anti-GBM antibodies is difficult due to the lack of standardized follow-up guidelines to reduce the risk of GS recurrence after kidney transplantation.\n\nKeywords\nKidney transplantGoodpasture syndrome (GS)Anti-glomerular basement membrane (GBM) diseaseEnd-stage renal disease (ESRD)issue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nGoodpasture Syndrome (GS) is an autoimmune disease mediated by anti-Glomerular Basement Membrane (GBM) antibodies the first description of which was attributed to Ernest Goodpasture [1]. The linear immunofluorescence staining for immunoglobulin G (IgG) on the GBM in kidney biopsy specimens is a pathognomonic finding of GS. This syndrome is characterized by the presence of Rapidly Progressive GlomeruloNephritis (RPGN) that leads to acute renal failure, and of potentially life-threatening pulmonary hemorrhages [2]. GS is commonly described as a monophasic illness. Although, its incidence has been recently estimated at 1.6 case per million per year [3], it accounts for approximately 20% of all RPGN cases. The titer of circulating antibodies against collagen type IV, alpha-3 [4] is considered a measure of disease severity and correlates with the renal outcomes [5]. It may also be a predictive factor of relapse. Moreover, Anti-Neutrophil Cytoplasmic Antibodies (ANCA) with affinity for myeloperoxidase are detected in 25% of patients with GS. Circulating antibodies are undetectable in about 5% of patients with GS [6].\n\nHere, we describe and discuss the case of a woman with a GS relapse without detectable circulating anti-GBM antibodies that led to acute renal allograft dysfunction one year after transplantation. The graft was performed 4 years after the first diagnosis of GS without circulating anti-GBM antibodies (in 2011), when the patient was considered in remission.\n\nCase presentation\nOn 16 December 2011, a 40-year-old white woman was hospitalized with dyspnea and a small-volume hemoptysis that had started 2 weeks before. She reported asthenia, but no weight loss, cigarette smoking (20 pack-years) that was not stopped afterwards, no exposure to toxic chemicals. Her medical history included pre-eclampsia during her two pregnancies, but no previous pulmonary disease or family history of renal/cardiac/pulmonary diseases. No other relevant finding was recorded.\n\nClinical examination upon admission highlighted apyrexia, hypertension (184/105 mmHg), pulse rate of 96 beats/minute, and skin pallor. A chest X-ray showed bilateral infiltrates, and the thoracic CT scan indicated diffuse and bilateral ground-glass opacification. The laboratory work-up showed normocytic normochromic anemia (hemoglobin level of 7 g/dL), but normal platelet and leucocyte counts. The creatinine level of 614 μmol/L (50 μmol/L in June 2011) indicated acute renal failure. Due to respiratory failure and renal impairment, the patients received three daily boluses of methylprednisolone (500 mg) followed by 1 mg/kg/day of prednisone.\n\nA bronchoscopy performed on day 4 after hospitalization revealed the presence of hematic traces with a Golde score of 197 (bacterial cultures were negative). Serologic tests for auto-antibodies (antinuclear antibodies, ANCA, and anti-GBM antibodies) were negative, and the hemolytic complement fractions within the normal values (C3 = 1.22 g/L and C4 = 0.28 g/L). The ELISA test for anti-GBM antibodies using purified collagen IV alpha3 chain was negative. The renal biopsy showed fibrinoid necrosis in 10 glomeruli (among the 29 assessed; 34.5%), glomerulosclerosis in 30% of glomeruli, and cellular glomerular crescents in 28%. Immunofluorescence analysis revealed linear deposition of IgG, compatible with GS.\n\nThe patient underwent daily PLasmatic EXchanges (PLEX) for 11 days and started oral immunosuppressive therapy (100 mg of cyclophosphamide per day) on day 13 of the prednisone treatment. Due to severe renal failure and anuria, hemodialysis (3 times per week) was started on December 20, 2011. Hemoptysis stopped rapidly, but diuresis was not improved. At day 37 of hospitalization, due to neutropenia (<1G/L), the cyclophosphamide treatment was reduced to 75 mg per day, and then discontinued after 3 months. The patient remained on dialysis. As the serologic tests were all negative in 2011, the anti-GBM antibodies could not be monitored, but the patient did not show any other GS symptom in the following years.\n\nIn 2014, when the patient was still taking 5 mg of prednisone per day, a new episode of hemoptysis occurred confirmed by bronchoscopy. This was associated with acute pneumonia of the left lung lower lobe, with favorable outcome after treatment with prednisone (50 mg per day for 1 week) and fluoroquinolone-based antibiotic therapy.\n\nIn March 2015, the patient received a living donor (her mother) kidney transplant. In the years from the GS episode to the kidney transplant, all serologic tests for auto-antibodies were negative. Conversely, panel-reactive antibodies against class I and class II antigens were detected, but not against the donor’s human leukocyte antigen (HLA) (identical HLA profiles for donor and patient). Anti-Epstein Barr virus and cytomegalovirus IgGs were detected in serum samples from donor and recipient. The patient was induced with anti-thymocyte globulin (rabbit) and received standard immunosuppressive therapy with mycophenolate mofetil (MMF), tacrolimus (residual serum tacrolimus between 6 and 8 ng/mL), and prednisone. After the graft, the creatinine level was stabilized between 110 and 130 μmol/L. She developed new onset diabetes after transplantation that was treated with metformin and repaglinide.\n\nIn November 2016, microscopic hematuria without any proteinuria or renal dysfunction (creatinine level = 104 μmol/L) was detected. In February 2017, the patient was hospitalized because of hemoptysis and anuric acute renal failure (creatinine level = 1696 μmol/L). Like in 2011, blood pressure was increased (220/113 mmHg). The laboratory work-up showed normocytic normochromic anemia (hemoglobin level of 10.4 g/dL), platelet count of 100G/L, and normal leucocyte levels. At this time, the patient was taking tacrolimus (5 mg per day; residual tacrolimus level = 4.2 ng/mL), MMF (500 mg twice per day), and prednisone (5 mg per day). The serologic tests for auto-antibodies (antinuclear antibodies, ANCA, and anti-GBM antibodies) were negative, and the hemolytic complement factors within normal levels (CH50 = 79 U/mL, C3 = 1.28 g/L and C4 = 0.35 g/L). Renal biopsy of the transplanted kidney (25 glomeruli) confirmed the GS relapse with glomerulosclerosis in 36% of the analyzed glomeruli, cellular glomerular crescents in 56%, and linear IgG deposition on the GBM (Fig. 1).Fig. 1 Renal biopsy showing cellular glomerular crescents and linear IgG deposition on the glomerular basement membrane (GBM). Panel a: Fibrocellular glomerular crescents with focal necrosis, Panel b: Glomeruli with semi-circumferential extracapillary crescents and segmental necrosis, Panel c: Immunofluorescence analysis to detect immunoglobulins G (IgG) on the GBM, Panel d: Immunofluorescence analysis to detect IgG1 on the GBM, Panel e: Immunofluorescence analysis to detect IgG4 on the GBM\n\n\n\nThe patient underwent daily PLEX for 14 days, and received prednisone (500 mg/day for the first 3 days followed by 1 mg/kg/day). At the end of the 14th PLEX, a bronchoscopy indicated active hemoptysis with the presence of 99.5% sideroblasts and a Golde score of 200. Due to the absence of effect, PLEX was stopped and intravenous infusion of cyclophosphamide (500 mg/m2 every 21 days) was introduced combined with prednisone (5 mg per day) and tacrolimus (2 mg twice per day).\n\nAfter five infusions of cyclophosphamide the patient has now recovered and the anemia is under control with EPO supplementation. Conversely, the grafted kidney does not work, and the patient needs hemodialysis 3 times per week. Tacrolimus has been stopped.\n\nDiscussion and conclusions\nRelapse is a rare event in GS and there is only a limited number of reported cases in the literature [2, 7–13]. This reflects the usually self-limited nature of auto-antibody formation in this disease. Histological GS relapse in kidney transplants has been reported in nearly 50% of patients, if the graft is done in the presence of serum anti-GBM antibodies [14]. For this reason, the current guidelines recommend serum anti-GBM antibody negative results for at least 12 months before kidney transplantation. When these guidelines are followed, GS relapse in transplanted kidneys is lower than 5% [15].\n\nThis case report highlights the complex management of patients with biopsy-proven GS and without serum anti-GBM antibodies for whom no guideline is available.\n\nMore than 20 years ago, it was shown that pathogenic auto-antibodies are predominantly directed against the non-collagenous domain of type IV collagen epitopes, mostly in a peptide sequence of the alpha-3 chain [4]. These epitopes are used in the most common assays to detect circulating anti-GBM antibodies. The patient serum was analyzed using different assays over the years (Table 1) and none could detect circulating anti-GBM antibodies. The rate of negative results with the most commonly employed assays (ELISA) that use human or bovine substrates is about 5%. Analyses to identify the IgG subtype highlighted the presence of IgG4 types and IgG1. It has been suggested that IgG4 subclass dominance could be explained by chronic antigen stimulation. In this patient, like in many of the previously reported cases, exposure of the Goodpasture antigen might have been triggered by the chronic smoking habit. This case report highlights the need for early renal biopsy and direct immunofluorescent microscopy analysis for the diagnosis of GS in clinically suspected cases with negative serum anti-GBM antibody tests.Table 1 List of the different assays used to test the patient’s serum. All were negative\n\n2011\tEnzyme-Linked Immunosorbent Assay (ELISA) with purified alpha 3 chain of the non-collagenous domain of type IV collagen as antigen.\t\n2011 to 2017\tImmunodot assay with recombinant alpha 3 chain of the non-collagenous domain of type IV collagen as antigen.\t\n2017\tChemiluminescence assay with native alpha 3 chain of the non-collagenous domain of type IV collagen as antigen.\t\n2017\tFluoro Enzymatic Immunoassay with recombinant alpha 3 chain of the non-collagenous domain of type IV collagen as antigen.\t\n2017\tImmunofluorescence assay with monkey tissue\t\n2017\tMultiplex particle-based flow cytometric assay with bovine native antigen.\t\n\n\nThe negative results of the serological tests can be explained by different reasons [16], particularly: (a) lack of sensitivity of the assay, especially for low-affinity antibodies [17]; (b) specific isotypes or sub-classes of anti-GBM antibodies (IgA or IgG4) that are not easily detected in ELISA or radioimmunoassays [18]; (c) disappearance of the antibodies from the circulation before the disease resolution; (d) very low levels of low-affinity antibodies due to the removal from circulation of high-affinity antibodies by an ‘immunological sink’; (e) antibodies that are highly specific for human GBM, and not for non-human (non-primate) antigens; (f) loss of lymphocyte T helpers that are required for the lymphocyte B response, resulting in the decline of auto-antibody production [19]; and (g) antibodies specific for other collagen subtypes that are not detected with the usual assays (e.g., alpha5(IV)NC1, alpha-4NC1…). The subsequent IgG subtype analysis in the transplant biopsy (showing IgG1 and a majority of IgG4) suggests the presence of a specific sub-class of anti-GBM antibodies that could not be detected by the used tests. New assays to detect rare subtypes of anti-GBM antibodies are needed.\n\nFinally, we would like to emphasize the need of practical guidelines for patients with kidney biopsy-proven GS and seronegative anti-GBM assays to improve their follow-up and decrease the risk of GS recurrence after kidney transplantation. Indeed, the impossibility to evaluate the disease activity exposes to the risk, as illustrated in this case, of recurrence in the kidney graft. Apart from quitting smoking, which is a recognized risk factor, the usual recommendations for patients with circulating anti-GBM antibodies (delay between diagnosis and transplant, level of immunosuppression…) cannot be applied to seronegative patients.\n\nAbbreviations\nANCAAntiNeutrophil Cytoplasmic Antibodies\n\nGBMGlomerular Basement Membrane\n\nGSGoodpasture Syndrome\n\nIgGImmunoglobulin G\n\nMMFMycophenolate MoFetil\n\nPLEXPLasmatic EXchanges\n\nRPGNRapidly Progressive GlomeruloNephritis\n\nWe thank Dr. Elisabetta Andermarcher for her careful proofreading of the paper.\n\nFunding\nNo funding was received by any of the authors for the work leading to the manuscript.\n\nAvailability of data and materials\nThe datasets used in the current case report are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nVT has managed the patient, done the literature review and the manuscript preparation. CV and SM were the treating physicians. NR carried out the histological examination and interpretation. NR, CV and SM revised the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this Case Report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Goodpasture EW Landmark Publication from The American journal of the medical sciences: The Significance Of Certain Pulmonary Lesions In Relation To The Etiology Of Influenza Am J Med Sci 2009 338 2 148 151 10.1097/MAJ.0b013e31818fff94 19680020 \n2. Wilson CB Dixon FJ Anti-glomerular basement membrane antibody-induced glomerulonephritis Kidney Int 1973 3 2 74 89 10.1038/ki.1973.14 4571918 \n3. Canney M O’Hara PV McEvoy CM Medani S Connaughton DM Abdalla AA Spatial and temporal clustering of anti-glomerular basement membrane disease Clin J Am Soc Nephrol 2016 11 8 1392 1399 10.2215/CJN.13591215 27401523 \n4. Kalluri R Wilson CB Weber M Gunwar S Chonko AM Neilson EG Identification of the alpha 3 chain of type IV collagen as the common autoantigen in antibasement membrane disease and Goodpasture syndrome J Am Soc Nephrol 1995 6 4 1178 1185 8589284 \n5. Yang R Hellmark T Zhao J Cui Z Segelmark M Zhao M Levels of epitope-specific autoantibodies correlate with renal damage in anti-GBM disease Nephrol Dial Transplant 2009 24 6 1838 1844 10.1093/ndt/gfn761 19151145 \n6. Rutgers A Slot M van Paassen P van Breda Vriesman P Heeringa P Tervaert JWC Coexistence of anti-glomerular basement membrane antibodies and myeloperoxidase-ANCAs in crescentic glomerulonephritis Am J Kidney Dis 2005 46 2 253 262 10.1053/j.ajkd.2005.05.003 16112043 \n7. Sauter M Schmid H Anders HJ Heller F Weiss M Sitter T Loss of a renal graft due to recurrence of anti-GBM disease despite rituximab therapy Clin Transplant 2009 23 1 132 136 10.1111/j.1399-0012.2008.00912.x 19087095 \n8. McPhaul JJJ Lordon RE Thompson ALJ Mullins JD Nephritogenic immunopathologic mechanisms and human renal transplants: the problem of recurrent glomerulonephritis Kidney Int 1976 10 2 135 138 10.1038/ki.1976.86 787616 \n9. Fonck C Loute G Cosyns J Pirson Y Recurrent fulminant anti-glomerular basement membrane nephritis at a 7- year interval Am J Kidney Dis 1998 32 2 323 327 10.1053/ajkd.1998.v32.pm9708621 9708621 \n10. Trpkov K Abdulkareem F Jim K Solez K Recurrence of anti-GBM antibody disease twelve years after transplantation associated with de novo IgA nephropathy Clin Nephrol 1998 49 2 124 128 9524784 \n11. Almkuist RD Buckalew VM Hirszel P Maher JF James PM Wilson CB Recurrence of Anti-Glomerular Basement Membrane Antibody Mediated Glomerulonephritis in an lsograft Clin Immunol Immunopathol 1981 18 1 54 60 10.1016/0090-1229(81)90007-6 7460397 \n12. Beleil OM Coburn JW Shinaberger JH Glassock RJ Recurrent glomerulonephritis due to anti-glomerular basement membrane-antibodies in two successive allografts Clin Nephrol 1973 1 6 377 380 4594999 \n13. Khandelwal M Recurrence of anti-GBM disease 8 years after renal transplantation Nephrol Dial Transplant 2004 19 2 491 494 10.1093/ndt/gfg393 14736982 \n14. Special Issue KDIGO clinical practice guideline for the Care of Kidney Transplant Recipients Am J Transplant 2009 9 S1 155 \n15. Floege J Recurrent glomerulonephritis following renal transplantation: an update Nephrol Dial Transplant 2003 18 7 1260 1265 10.1093/ndt/gfg102 12808159 \n16. Glassock RJ Atypical anti-glomerular basement membrane disease: lessons learned Clin Kidney J 2016 9 5 653 656 10.1093/ckj/sfw068 27679709 \n17. Sinico RA Radice A Corace C Sabadini E Bollini B Anti-glomerular basement membrane antibodies in the diagnosis of Goodpasture syndrome: a comparison of different assays Nephrol Dial Transplant 2006 21 2 397 401 10.1093/ndt/gfi230 16234289 \n18. Ohlsson S Herlitz H Lundberg S Selga D Mölne J Wieslander J Circulating anti–glomerular basement membrane antibodies with predominance of subclass IgG4 and false-negative immunoassay test results in anti–glomerular basement membrane disease Am J Kidney Dis 2014 63 2 289 293 10.1053/j.ajkd.2013.08.032 24189476 \n19. Salama AD Chaudhry AN Holthaus KA Mosley K Kalluri R Sayegh MH Regulation by CD25+ lymphocytes of autoantigen-specific T-cell responses in Goodpasture’s (anti-GBM) disease Kidney Int 2003 64 5 1685 1694 10.1046/j.1523-1755.2003.00259.x 14531801\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "20(1)",
"journal": "BMC nephrology",
"keywords": "Anti-glomerular basement membrane (GBM) disease; End-stage renal disease (ESRD); Goodpasture syndrome (GS); Kidney transplant",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D000328:Adult; D019867:Anti-Glomerular Basement Membrane Disease; D001323:Autoantibodies; D005260:Female; D050533:Glomerular Basement Membrane; D006801:Humans; D007166:Immunosuppressive Agents; D007678:Kidney Glomerulus; D016030:Kidney Transplantation; D019520:Living Donors; D010951:Plasma Exchange; D011183:Postoperative Complications; D012008:Recurrence; D006435:Renal Dialysis; D012086:Reoperation",
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "6",
"pmc": null,
"pmid": "30621605",
"pubdate": "2019-01-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19680020;27401523;19151145;9524784;16112043;8589284;4571918;16234289;14736982;19845597;7460397;12808159;14531801;787616;24189476;27679709;4594999;19087095;9708621",
"title": "Recurrence of Goodpasture syndrome without circulating anti-glomerular basement membrane antibodies after kidney transplant, a case report.",
"title_normalized": "recurrence of goodpasture syndrome without circulating anti glomerular basement membrane antibodies after kidney transplant a case report"
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},
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}
],
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{
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"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Diabetes mellitus",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Haemoptysis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Glomerulosclerosis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Haematuria",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Blood pressure increased",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Transplant failure",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Normochromic normocytic anaemia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 201611"
}
},
"primarysource": {
"literaturereference": "THIBAUD V, RIOUX-LECLERCQ N, VIGNEAU C, MORICE S. RECURRENCE OF GOODPASTURE SYNDROME WITHOUT CIRCULATING ANTI-GLOMERULAR BASEMENT MEMBRANE ANTIBODIES AFTER KIDNEY TRANSPLANT, A CASE REPORT. BMC NEPHROLOGY. 2019?20(6):NO INFORMATION",
"literaturereference_normalized": "recurrence of goodpasture syndrome without circulating anti glomerular basement membrane antibodies after kidney transplant a case report",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20190214",
"receivedate": "20190214",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15961213,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
}
] |
{
"abstract": "We report the technical details of minimally invasive open-window thoracostomy using wound edge protectors for postoperative pyothorax caused by a bronchopleural fistula with acute exacerbation of idiopathic pulmonary fibrosis under epidural and local anesthesia.",
"affiliations": "Division of General Thoracic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Gunma, Japan. Electronic address: kmshimizu@gmail.com.;Division of General Thoracic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Gunma, Japan.;Division of General Thoracic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Gunma, Japan.;Division of General Thoracic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Gunma, Japan.;Division of General Thoracic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Gunma, Japan.;Division of General Thoracic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Gunma, Japan.;Division of General Thoracic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Gunma, Japan.;Division of General Thoracic Surgery, Integrative Center of General Surgery, Gunma University Hospital, Gunma, Japan.",
"authors": "Shimizu|Kimihiro|K|;Ohtaki|Yoichi|Y|;Nakazawa|Seshiru|S|;Obayashi|Kai|K|;Nagashima|Toshiteru|T|;Yajima|Toshiki|T|;Mogi|Akira|A|;Shirabe|Ken|K|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.athoracsur.2018.10.064",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "107(5)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D001983:Bronchial Fistula; D002294:Carcinoma, Squamous Cell; D016724:Empyema, Pleural; D006801:Humans; D054990:Idiopathic Pulmonary Fibrosis; D008175:Lung Neoplasms; D019060:Minimally Invasive Surgical Procedures; D011013:Pneumonectomy; D011183:Postoperative Complications; D013907:Thoracostomy",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "e371-e373",
"pmc": null,
"pmid": "30529214",
"pubdate": "2019-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Minimally Invasive Open-Window Thoracostomy Using Wound Edge Protectors.",
"title_normalized": "minimally invasive open window thoracostomy using wound edge protectors"
} | [
{
"companynumb": "JP-FRESENIUS KABI-FK202000095",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
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},
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"medicinalproduct": "METHYLPREDNISOLONE (MANUFACTURER UNKNOWN)"
},
{
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"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "040583",
"drugbatchnumb": "UNKNOWN,UNKNOWN",
"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
"drugdosageform": "UNKNOWN",
"drugdosagetext": null,
"drugenddate": null,
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"drugindication": "PULMONARY FIBROSIS",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugstartdate": null,
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"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHYLPREDNISOLONE (MANUFACTURER UNKNOWN)"
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Infectious pleural effusion",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Bronchopleural fistula",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SHIMIZU K, OHTAKI Y, NAKAZAWA S, OBAYASHI K, NAGASHIMA T, YAJIMA T, MOGI A, SHIRABE K. MINIMALLY INVASIVE OPEN-WINDOW THORACOSTOMY USING WOUND EDGE PROTECTORS. ANNALS OF THORACIC SURGERY. 2019 MAY?107 (5):E371-E373.",
"literaturereference_normalized": "minimally invasive open window thoracostomy using wound edge protectors",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20200106",
"receivedate": "20200106",
"receiver": {
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"receivertype": "6"
},
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},
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}
] |
{
"abstract": "Restless legs syndrome (RLS) is a distinct disorder, differing from chronic pain in many ways. Refractory RLS is characterized by unresponsiveness to dopamine agonists or alpha-2-delta ligands due to inadequate efficacy, augmentation, or adverse effects. This may result in severely impaired quality of life, profound insomnia, and suicidal depression. Opioid therapy is a mainstay in the management of these patients. This article summarizes the basic science and clinical evidence in support of their use, including the positive result of a large controlled multicenter study of 306 subjects, and outlines an approach to their use in clinical practice. Treatable explanations for RLS refractoriness, such as low iron stores, and other therapeutic options, such as combination therapy, should be considered before prescribing opioids. The agents most commonly used are oxycodone and methadone, but tramadol, codeine, morphine, and hydrocodone can also be considered. Controlled-release medication should be used for evening dosage and short-acting drugs, if needed, during the day. Effective doses are considerably lower than used for chronic pain (oxycodone 10-30 mg daily; methadone 5-20 mg daily) and the risk of opioid use disorder is relatively low. However, sensible precautions should be undertaken, including assessing opioid risk with standard questionnaires, using an opioid contract, using urine drug screens, consulting state prescription drug monitoring programs, and frequent reevaluation of effectiveness and side effects. Opioid use in selected patients with refractory RLS may be life-transforming with favorable risk-benefit ratio.",
"affiliations": "Department of Neurology and Center for Sleep Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN. Electronic address: msilber@mayo.edu.;Sleep Medicine Associates of Texas and Department of Psychiatry, University of Texas Southwestern Medical Center, Dallas, TX.;Department of Psychiatry and Behavioral Science, Stanford School of Medicine, Stanford, CA.;Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD.;Methodist Research Institute and Department of Neurology, Weill Cornell Medical School, Houston, TX.;Division of Sleep Medicine, Vanderbilt University School of Medicine, Nashville, TN.;Department of Psychiatry and Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA.",
"authors": "Silber|Michael H|MH|;Becker|Philip M|PM|;Buchfuhrer|Mark J|MJ|;Earley|Christopher J|CJ|;Ondo|William G|WG|;Walters|Arthur S|AS|;Winkelman|John W|JW|;|||",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "England",
"delete": false,
"doi": "10.1016/j.mayocp.2017.11.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-6196",
"issue": "93(1)",
"journal": "Mayo Clinic proceedings",
"keywords": null,
"medline_ta": "Mayo Clin Proc",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000701:Analgesics, Opioid; D059350:Chronic Pain; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009293:Opioid-Related Disorders; D017410:Practice Guidelines as Topic; D012148:Restless Legs Syndrome",
"nlm_unique_id": "0405543",
"other_id": null,
"pages": "59-67",
"pmc": null,
"pmid": "29304922",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Appropriate Use of Opioids in the Treatment of Refractory Restless Legs Syndrome.",
"title_normalized": "the appropriate use of opioids in the treatment of refractory restless legs syndrome"
} | [
{
"companynumb": "US-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2018-BI-007877",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE DIHYDROCHLORIDE"
},
"drugadditional": "2",
"drugadministrationroute": "065",
"drugauthorizationnumb": "020667",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugdosagetext": null,
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"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
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"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MIRAPEX"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE DIHYDROCHLORIDE"
},
"drugadditional": "2",
"drugadministrationroute": "065",
"drugauthorizationnumb": "020667",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "RESTLESS LEGS SYNDROME",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
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"drugstructuredosagenumb": ".25",
"drugstructuredosageunit": "003",
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"medicinalproduct": "MIRAPEX"
}
],
"patientagegroup": null,
"patientonsetage": "59",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
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"reactionmeddraversionpt": "21.0",
"reactionoutcome": "3"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SILBER M, BECKER P, BUCHFUHRER M, EARLEY C, ONDO W, WALTERS A, ET AL. THE APPROPRIATE USE OF OPIOIDS IN THE TREATMENT OF REFRACTORY RESTLESS LEGS SYNDROME. MAYO CLINIC PROCEEDINGS. 2018 JAN?93:1:59-67.",
"literaturereference_normalized": "the appropriate use of opioids in the treatment of refractory restless legs syndrome",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20180214",
"receivedate": "20180214",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14532897,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20180509"
},
{
"companynumb": "US-UCBSA-2018009567",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "PRAMIPEXOLE"
},
"drugadditional": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "0.25 MG, TAKEN 2 HOURS BEFORE GOING TO BED",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "RESTLESS LEGS SYNDROME",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": ".25",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PRAMIPEXOLE."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ROTIGOTINE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TRANSDERMAL PATCH",
"drugdosagetext": "3 MG DAILY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "RESTLESS LEGS SYNDROME",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "ROTIGOTINE"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "DOSE INCREASED TO 1 MG DAILY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PRAMIPEXOLE."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SILBER MH, BECKER PM, BUCHFUHRER MJ, EARLEY CJ, ONDO WG, WALTERS AS, ET AL. THE APPROPRIATE USE OF OPIOIDS IN THE TREATMENT OF REFRACTORY RESTLESS LEGS SYNDROME. MAYO CLINIC PROCEEDINGS. 2018?93(1):59-67",
"literaturereference_normalized": "the appropriate use of opioids in the treatment of refractory restless legs syndrome",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200402",
"receivedate": "20191227",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17208208,
"safetyreportversion": 2,
"sender": {
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"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200713"
},
{
"companynumb": "US-APOTEX-2018AP006781",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PRAMIPEXOLE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "0.25 MG, Q.H.S.",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "RESTLESS LEGS SYNDROME",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": ".25",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PRAMIPEXOLE."
},
{
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{
"abstract": "Although macrophage activation syndrome (MAS) develops in some patients with chronic granulomatous disease (CGD), all of the reported cases have been associated with pathogenic microbial infections. We report a 2-year-old boy with CGD-associated colitis who suffered from MAS without any clinical signs of a microbial infection. He was treated with 1 course of methylprednisolone pulse therapy and the clinical symptoms improved; however, the colitis was difficult to control even with immunosuppressive drugs, and he eventually required hematopoietic stem cell transplantation 1 year after the onset of MAS. It is likely that MAS develops in patients with CGD colitis independent of microbial infections.",
"affiliations": "Departments of *Interdisciplinary Medicine †Human Genetics ‡Division of Gastroenterology, National Center for Child Health and Development §Department of Pediatrics, The Jikei University School of Medicine, Tokyo, Japan.",
"authors": "Akagi|Kazuko|K|;Kawai|Toshinao|T|;Watanabe|Nobuyuki|N|;Yokoyama|Midori|M|;Arai|Katsuhiro|K|;Harayama|Shizuko|S|;Oana|Shinji|S|;Onodera|Masafumi|M|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D008775:Methylprednisolone",
"country": "United States",
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"issue": "36(3)",
"journal": "Journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "J Pediatr Hematol Oncol",
"mesh_terms": "D000893:Anti-Inflammatory Agents; D002675:Child, Preschool; D003092:Colitis; D003131:Combined Modality Therapy; D006105:Granulomatous Disease, Chronic; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D055501:Macrophage Activation Syndrome; D008297:Male; D008775:Methylprednisolone; D011379:Prognosis",
"nlm_unique_id": "9505928",
"other_id": null,
"pages": "e169-72",
"pmc": null,
"pmid": "23652865",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A case of macrophage activation syndrome developing in a patient with chronic granulomatous disease-associated colitis.",
"title_normalized": "a case of macrophage activation syndrome developing in a patient with chronic granulomatous disease associated colitis"
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"abstract": "Due to the lack of literature on the effects of trastuzumab in pregnancy, an interest has been taken in a patient that incidentally became pregnant while on adjuvant treatment in the first trimester following diagnosis of locally advanced breast cancer.",
"affiliations": "Department of Medical Oncology, Northwest Regional Cancer Centre, Tamworth, Australia.;Department of Medical Oncology, Northwest Regional Cancer Centre, Tamworth, Australia.;Department of Medical Oncology, Northwest Regional Cancer Centre, Tamworth, Australia.",
"authors": "Pianca|Natasha|N|;Shafiei|Mohsen|M|;George|Mathew|M|",
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"fulltext": "\n==== Front\nWorld J OncolWorld J OncolElmer PressWorld Journal of Oncology1920-45311920-454XElmer Press 10.14740/wjon919wCase ReportTrastuzumab Exposure in Early Pregnancy for a Young Lady With Locally Invasive Breast Cancer Trastuzumab Exposure in Early PregnancyPianca Natasha aShafiei Mohsen abGeorge Mathew aa Department of Medical Oncology, Northwest Regional Cancer Centre, Tamworth, Australiab Corresponding Author: Mohsen Shafiei, Department of Medical Oncology, Northwest Regional Cancer Centre, Tamworth, Australia. Email: Mohsen.Shafiei@calvarymater.org.au6 2015 12 6 2015 6 3 381 382 21 5 2015 Copyright 2015, Pianca et al.2015This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Due to the lack of literature on the effects of trastuzumab in pregnancy, an interest has been taken in a patient that incidentally became pregnant while on adjuvant treatment in the first trimester following diagnosis of locally advanced breast cancer.\n\nTrastuzumabBreast cancerPregnancy\n==== Body\nIntroduction\nInfiltrating ductal carcinoma accounts for 70-80% of invasive breast cancers [1], making it the most common type. It can be classified into three grades depending on its degree of differentiation, with grade 3 being poorly differentiated. Most women present with an abnormal mammogram or a breast mass they have detected themselves [2].\n\nTrastuzumab is indicated for the treatment of patients with HER2-positive localized breast cancer following surgery, as well as with any adjuvant chemotherapy or radiotherapy [3]. HER2 is the human epidermal growth factor receptor which becomes overexpressed in HER2-positive breast cancers. Trastuzumab is a human monoclonal antibody that inhibits the proliferation and survival of such HER2-dependent tumors [4]. In pregnancy, trastuzumab is classed as a category D drug, as it causes embryo-fetal toxicity. Exposure has been known to cause oligohydramnios and oligohydramnios sequence according to the US FDA [5].\n\nCase Report\nThe young lady had a previous diagnosis of polycystic ovarian syndrome and was commenced on metformin. She had been trying to become pregnant unsuccessfully in the past and underwent embryo freezing prior to commencing treatment.\n\nOur patient received her diagnosis of grade 2 invasive ductal carcinoma in her left breast (T2N0M0) in 2005, at 30 years of age. It was estrogen and progesterone receptor negative and HER2-positive. The therapeutic wide local excision and axillary dissection demonstrated a 31 mm lesion in the left breast with lymphovascular invasion. She underwent six cycles of adjuvant fluorouracil, epirubicin and cyclophosphamide chemotherapy, followed by left breast irradiation and 4 months of herceptin.\n\nThe herceptin was ceased prematurely when she discovered she was pregnant using a urine pregnancy test in late December 2006. USS dating confirmed a viable intra-uterine pregnancy dated at 28/40 weeks. There are a few factors that were retrospectively explored as to why such a mature pregnancy was not picked up earlier, those including: patient body habitus (obesity), as well as amenorrhea secondary to chemotherapy and polycystic ovarian syndrome, and a past history of infertility. Of her seven treatments with herceptin, two of these were thought to have been while pregnant.\n\nNaturally, the patient was monitored throughout her high risk pregnancy by the maternal fetal medicine unit. An USS at 29/40 demonstrated relatively small abdominal circumference and oligohydramnios (AFI 7.7). IUGR was suspected, although no abnormality of the fetus was ever noticed despite there being restricted fetal movements and its continuity of extended breech presentation throughout the pregnancy.\n\nIn March 2007, a healthy female was born by an emergency LSCS after SROM and contractions commenced on a breech presentation. The CTG was reassuring after the SROM at 37/40 and Apgars were 4 and 8. Birth weight was 2,735g and baby required minimal resuscitation with O2 therapy, suction and IPPR bag and mask. No birth defect was noted. Postnatally, issues breastfeeding after radiotherapy were the only problems encountered and mum seemed to be settling into the role very well, introducing bottle feeds early on. The child, now 7 years old, still does not display any signs of congenital exposure to trastuzumab.\n\nThe Literature\nThe use of trastuzumab in pregnancy has limited data available, especially in regard to effects on human pregnancies. Until 2010, trastuzumab was listed as a category B drug in the US FDA [5].\n\nDespite the lack of trials, there have been a number of case reports similar to this that describes the outcomes of incidental trastuzumab intake whilst pregnant [6-8]. Most conclude trastuzumab has no immediate adverse effect on the fetus; however, many report the presence of oligohydramnios during pregnancy.\n\nThe HERA trial was a large phase III randomized clinical trial in which early HER2-positive breast cancer patients were randomized to receive 1 or 2 years of trastuzumab or observation after chemotherapy [9]. Researchers looked into patients who fell pregnant whilst on therapy that were enrolled in the HERA trial, and found that pregnancy occurring during and up to 3 months after trastuzumab treatment caused larger numbers of spontaneous abortions than the average population (25% patients) and short-term fetal outcomes were normal across all groups being studied. It was also noted that no congenital abnormalities were reported in those patients exposed to trastuzumab in utero [10]. This was the first large trial assessing the effects of trastuzumab on human pregnancies and was looking to collaborate data with any other trials to confirm findings.\n\nConclusion\nThe available literature on the effects of trastuzumab on pregnancy in the first trimester is limited. Case reports discuss the presence of oligohydramnios on fetal USS that results in a living baby that seemingly lacks any abnormalities. There may also be a link with higher rates of spontaneous abortion. We describe a young 32-year-old patient on trastuzumab for a locally invasive HER2-positive breast cancer who became pregnant with fetal exposure to the treatment. After cessation of trastuzumab at 28 weeks, she delivered a healthy baby girl at 37 weeks gestation who, at 7 years of age now, still does not display any evidence of negative effects of trastuzumab exposure.\n==== Refs\nReferences\n1 Bleiweiss IJ MD Pathology of breast cancer UpToDate, Chagpar AB, Duda RB Last updated Dec 19, 2013, Literature current Feb 2014 \n2 Esserman LJ Joe BN Clinical features, diagnosis, and staging of newly diagnosed breast cancer Up To Date, Gralow JR, Duda RB Last updated May 20, 2013, Literature current Feb 2014 \n3 Pharmaceutical Benefits Scheme. Trastuzumab, powder for I.V. infusion, 60mg and 150mg, Herceptin. Australian Government Department of Health, Public Summary Document Roche Products Pty Ltd \n4 Hudis CA Trastuzumab--mechanism of action and use in clinical practice N Engl J Med 2007 357 1 39 51 10.1056/NEJMra043186 17611206 \n5 US Food and Drug Administration. Trastuzumab - (Labelling Change). U.S. Department of Health and Human Services updated Feburary 11, 2010 \n6 Waterston AM Graham J Effect of adjuvant trastuzumab on pregnancy J Clin Oncol 2006 24 2 321 322 10.1200/JCO.2005.04.6607 16401684 \n7 Pant S Landon MB Blumenfeld M Farrar W Shapiro CL Treatment of breast cancer with trastuzumab during pregnancy J Clin Oncol 2008 26 9 1567 1569 10.1200/JCO.2008.16.0309 18349415 \n8 Azim HA Jr Peccatori FA Liptrott SJ Catania C Goldhirsch A Breast cancer and pregnancy: how safe is trastuzumab? Nat Rev Clin Oncol 2009 6 6 367 370 10.1038/nrclinonc.2009.48 19483741 \n9 Goldhirsch A Gelber RD Piccart-Gebhart MJ de Azambuja E Procter M Suter TM Jackisch C et al 2 years versus 1 year of adjuvant trastuzumab for HER2-positive breast cancer (HERA): an open-label, randomised controlled trial Lancet 2013 382 9897 1021 1028 10.1016/S0140-6736(13)61094-6 23871490 \n10 Azim HA Jr Metzger-Filho O de Azambuja E Loibl S Focant F Gresko E Arfi M et al Pregnancy occurring during or following adjuvant trastuzumab in patients enrolled in the HERA trial (BIG 01-01) Breast Cancer Res Treat 2012 133 1 387 391 10.1007/s10549-012-1996-6 22367645\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1920-4531",
"issue": "6(3)",
"journal": "World journal of oncology",
"keywords": "Breast cancer; Pregnancy; Trastuzumab",
"medline_ta": "World J Oncol",
"mesh_terms": null,
"nlm_unique_id": "101564097",
"other_id": null,
"pages": "381-382",
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"pmid": "28983334",
"pubdate": "2015-06",
"publication_types": "D002363:Case Reports",
"references": "22367645;17611206;23871490;16401684;19483741;18349415",
"title": "Trastuzumab Exposure in Early Pregnancy for a Young Lady With Locally Invasive Breast Cancer.",
"title_normalized": "trastuzumab exposure in early pregnancy for a young lady with locally invasive breast cancer"
} | [
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"abstract": "The present study compared the efficacy and safety of mizoribine (MZR) with mycophenolate mofetil (MMF) in kidney transplantation. This multicenter, randomized clinical trial. Employed doses of study drug tailored to the immunosuppressive need. The primary efficacy outcome was the incidence of biopsy-proven acute rejection episodes (BPAR). The safety of the study drug was assessed using the incidences of adverse events, drug discontinuations, and abnormal laboratory results. The 7 (6.4%) BPARs above grade II were observed in the MZR group noninferior to the 2 (1.8%) in the MMF group (95% confidence interval, -0.007-0.097 > noninferiority limit [-0.2]). BPAR was significantly decreased in the MZR group after the dose change (17/41 [41.4%] vs 8/69 [11.6%]; P < .0001) and the incidence of BPAR was similar between the MZR and MMF groups after the dose change (P = .592). The uric acid level was significantly elevated in the MZR group (P = .002). In conclusion, the efficacy and safety of MZR were similar and statistically noninferior to MMF in combination therapy with tacrolimus.",
"affiliations": "Department of Surgery, Gangnam Severance Hospital, Yonsei University Health System, Seoul, Korea.",
"authors": "Ju|M K|MK|;Huh|K H|KH|;Park|K T|KT|;Kim|S J|SJ|;Cho|B H|BH|;Kim|C D|CD|;So|B J|BJ|;Kang|C M|CM|;Lee|S|S|;Joo|D J|DJ|;Kim|Y S|YS|",
"chemical_list": "D007166:Immunosuppressive Agents; D012263:Ribonucleosides; C010052:mizoribine; D009173:Mycophenolic Acid; D016559:Tacrolimus",
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"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D000368:Aged; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid; D012263:Ribonucleosides; D016559:Tacrolimus; D055815:Young Adult",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1481-6",
"pmc": null,
"pmid": "23726602",
"pubdate": "2013-05",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Mizoribine versus mycophenolate mofetil in combination therapy with tacrolimus for de novo kidney transplantation: evaluation of efficacy and safety.",
"title_normalized": "mizoribine versus mycophenolate mofetil in combination therapy with tacrolimus for de novo kidney transplantation evaluation of efficacy and safety"
} | [
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"drugdosagetext": "0.1 MG/KG, BID",
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"literaturereference": "JU MK, HUH KH, PARK KT, KIM SJ, CHO BH, KIM CD ET AL. MIZORIBINE VERSUS MYCOPHENOLATE MOFETIL IN COMBINATION THERAPY WITH TACROLIMUS FOR DE NOVO KIDNEY TRANSPLANTATION: EVALUATION OF EFFICACY AND SAFETY. TRANSPLANTATION PROCEEDINGS. 2013;45:1481-6",
"literaturereference_normalized": "mizoribine versus mycophenolate mofetil in combination therapy with tacrolimus for de novo kidney transplantation evaluation of efficacy and safety",
"qualification": "3",
"reportercountry": "KR"
},
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"receiptdate": "20170901",
"receivedate": "20170901",
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},
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"sendertype": "2"
},
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{
"abstract": "BACKGROUND\nThe total kidney volume (TKV) and total liver volume (TLV) increase and renal function decreases progressively in patients with autosomal dominant polycystic kidney disease (ADPKD). Somatostatin analogues, such as octreotide, reduce these increases in TKV and TLV. The aim of this study was to examine the safety of the short-term administration of octreotide long-acting release (octreotide-LAR) in a small number of cases.\n\n\nMETHODS\nFour ADPKD patients with an estimated glomerular filtration rate (eGFR) > 45 mL/min/1.73 m(2), TKV > 1,000 mL, and TLV > 3,000 mL were enrolled. Two 20-mg octreotide-LAR intramuscular injections were repeated every 4 weeks for 24 weeks. Laboratory and clinical assessments were repeated every 4 weeks, and TKV and TLV were measured by magnetic resonance imaging before and after the study.\n\n\nRESULTS\nIn the laboratory tests, there was no abnormal variable except for a significant decrease of alanine aminotransferase. The means of TKV and TLV decreased from 2,007 to 1,903 mL and from 9,197 to 8,866 mL, respectively, but the changes were not significant. eGFR did not change significantly. Adverse events involved loose stools in two patients, as well as injection site granuloma and abdominal pain in one patient each, which resolved spontaneously.\n\n\nCONCLUSIONS\nOctreotide-LAR may be safe and effective for preventing TKV and TLV increases (UMIN000009214).",
"affiliations": "Department of ADPKD Research, Kyorin University School of Medicine, 6-20-2 Shinkawa, Mitaka, Tokyo, 181-8611, Japan, ehigashi@ks.kyorin-u.ac.jp.",
"authors": "Higashihara|Eiji|E|;Nutahara|Kikuo|K|;Okegawa|Takatsugu|T|;Tanbo|Mitsuhiro|M|;Mori|Hideaki|H|;Miyazaki|Isao|I|;Nitatori|Toshiaki|T|;Kobayashi|Kuninori|K|",
"chemical_list": "D005765:Gastrointestinal Agents; D013004:Somatostatin; D015282:Octreotide",
"country": "Japan",
"delete": false,
"doi": "10.1007/s10157-014-1047-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1342-1751",
"issue": "19(4)",
"journal": "Clinical and experimental nephrology",
"keywords": null,
"medline_ta": "Clin Exp Nephrol",
"mesh_terms": "D000328:Adult; D005260:Female; D005765:Gastrointestinal Agents; D006801:Humans; D007564:Japan; D008297:Male; D008875:Middle Aged; D015282:Octreotide; D016891:Polycystic Kidney, Autosomal Dominant; D013004:Somatostatin",
"nlm_unique_id": "9709923",
"other_id": null,
"pages": "746-52",
"pmc": null,
"pmid": "25351823",
"pubdate": "2015-08",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "19339088;17434405;23864346;19646443;23972263;18945943;2869974;12920399;12062067;7377224;10864573;10760082;11687880;15954910;9370187;23121377;12239239;6133212;22397653;1614046;14991049;17383431;22111942;19065671;21816754;20431041;22773240;17699277;19887788;11087998;14598246;20185596;9832641;21903984;1732586;16952559;22344503;14502283;22892396",
"title": "Safety study of somatostatin analogue octreotide for autosomal dominant polycystic kidney disease in Japan.",
"title_normalized": "safety study of somatostatin analogue octreotide for autosomal dominant polycystic kidney disease in japan"
} | [
{
"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2015RR-109432",
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"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OCTREOTIDE"
},
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"drugdosagetext": "2 X 20 MG, EVERY 4 WEEKS",
"drugenddate": null,
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"drugindication": "CONGENITAL CYSTIC KIDNEY DISEASE",
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"medicinalproduct": "OCTREOTIDE."
}
],
"patientagegroup": null,
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"patientsex": null,
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"reaction": [
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Injection site granuloma",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HIGASHIHARA E, NUTAHARA K, OKEGAWA T, TANBO M, MORI H, MIYAZAKI I, ET AL. SAFETY STUDY OF SOMATOSTATIN ANALOGUE OCTREOTIDE FOR AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE IN JAPAN. CLIN-EXP-NEPHROL. 2014?19 (4):746-752",
"literaturereference_normalized": "safety study of somatostatin analogue octreotide for autosomal dominant polycystic kidney disease in japan",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20160122",
"receivedate": "20160122",
"receiver": {
"receiverorganization": "FDA",
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},
"reporttype": "1",
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160526"
}
] |
{
"abstract": "BACKGROUND\nOutpatient cancer chemotherapy may lead to improved quality of life (QOL) by allowing treatment to continue without impairing the social lives of patients compared with hospitalization. However, the occurrence of serious adverse events may cause a decline in QOL. We investigated the relationship between outpatient chemotherapy-induced adverse events and QOL.\n\n\nMETHODS\nA single-center retrospective descriptive study was conducted in patients who received outpatient chemotherapy at Gifu University Hospital (Gifu, Japan) between September 2017 and December 2018. The utility values of QOL, type and severity of adverse events, type of cancer, chemotherapy regimen, and other patient demographics were analyzed. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. QOL was evaluated using the Japanese version of the EuroQol 5 Dimension 5 Level (EQ-5D-5L). Associations between the EQ-5D-5L utility value and serious adverse events were assessed using adjusted (age and sex) odds ratios obtained with a proportional odds logistic regression model.\n\n\nRESULTS\nData from 1008 patients who received 4695 chemotherapy cycles were analyzed. According to proportional odds logistic regression, the adverse events that significantly correlated with a decreased EQ-5D-5L utility value were malaise, edema of the limbs, peripheral neuropathy, pruritus, and dry skin. Based on the proportional odds logistic analysis, neither cancer type nor anticancer drugs were significantly correlated with the EQ-5D-5L utility value in patients who received chemotherapy. Pharmaceutical care for peripheral neuropathy significantly improved patients' EQ-5D-5L utility value from 0.747 to 0.776 (P < 0.01).\n\n\nCONCLUSIONS\nAdverse events (i.e., peripheral neuropathy, malaise, and edema of the limbs) are significantly correlated with a decrease in QOL, regardless of the type of cancer or anticancer drugs used. Pharmaceutical care provided by pharmacists in collaboration with physicians may improve QOL.",
"affiliations": "Department of Pharmacy, Gifu University Hospital, Gifu, Japan.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan. h_fujii@gifu-u.ac.jp.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan.;Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.;Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.;Division of Nursing, Gifu University Hospital, Gifu, Japan.;Division of Nursing, Gifu University Hospital, Gifu, Japan.;Gifu University Hospital Innovative and Clinical Research Promotion Center, Gifu University, Gifu, Japan.;Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, Gifu, Japan.;Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan.;Department of Pharmacy, Gifu University Hospital, Gifu, Japan.",
"authors": "Hirose|Chiemi|C|;Fujii|Hironori|H|;Iihara|Hirotoshi|H|;Ishihara|Masashi|M|;Nawa-Nishigaki|Minako|M|;Kato-Hayashi|Hiroko|H|;Ohata|Koichi|K|;Sekiya|Kumiko|K|;Kitahora|Mika|M|;Matsuhashi|Nobuhisa|N|;Takahashi|Takao|T|;Okuda|Kumiko|K|;Naruse|Masayo|M|;Ishihara|Takuma|T|;Sugiyama|Tadashi|T|;Yoshida|Kazuhiro|K|;Suzuki|Akio|A|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-020-05443-8",
"fulltext": "\n==== Front\nSupport Care Cancer\nSupport Care Cancer\nSupportive Care in Cancer\n0941-4355 1433-7339 Springer Berlin Heidelberg Berlin/Heidelberg \n\n32281034\n5443\n10.1007/s00520-020-05443-8\nOriginal Article\nReal-world data of the association between quality of life using the EuroQol 5 Dimension 5 Level utility value and adverse events for outpatient cancer chemotherapy\nHirose Chiemi 1 Fujii Hironori h_fujii@gifu-u.ac.jp 1 Iihara Hirotoshi 1 Ishihara Masashi 1 Nawa-Nishigaki Minako 1 Kato-Hayashi Hiroko 1 Ohata Koichi 1 Sekiya Kumiko 1 Kitahora Mika 1 Matsuhashi Nobuhisa 2 Takahashi Takao 2 Okuda Kumiko 3 Naruse Masayo 3 Ishihara Takuma 4 Sugiyama Tadashi 5 Yoshida Kazuhiro 2 Suzuki Akio 1 1 grid.411704.7Department of Pharmacy, Gifu University Hospital, Gifu, Japan \n2 grid.256342.40000 0004 0370 4927Department of Surgical Oncology, Gifu University Graduate School of Medicine, Gifu, Japan \n3 grid.411704.7Division of Nursing, Gifu University Hospital, Gifu, Japan \n4 grid.256342.40000 0004 0370 4927Gifu University Hospital Innovative and Clinical Research Promotion Center, Gifu University, Gifu, Japan \n5 grid.411697.c0000 0000 9242 8418Laboratory of Pharmacy Practice and Social Science, Gifu Pharmaceutical University, Gifu, Japan \n12 4 2020 \n12 4 2020 \n2020 \n28 12 5943 5952\n11 11 2019 27 3 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.Background\nOutpatient cancer chemotherapy may lead to improved quality of life (QOL) by allowing treatment to continue without impairing the social lives of patients compared with hospitalization. However, the occurrence of serious adverse events may cause a decline in QOL. We investigated the relationship between outpatient chemotherapy–induced adverse events and QOL.\n\nMethods\nA single-center retrospective descriptive study was conducted in patients who received outpatient chemotherapy at Gifu University Hospital (Gifu, Japan) between September 2017 and December 2018. The utility values of QOL, type and severity of adverse events, type of cancer, chemotherapy regimen, and other patient demographics were analyzed. Adverse events were graded according to the Common Terminology Criteria for Adverse Events, version 4.0. QOL was evaluated using the Japanese version of the EuroQol 5 Dimension 5 Level (EQ-5D-5L). Associations between the EQ-5D-5L utility value and serious adverse events were assessed using adjusted (age and sex) odds ratios obtained with a proportional odds logistic regression model.\n\nResults\nData from 1008 patients who received 4695 chemotherapy cycles were analyzed. According to proportional odds logistic regression, the adverse events that significantly correlated with a decreased EQ-5D-5L utility value were malaise, edema of the limbs, peripheral neuropathy, pruritus, and dry skin. Based on the proportional odds logistic analysis, neither cancer type nor anticancer drugs were significantly correlated with the EQ-5D-5L utility value in patients who received chemotherapy. Pharmaceutical care for peripheral neuropathy significantly improved patients’ EQ-5D-5L utility value from 0.747 to 0.776 (P < 0.01).\n\nConclusions\nAdverse events (i.e., peripheral neuropathy, malaise, and edema of the limbs) are significantly correlated with a decrease in QOL, regardless of the type of cancer or anticancer drugs used. Pharmaceutical care provided by pharmacists in collaboration with physicians may improve QOL.\n\nElectronic supplementary material\nThe online version of this article (10.1007/s00520-020-05443-8) contains supplementary material, which is available to authorized users.\n\nKeywords\nQuality of lifeOutpatient cancer chemotherapyChemotherapy-induced adverse eventsProportional odds logistic regression modelRetrospective descriptive studyissue-copyright-statement© Springer-Verlag GmbH Germany, part of Springer Nature 2020\n==== Body\nIntroduction\nThe number of patients who undergo cancer chemotherapy is increasing in parallel with the morbidity and mortality associated with cancer worldwide. Moreover, cancer chemotherapy has transitioned from inpatient to outpatient settings because of advancements in supportive care measures against cancer and changes in the healthcare environment to reduce medical costs [1–4]. Hence, patients are able to continue their personal life and work by undergoing chemotherapy in an outpatient setting. In fact, Ishiura et al. [5] reported that in patients with non-small lung cancer who received vinorelbine, “psychological condition” related to quality of life (QOL) was significantly improved by a transition from inpatient therapy to outpatient chemotherapy.\n\nHowever, outpatient cancer chemotherapy is characterized by a high incidence of adverse events [6–8], and severe adverse events may directly influence the personal life and work of patients. This effect may reduce patients’ QOL. Tachi et al. [8] showed that the occurrence of anorexia induced by chemotherapy significantly reduced the QOL of patients with breast cancer. Furthermore, Mark et al. [9] reported that patients with advanced-stage lung cancer who experienced strong negative feelings related to side effects have decreased health-related QOL, and recommended facilitating vigorous management of low-grade adverse events to enhance the health-related QOL of patients. Moreover, Hagiwara et al. [10] showed that grade 1 oral mucositis, grade 1 and 2 fatigue, and grade 2 sensory neuropathy were significantly associated with impaired global health status in the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 in patients receiving first-line chemotherapy for metastatic breast cancer.\n\nThese findings highlight the importance of reducing adverse events in order to maintain QOL in patients receiving outpatient chemotherapy. Nevertheless, these studies [8–10] investigated only a limited number of cancer types and anticancer agents. Few cross-sectional studies have investigated the association between a decline in QOL and adverse events in patients with a variety of cancer types and taking a variety of anticancer drugs.\n\nIn this study, we conducted a retrospective analysis to investigate the impact of current outpatient chemotherapy-related adverse events on QOL.\n\nPatients and methods\nStudy design\nThis single-center, retrospective, and descriptive study was conducted at Gifu University Hospital, which is affiliated with Gifu University (Gifu, Japan). Patients who underwent cancer chemotherapy at the Gifu University Hospital outpatient cancer chemotherapy clinic between September 2017 and December 2018 were enrolled in the present study. The utility values of QOL, type and severity of adverse events, type of cancer, chemotherapy regimen, and other patient demographics were extracted from the electronic medical records of the hospital and retrospectively analyzed.\n\nOutpatient chemotherapy clinic\nWe previously reported the system in our outpatient chemotherapy clinic [11, 12]. Briefly, full-time medical staff consisted of two physicians, eight nurses, and four pharmacists. The pharmacists verified prescription orders based on patients’ cancer chemotherapy regimens, provided pharmaceutical care services to all outpatients who received cancer chemotherapy, monitored adverse events, and proposed prescriptions to physicians regarding supportive care. The pharmacists also provided drug information to other medical staff.\n\nAssessment of QOL\nThe EuroQol 5 Dimension 5 Level (EQ-5D-5L) questionnaire was developed by the EuroQol group to investigate health-related QOL in adults [13]. The Japanese version of the EQ-5D-5L was developed by Shiroiwa et al. [14] to evaluate QOL reflecting Japanese values. The EQ-5D-5L is widely used in clinical studies and health status surveys targeting the general population and uses a comprehensive scale based on preferences to assess cardinal changes in health status [15, 16]. While the values in the Japanese version [14] differ from those in the original, the utility values of QOL in this study were calculated using the Japanese version of the EQ-5D-5L to reflect the values of the Japanese people. We used a hybrid model prepared by mapping discrete choice experiment (DCE) data onto composite time trade-off (cTTO) data [14] to determine the EQ-5D-5L utility value.\n\nWe applied to the EuroQoL Group for use of the Japanese version of the questionnaire and obtained permission before use. The Japanese version of the EQ-5D-5L questionnaire was used in face-to-face interviews to estimate the utility values of QOL [14] and was routinely implemented by pharmacists during each patient visit. The utility values were recorded in the hospital’s electronic medical records.\n\nThe five dimensions assessed by the EQ-5D-5L are mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each of these is assessed according to five levels of severity: level 1, no problem; level 2, slight problem; level 3, moderate problem; level 4, severe problem; and level 5, unable or extreme problem [13]. A utility value ranging from 0 to 1 was calculated from the EQ-5D-5L, which was defined as the primary outcome of this study. According to the Japanese version of the utility value conversion table, “0” indicates death and “1” indicates full health [17]. The EQ-5D-5L contains only five questions, and patients receiving outpatient chemotherapy can easily answer these questions at each cycle. For these reasons, we used the EQ-5D-5L questionnaire in the present study.\n\nAssessment of adverse events\nAll patients were provided with a daily checklist to confirm their side effects on their first visit to the outpatient chemotherapy clinic. Using the checklist, patients recorded the occurrence of daily adverse events after chemotherapy. From the returned checklists and the results of the interviews, pharmacists, in collaboration with physicians, recorded the severity of adverse events in the electronic medical records. The severity of adverse events was graded according to the Common Terminology Criteria for Adverse Events version 4.0 (National Cancer Institute, Bethesda, MD, USA) [18].\n\nIf moderate or severe adverse events occurred in a patient receiving outpatient chemotherapy, physicians and pharmacists implemented a pharmaceutical care intervention based on clinical practice guidelines. Pharmaceutical care for adverse events was provided by pharmacists in collaboration with physicians, and the impact of this intervention on the adverse events was assessed during the subsequent visit.\n\nEffect of pharmaceutical care on peripheral sensory neuropathy\nEvidence suggests that moderate peripheral neuropathy (grade ≥ 2) has a strong negative impact on QOL [10]. Therefore, we investigated the changes in QOL induced by anticancer drugs in patients with peripheral neuropathy. These changes were examined at three time points: prior to peripheral sensory neuropathy (control), during the development of peripheral sensory neuropathy (pre-intervention), and after pharmaceutical intervention for peripheral sensory neuropathy (post-intervention).\n\nSpecifically, to show that utility values for QOL were reduced by the appearance of peripheral neuropathy, we compared utility values for QOL between “control” and “pre-intervention” time points. In addition, to show that the effect of pharmaceutical intervention for peripheral neuropathy increased utility values for QOL, we compared utility values for QOL between “pre-intervention” and “post-intervention” time points.\n\nStatistical analysis\nPatient demographics were summarized using medians with the 25th and 75th percentiles for parametric variables. Frequencies and percentages are shown for non-parametric variables. As the distribution of the EQ-5D-5L utility value was heavily skewed, we employed proportional odds logistic regression to assess the effect of adverse events on QOL after adjusting for covariates. The proportional odds logistic model, also termed the ordinal logistic model, is a popular model for analyzing ordered outcome variables. This model performs well for skewed continuous outcome variables using the ranks of data. In addition to the moving difference between the current and previous grade of adverse events (changing grade), age and sex were included in the multivariable model. Adjusted associations were analyzed using a regression model with the Huber-White robust sandwich estimator, with patients as a clustering variable. In the secondary analysis, we confirmed the effect of cancer type and anticancer drugs on the EQ-5D-5L utility value using a proportional odds logistic model with adjustment for covariates. An adjusted odds ratio < 1 indicates that QOL is more likely to be worse on average in patients with adverse events, cancer, or those taking anticancer drugs. For comparisons assessing the effects of pharmaceutical intervention on peripheral neuropathy, the Wilcoxon signed-rank test for pair-wise comparisons was performed.\n\nFindings with two-sided P values < 0.05 were considered statistically significant. Data were analyzed using IBM SPSS version 22.0 (IBM Japan Ltd., Tokyo, Japan) and R software version 3.5.1 (www.r-project.org).\n\nEthical considerations\nThe present study was performed in accordance with the guidelines for care in human studies adopted by the Medical Review Board of Gifu University Graduate School of Medicine, and was approved by the Institutional Review Board of the Japanese Government (approval no. 2019-004). Owing to the retrospective nature of the study, the provision of informed consent by the patients was not required.\n\nResults\nPatients\nPatient demographics are shown in Table 1. A total of 1008 patients received 4695 chemotherapy cycles between September 2017 and December 2018 in our outpatient chemotherapy clinic. The most common type of cancer was colorectal cancer (16.8%), followed by gastric cancer (15.1%), lung cancer (12.1%), breast cancer (11.5%), malignant lymphoma (6.7%), pancreatic cancer (6.4%), head and neck cancer (4.1%), and esophageal cancer (1.7%).Table 1 Patient demographics\n\nNumber of patients (male/female)\t1008\t(516/492)\t\nAge, median (min–max)\t67\t(18–90)\t\nNumber of chemotherapy courses\t4695\t\nCancer\t\n Colorectal cancer\t169\t16.8%\t\n Gastric cancer\t152\t15.1%\t\n Lung cancer\t122\t12.1%\t\n Breast cancer\t116\t11.5%\t\n Ovarian cancer/cervical cancer/uterine cancer\t113\t11.2%\t\n Malignant lymphoma\t68\t6.7%\t\n Pancreatic cancer\t65\t6.4%\t\n Bladder cancer/testicular cancer/urothelial cancer\t57\t5.7%\t\n Head and neck cancer\t41\t4.1%\t\n Leukemia\t26\t2.6%\t\n Biliary tract cancer\t19\t1.9%\t\n Esophageal cancer\t17\t1.7%\t\n Malignant melanoma\t16\t1.6%\t\n Malignant soft tissue tumor\t12\t1.2%\t\n Malignant glioma\t12\t1.2%\t\n Neuroendocrine carcinoma\t3\t0.3%\t\nRegimen\t\n L-OHP + fluoropyrimidines ± Bmab/Cmab/Pmab\t154\t15.3%\t\n Weekly PTX/Nab-PTX ± Tmab/ramucirumab/Cmab\t132\t13.1%\t\n Pembrolizumab/nivolumab\t115\t11.4%\t\n CBDCA + PTX/PEM/DOC/VNR/GEM/S-1/CPT-11 ± Bmab\t87\t8.6%\t\n Maintenance chemotherapy (Bmab/Tmab/rituximab)\t76\t7.5%\t\n CPT-11 ± fluoropyrimidines ± Bmab/aflibercept/ramucirumab\t57\t5.7%\t\n GEM ± S-1\t38\t3.8%\t\n DOC/GEM/LipoDOX/VNR ± Bmab\t35\t3.5%\t\n FOLFIRINOX/FOLFOXIRI ± Bmab/Cmab\t30\t3.0%\t\n GEM + Nab-PTX\t28\t2.8%\t\n CHOP/THP-COP ± rituximab\t28\t2.8%\t\n PEM ± Bmab\t26\t2.6%\t\n DOC/GEM/EPI/VNR/S-1 ± PER ± Tmab\t25\t2.5%\t\n Anthracyclines + cyclophosphamide\t25\t2.5%\t\n Fluoropyrimidines/TAS102 + Bmab\t22\t2.2%\t\n S-1 + DOC\t14\t1.4%\t\n Rituximab + bendamustine\t13\t1.3%\t\n Cisplatin + GEM\t9\t0.9%\t\n Cmab/Pmab\t9\t0.9%\t\n Other\t85\t8.4%\t\nL-OHP, oxaliplatin; Bmab, bevacizumab; Cmab, cetuximab; Pmab, panitumumab; PTX, paclitaxel; Nab-PTX, nanoparticle albumin-bound paclitaxel; Tmab, trastuzumab; CBDCA, carboplatin; PEM, pemetrexed; DOC, docetaxel; VNR, vinorelbine; GEM, gemcitabine; S-1, tegafur + gimeracil + oteracil; CPT-11, irinotecan; LipoDOX, doxorubicin liposomal; EPI, epirubicin; FOLFIRINOX/FOLFOXIRI, L-OHP + CPT-11 + 5-FU; CHOP, cyclophosphamide + doxorubicin + vincristine + prednisolone; THP-COP, cyclophosphamide + pirarubicin + vincristine + prednisolone; TAS102, trifluridine + tipiracil\n\n\n\nThe most common type of regimen was oxaliplatin-based chemotherapy (15.3%), followed by paclitaxel/nanoparticle albumin-bound paclitaxel-based chemotherapy (13.1%), and pembrolizumab/nivolumab (11.4%).\n\nRelationship between the degree of changing grade for adverse events and the EQ-5D-5L utility value\nThe mean EQ-5D-5L utility value of all enrolled patients was 0.827. The mean EQ-5D-5L utility value for each patient visit is shown in Supplemental Table 1 by cancer type, regimen, and adverse events. The mean EQ-5D-5L utility value when any adverse event occurred was lower than that of all patients.\n\nIncidence of adverse events (grade ≥ 2) in patients under different regimens is shown in Table 2. Although the incidence of constipation (grade ≥ 2) was more than 10% higher in patients receiving vincristine, no other adverse events occurred at ≥ 10% incidence for any given regimen.Table 2 Incidence of grade ≥ 2 adverse events in patients under different regimens\n\nAdverse event\tOxaliplatin\tPaclitaxel\tIrinotecan\tCetuximab/panitumumab\tAnthracycline + cyclophosphamide\tVincristine\tDocetaxel\tCarboplatin\tGemcitabine\tNivolumab/pembrolizumab\t\n\tN = 726\tN = 1259\tN = 529\tN = 221\tN = 181\tN = 113\tN = 172\tN = 188\tN = 547\tN = 568\t\nConstipation\t2.75%\t3.57%\t2.08%\t0.04%\t9.39%\t15.04%\t7.56%\t3.72%\t3.47%\t1.41%\t\nNausea\t2.62%\t0.48%\t3.78%\t0.01%\t1.66%\t0.00%\t0.58%\t0.00%\t0.91%\t0.18%\t\nDiarrhea\t0.55%\t0.56%\t0.57%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.18%\t0.53%\t\nVomiting\t0.41%\t0.32%\t0.57%\t0.00%\t0.55%\t0.00%\t0.00%\t0.00%\t0.37%\t0.35%\t\nOral mucositis\t0.55%\t0.08%\t1.13%\t0.01%\t1.66%\t0.88%\t2.33%\t0.00%\t0.00%\t0.00%\t\nMalaise\t1.52%\t2.07%\t1.89%\t0.01%\t2.76%\t4.42%\t2.91%\t4.26%\t4.20%\t0.53%\t\nPain\t0.00%\t1.03%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.73%\t0.00%\t\nEdema limbs\t0.00%\t0.08%\t0.00%\t0.00%\t0.00%\t0.00%\t1.16%\t0.00%\t0.00%\t0.88%\t\nNail fever\t0.69%\t0.00%\t0.76%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t\nAnorexia\t3.72%\t2.94%\t3.78%\t0.00%\t0.55%\t0.00%\t7.56%\t2.66%\t3.29%\t2.11%\t\nArthralgia\t0.00%\t0.64%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.53%\t0.73%\t0.00%\t\nMuscle pain\t0.00%\t0.56%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.53%\t0.91%\t0.00%\t\nTumor pain\t0.41%\t0.87%\t0.57%\t0.00%\t0.00%\t0.00%\t0.58%\t0.00%\t0.37%\t0.70%\t\nPeripheral neuropathy\t3.17%\t3.65%\t3.78%\t0.03%\t6.08%\t9.73%\t0.58%\t0.00%\t3.29%\t1.23%\t\nTaste disorder\t0.96%\t0.87%\t0.95%\t0.00%\t0.55%\t0.00%\t2.33%\t0.00%\t3.66%\t0.53%\t\nHand-foot syndrome\t0.14%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t\nAlopecia\t0.14%\t5.00%\t0.95%\t0.00%\t0.55%\t0.00%\t4.07%\t2.66%\t2.01%\t1.06%\t\nPruritus\t0.00%\t0.00%\t0.19%\t0.00%\t0.00%\t0.00%\t0.58%\t0.00%\t0.00%\t0.00%\t\nDry skin\t0.41%\t0.00%\t0.95%\t0.00%\t0.00%\t0.00%\t1.16%\t0.00%\t0.00%\t0.18%\t\nAcneiform eruption\t0.14%\t0.08%\t0.19%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t0.00%\t\n\n\nWe analyzed the relationship between the degree of changing grade for adverse events and the EQ-5D-5L utility value using proportional odds logistic regression. As shown in Table 3, malaise, edema of the limbs, peripheral sensory neuropathy, pruritus, and dry skin were significantly correlated with a decreased EQ-5D-5L utility value (malaise: odds ratio [OR] 0.18, P = 0.001; edema of the limbs: OR 0.09, P = 0.031; peripheral sensory neuropathy: OR 0.1, P < 0.001; pruritus: OR 0.14, P = 0.001; dry skin: OR 0.05, P = 0.01).Table 3 Multivariable proportional odds logistic analysis of adverse events (A), cancer type (B), and anticancer drugs (C) and their association with the EQ-5D-5L utility value in patients who received chemotherapy\n\nFactor\tAdjusted odds ratio\t95% CI\tP value\t\nA: adverse events\t\n Constipation\t0.55\t0.23–1.34\t0.191\t\n Nausea\t4.37\t0.83–23.02\t0.082\t\n Diarrhea\t1.66\t0.18–15.58\t0.659\t\n Vomiting\t0.01\t0–3.03\t0.121\t\n Oral mucositis\t1.33\t0.25–7.17\t0.741\t\n Malaise\t0.18\t0.06–0.5\t0.001\t\n Pain\t1.19\t0.22–6.4\t0.836\t\n Edema of the limbs\t0.09\t0.01–0.8\t0.031\t\n Nail fever\t7.5\t1.27–44.23\t0.026\t\n Anorexia\t1.44\t0.32–6.54\t0.639\t\n Arthralgia\t1.6\t0.25–10.1\t0.618\t\n Muscle pain\t0.95\t0.09–9.91\t0.968\t\n Tumor pain\t0.14\t0–8.89\t0.355\t\n Peripheral neuropathy\t0.1\t0.03–0.35\t< 0.001\t\n Taste disorder\t0.68\t0.21–2.21\t0.518\t\n Hand-foot syndrome\t0.77\t0.14–4.15\t0.762\t\n Alopecia\t2.03\t0.76–5.43\t0.157\t\n Pruritus\t0.14\t0.04–0.43\t0.001\t\n Dry skin\t0.05\t0.01–0.49\t0.01\t\n Acneiform eruption\t0.21\t0.01–3.06\t0.255\t\nB: cancer type\t\n Pancreatic cancer\t0.64\t0.35–1.15\t0.134\t\n Gastric cancer\t0.76\t0.44–1.32\t0.324\t\n Esophageal cancer\t1.45\t0.7–3\t0.318\t\n Head and neck cancer\t0.78\t0.37–1.66\t0.524\t\n Colorectal cancer\t0.96\t0.64–1.45\t0.858\t\n Lung cancer\t0.99\t0.63–1.53\t0.951\t\nC: anticancer drugs\t\n Oxaliplatin\t0.96\t0.68–1.35\t0.811\t\n Paclitaxel\t0.91\t0.64–1.3\t0.623\t\n Irinotecan\t0.71\t0.47–1.05\t0.088\t\n Cetuximab/panitumumab\t1.1\t0.6–2.02\t0.76\t\n Anthracycline + cyclophosphamide\t1.7\t0.94–3.07\t0.081\t\n Vincristine\t0.47\t0.19–1.14\t0.093\t\n Docetaxel\t1.2\t0.6–2.41\t0.612\t\n Carboplatin\t0.86\t0.56–1.34\t0.511\t\n Gemcitabine\t0.84\t0.46–1.54\t0.568\t\n Nivolumab/pembrolizumab\t0.9\t0.57–1.45\t0.675\t\nAdjusted odds ratio (OR) and 95% confidence intervals (CI) are indicated. Analysis was performed with adjustment for age, sex, and administered cycle\n\n\n\nAssessment of QOL using the EQ-5D-5L utility value\nWe investigated the association between the EQ-5D-5L utility value and cancer type, including pancreatic cancer, gastric cancer, esophageal cancer, head and neck cancer, colorectal cancer, and lung cancer. We performed proportional odds logistic analysis, adjusting for age and sex. Breast and gynecologic cancers, in which all patients are female, could not be adjusted for sex. This analysis excluded these cancer types and was limited to cancer types that affect both male and female patients. As shown in Table 3, based on the proportional odds logistic analysis, cancer type was not significantly correlated with the EQ-5D-5L utility value in patients who received chemotherapy. However, patients with pancreatic cancer showed a tendency toward reduced EQ-5D-5L utility values (OR 0.64, P = 0.134).\n\nIn addition, we investigated the association between the EQ-5D-5L utility value and anticancer drugs, such as oxaliplatin, paclitaxel, irinotecan, cetuximab/panitumumab, anthracycline plus cyclophosphamide, vincristine, docetaxel, carboplatin, gemcitabine, and nivolumab/pembrolizumab. As shown in Table 3, administration of irinotecan and vincristine tended to decrease the EQ-5D-5L utility value (irinotecan: OR 0.71, P = 0.088; vincristine: OR 0.47, P = 0.093).\n\nChange in the EQ-5D-5L utility value after pharmaceutical care for peripheral sensory neuropathy\nOf the 163 patients who experienced peripheral sensory neuropathy, 36 patients underwent pharmaceutical intervention for peripheral neuropathy. The demographics of the patients are shown in Supplemental Table 2. We evaluated the degree of change in the EQ-5D-5L utility value for the control, pre-intervention, and post-intervention time points.\n\nThe compositions of the regimens were as follows: containing taxane (17 patients, 47.2%), containing oxaliplatin (14 patients, 38.9%), and others (five patients, 13.9%). Details of the pharmaceutical interventions were the additional oral administration of pregabalin (36.1%), duloxetine (55.6%), and gosyajinkigan (2.8%). The latter is a Japanese herbal medicine used to alleviate neuropathy and general pain. Two patients underwent cryotherapy for the hands and feet during the administration of anticancer drugs.\n\nAs shown in Fig. 1, the EQ-5D-5L utility value was significantly decreased after the development of peripheral sensory neuropathy (control, 0.807; pre-intervention, 0.747; P < 0.001), and significantly higher after pharmaceutical intervention (pre-intervention, 0.747; post intervention, 0.776; P = 0.015).Fig. 1 Comparison of mean EuroQol 5 Dimension 5 Level utility values among the control, pre-intervention, and post-intervention time points for peripheral neuropathy. The Wilcoxon signed-rank test was used. Asterisk indicates P < 0.05. Control, prior to the development of peripheral sensory neuropathy: pre-intervention, during the development of peripheral sensory neuropathy; post-intervention, after pharmaceutical intervention for peripheral sensory neuropathy\n\n\n\nAs shown in Table 4, among the five dimensions, the score for mobility, personal care, pain/discomfort, and anxiety/depression was improved by pharmaceutical intervention. In particular, the change noted in the pain/discomfort score was the most pronounced.Table 4 The 5 dimensions of the EuroQol 5 Dimension 5 Level questionnaire at control, pre-intervention, and post-intervention time points for peripheral neuropathy\n\n\tControl\tPre-intervention\tPost-intervention\t\nMobility\t1\t57%\t33%\t36%\t\n2\t43%\t58%\t56%\t\n3\t0%\t6%\t8%\t\n4\t0%\t3%\t0%\t\n5\t0%\t0%\t0%\t\nPersonal care\t1\t86%\t67%\t81%\t\n2\t14%\t28%\t14%\t\n3\t0%\t6%\t6%\t\n4\t0%\t0%\t0%\t\n5\t0%\t0%\t0%\t\nUsual activities\t1\t39%\t44%\t44%\t\n2\t54%\t47%\t44%\t\n3\t4%\t8%\t8%\t\n4\t4%\t0%\t3%\t\n5\t0%\t0%\t0%\t\nPain/discomfort\t1\t50%\t19%\t33%\t\n2\t46%\t53%\t56%\t\n3\t4%\t22%\t6%\t\n4\t0%\t6%\t6%\t\n5\t0%\t0%\t0%\t\nAnxiety/depression\t1\t54%\t42%\t56%\t\n2\t43%\t50%\t36%\t\n3\t4%\t6%\t8%\t\n4\t0%\t3%\t0%\t\n5\t0%\t0%\t0%\t\nThe values for the 5 dimensions indicate percentage of each item\n\n\n\nDiscussion\nIn this study, we used real-world data to examine the potential association between QOL using the EQ-5D-5L and adverse events in 1008 patients who received 4695 cycles of outpatient cancer chemotherapy. Clinical trial data were obtained from a “selected population” that met the inclusion and exclusion criteria defined in the protocol. Additionally, real-world data were obtained from daily medical practice. Therefore, the data were not limited to the background of patients but are considered real-world data as they represent the actual situation in clinical practice.\n\nMultivariable proportional odds logistic analysis indicated that malaise, edema of the limbs, peripheral sensory neuropathy, pruritus, and dry skin were significant factors for reducing the EQ-5D-5L utility value. Several reports support the present results, highlighting the association between adverse events and decreased QOL [8, 19–21]. Secondary analysis using proportional odds logistic regression did not show a significant association between QOL and cancer type or anticancer drugs. Regardless of the type of cancer or anticancer drugs, the development of adverse events appeared to be an important factor for decreasing QOL in patients receiving outpatient chemotherapy.\n\nTachi et al. [8] showed that in current breast cancer patients, the rate of deterioration of the utility value after treatment was significant for patients with malaise (P = 0.028) in the usual activities dimension. Limb edema is a characteristic finding in patients with malnutrition. Onishi et al. [19] reported that malnutrition in cancer patients is associated with decreased QOL. Additionally, Hershman et al., using the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity, reported that QOL scores decreased from 37.5 to 28.7 post-treatment (P = 0.0002).\n\nThe EQ-5D-5L is not specific to patients with cancer and contains only a few questions; thus, this tool is characterized by low sensitivity. However, this study showed an association between the changing grade for various adverse events and QOL score using the EQ-5D-5L. Although it is important to continuously evaluate the QOL of patients, in the real world, a large number of question items for each relevant anticancer drug can be burdensome to answer and may interfere with continuous evaluation.\n\nSubsequently, we examined changes in the EQ-5D-5L utility value after pharmaceutical care for chemotherapy-induced peripheral neuropathy. Peripheral neuropathy is a relatively frequent adverse event during cancer chemotherapy, including regimens using taxanes, vinca alkaloids, and platinum agents. The occurrence of moderate-to-severe peripheral neuropathy leads to discontinuation of cancer chemotherapy or dose reduction, which reduces dose intensity and the QOL of the patient [10, 22].\n\nThe efficacy of the administration of pregabalin [23, 24], duloxetine [25, 26], and gosyajinkigan [27] for improving chemotherapy-induced peripheral neuropathy has been reported. In addition, Hanai et al. [28] reported that cryotherapy is useful for preventing both the objective and subjective symptoms of paclitaxel-induced peripheral neuropathy and resulting dysfunction.\n\nIn this study, the EQ-5D-5L utility value was significantly improved after pharmaceutical intervention (pre-intervention: 0.747; post-intervention: 0.776; P < 0.01). Although the minimally important difference for Japan reported by McClure et al. [29] in a simulation-based approach was 0.045, the increase in utility value after intervention in our present study did not exceed the difference. However, 0.807 indicates the approximately 45th percentile, and 0.747 indicates the approximately 35th percentile in the overall data. Therefore, given that the change from control to pre-intervention can be interpreted as a decrease in QOL of about 10% in all people, the effect on control from pre-intervention can be considered significant. As with the interpretation above, 0.776 indicates approximately the 41st percentile in the overall data. Thus, the change from pre-intervention to post-intervention contributed to a 6% increase in QOL in the overall data.\n\nMoreover, among the five dimensions (mobility, personal care, usual activities, pain/discomfort, and anxiety/depression), pain/discomfort scores were significantly elevated prior to and after the onset of peripheral neuropathy (from 1.540 to 2.140). Notably, pain/discomfort scores were significantly decreased prior to and after pharmaceutical care (from 2.140 to 1.830). Among the five dimensions, the change in pain/discomfort scores was the most pronounced. This dimension may influence the change in EQ-5D-5L utility values. Costa et al. [30] analyzed the association between the presence of pain and QOL in breast cancer patients using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Version 3.0 and showed that pain negatively influenced QOL with or without metastasis. In the present study, pain due to peripheral neuropathy reduced QOL; however, amelioration of pain due to the administration of pregabalin or duloxetine improved QOL. Temel et al. [31] showed that early palliative care for lung cancer patients resulted in improved QOL and extended survival compared with standard care. Improved QOL contributes to prolonging survival; this finding supports the present results showing that pharmaceutical care provided by pharmacists in collaboration with physicians may improve therapeutic efficacy.\n\nThere were several limitations to the present study. First, there were no control patients (i.e., individuals who did not receive anticancer drug treatment) for comparison of QOL with that of patients who received cancer chemotherapy. Second, the degree of cancer progression is strongly associated with QOL, and patients who receive cancer chemotherapy exhibit progressively worse physical status over time. We did not adequately examine patient confounding factors including tumor metastasis, line of treatment, progression or recurrence of disease, or employment and marital status. Third, our evaluation was limited to the effects of pharmaceutical care for peripheral neuropathy, and we did not report the effects of pharmaceutical care on malaise, edema of the limbs, pruritus, and dry skin. These reports are currently in progress. Finally, there is a lack of information regarding the degree of compliance with treatment, the possible influence of over-the-counter or complementary medicines on QOL scores, comorbidity, and treatment status.\n\nConclusions\nThis study presented real-world data analyses showing that adverse events, such as peripheral neuropathy, malaise, and edema of the limbs, are significantly correlated with a decrease in QOL, regardless of the type of cancer or anticancer drugs used. Pharmaceutical care provided by pharmacists in collaboration with physicians may improve QOL.\n\nElectronic supplementary material\n\nESM 1 (DOCX 39 kb)\n\n \n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nChiemi Hirose and Hironori Fujii contributed equally to this work.\n\nWe appreciate the participants for their contribution to this study. We are grateful to Y. Otsuka (Assistant of Pharmacy) and Ryo Kobayashi (Vice-director of Pharmacy) for helping with this study.\n\nCompliance with ethical standards\nConflict of interest\nK. Yoshida has received honoraria for lectures from Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eli Lilly and Company, Yakult Honsha Co., Ltd., Merck Sharp & Dohmegrants Co., Ltd., Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Merck Serono Co., Ltd., Johnson & Johnson Co., Ltd., Covidien Co., Ltd., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sanofi K.K., Nippon Kayaku Co., Ltd., Asahi Kasei Co., Ltd., Tsumura Co., Ltd., EA Pharma Co., Ltd., Bayer Yakuhin Co., Ltd., Olympus Co., Ltd., Terumo Co., Ltd., Bristol-Myers Squibb Co., Ltd., Denka Co., Ltd., Teijin Co., Ltd., SBI Pharmaceuticals Co., Ltd., Intuitive Surgical Co., Ltd., and Novartis Pharma K.K., Pfizer Inc., and research funding from Chugai Pharmaceutical Co., Ltd., Taiho Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eli Lilly and Company, Yakult Honsha Co., Ltd., Merck Sharp & Dohmegrants Co., Ltd., Daiichi Sankyo Co., Ltd., Ono Pharmaceutical Co., Ltd., Merck Serono Co., Ltd., Johnson & Johnson Co., Ltd., Covidien Co., Ltd., Eisai Co., Ltd., Otsuka Pharmaceutical Co., Ltd., Sanofi K.K., Nippon Kayaku Co., Ltd., Asahi Kasei Co., Ltd., Tsumura Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Astellas Pharma Co., Ltd., Toyama Chemical Co., Ltd., Kinetic Concepts Co., Ltd., Abbott Japan Co., Ltd., and Toray Industries, Co., Ltd. outside the submitted work.\n\nT. Takahashi has received honoraria for lectures from Takeda Pharmaceutical Co., Ltd. and Sanofi Co., Ltd. The other authors have no conflicts of interest.\n==== Refs\nReferences\n1. Dollinger M Guidelines for hospitalization for chemotherapy Oncologist 1996 1 1 & 2 107 111 10.1634/theoncologist.1-1-107 10387975 \n2. Morita T Fujimoto K Namba M Sasaki N Ito T Yamada C Ohba A Hiroyoshi M Niwa H Yamada T Noda T Palliative care needs of cancer outpatients receiving chemotherapy: an audit of a clinical screening project Support Care Cancer 2008 16 101 107 10.1007/s00520-007-0271-6 17611783 \n3. Kitada N Nakagawa F Fukushima Y Analysis of current status of cancer chemotherapy management in outpatients at general hospital —case of Takarazuka Municipal Hospital Jpn J Pharm Health Care Sci 2006 32 835 841 10.5649/jjphcs.32.835 \n4. Fujii T Yamamoto T Tomita N Preparation of worksheets to support pharmaceutical management in cancer chemotherapy for outpatients —project of 5th chapter of oncology research group, Aichi Prefectual Society of Hospital Pharmacists Jpn J Pharm Health Care Sci 2006 32 946 955 10.5649/jjphcs.32.946 \n5. Ishiura Y Terasaki Y Yamamoto H Analysis of factors associated with quality of life for patients with non-small lung cancer receiving outpatient vinorelbine therapy as alternative inpatient therapy JPN J Cancer Chemother 2007 34 1401 1404 \n6. Miyake T Hashida T Kobayashi M Survey on use of amrubicin hydrochloride in outpatients with lung cancer and evaluation of its hematologictoxicity Jpn J Pharm Health Care Sci 2008 34 268 273 10.5649/jjphcs.34.268 \n7. Fernandez-Ortega P Caloto MT Chirveches E Chemotherapy-induced nausea and vomiting in clinical practice: impact on patients’ quality of life Support Care Cancer 2012 20 3141 3148 10.1007/s00520-012-1448-1 22460057 \n8. Tachi T Teramachi H Tanaka K The impact of outpatient chemotherapy-related adverse events on the quality of life of breast cancer patients PLoS One 2015 10 e0124169 10.1371/journal.pone.0124169 25915539 \n9. de Mol M Visser S den Oudsten BL Lodder P van Walree N Belderbos H Aerts JG Frequency of low-grade adverse events and quality of life during chemotherapy determine patients’ judgement about treatment in advanced-stage thoracic cancer Support Care Cancer 2019 27 3563 3572 10.1007/s00520-019-4659-x 30690684 \n10. Hagiwara Y Shiroiwa T Shimozuma K Impact of adverse events on health utility and health-related quality of life in patients receiving first-line chemotherapy for metastatic breast cancer: results from the SELECT BC study Pharmacoeconomics 2018 36 215 223 10.1007/s40273-017-0580-7 29043567 \n11. Iihara H Ishihara M Matsuura K Kurahashi S Takahashi T Kawaguchi Y Yoshida K Itoh Y Pharmacists contribute to the improved efficiency of medical practices in the outpatient cancer chemotherapy clinic J Eval Clin Pract 2012 18 753 760 10.1111/j.1365-2753.2011.01665.x 21414113 \n12. Yoshimi C Yamada M Fujii H Evaluation of the efforts of pharmaceutical care services before medical examination at an outpatient cancer chemotherapy clinic JPN J Cancer Chemother 2013 40 349 354 \n13. Herdman M Gudex C Lloyd A Janssen M Kind P Parkin D Bonsel G Badia X Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L) Qual Life Res 2011 20 1727 1736 10.1007/s11136-011-9903-x 21479777 \n14. Shiroiwa T Ikeda S Noto S Igarashi A Fukuda T Saito S Shimozuma K Comparison of value set based on DCE and/or TTO data: scoring for EQ-5D-5L health states in Japan Value Health 2016 19 648 654 10.1016/j.jval.2016.03.1834 27565282 \n15. Sakamaki H Ikeda S Ikegami N Uchigata Y Iwamoto Y Origasa H Otani T Otani Y Measurement of HRQL using EQ-5D in patients with type 2 diabetes mellitus in Japan Value Health 2006 9 47 53 10.1111/j.1524-4733.2006.00080.x 16441524 \n16. Khanna R Jariwala K Bentley JP Health utility assessment using EQ-5D among caregivers of children with autism Value Health 2013 16 778 788 10.1016/j.jval.2013.04.007 23947971 \n17. Okamoto T Hashimoto K Ohashi M Survey on health-related quality of life (HRQOL) and cost-effectiveness for rehabilitation hospital inpatients by EuroQOL Jpn J Rehabil Med 2004 41 678 685 10.2490/jjrm1963.41.678 \n18. US Department of Health and Human Services, National Institutes of Health National Cancer Institute Common terminology criteria for adverse events (CTCAE) version 4.0. (2009) Available online: https://www.eortc.be/services/doc/ctc/ (accessed on 19 July 2019)\n19. Onichi S Shiraki M Nishimura K Hanai T Moriwaki H Shimizu M Prevalence of sarcopenia and its relationship with nutritional state and quality of life in patients with digestive diseases J Nutr Sci Vitaminol 2018 64 445 453 10.3177/jnsv.64.445 30606967 \n20. Hershman DL Weimer LH Wang A Kranwinkel G Brafman L Fuentes D Awad D Crew KD Association between patient reported outcomes and quantitative sensory tests for measuring long-term neurotoxicity in breast cancer survivors treated with adjuvant paclitaxel chemotherapy Breast Cancer Res Treat 2011 125 767 774 10.1007/s10549-010-1278-0 21128110 \n21. Lu LC Tsay SL Chang SY Chen CM Liu CY Daily activity, mood, and quality of life in colorectal cancer patients with chemotherapy-induced peripheral neuropathy: a mediation effect analysis Cancer Med 2019 8 963 971 10.1002/cam4.1976 30741481 \n22. Argyriou AA Bruna J Marmiroli P Chemotherapy-induced peripheral neurotoxicity (CIPN): an update Crit Rev Oncol Hematol 2012 82 51 77 10.1016/j.critrevonc.2011.04.012 21908200 \n23. Rosenstock J Tuchman M LaMoreaux L Pregabalin for the treatment of painful diabetic peripheral neuropathy: a double-blind, placebo-controlled trial Pain 2004 110 628 638 10.1016/j.pain.2004.05.001 15288403 \n24. Saif MW Syrigos K Kaley K Isufi I Role of pregabalin in treatment of oxaliplatin-induced sensory neuropathy Anticancer Res 2010 30 2927 2933 20683034 \n25. Smith T Nicholson RA Review of duloxetine in the management of diabetic peripheral neuropathic pain Vasc Health Risk Manag 2007 3 833 844 18200804 \n26. Smith EM Pang H Cirrincione C Fleishman S Paskett ED Ahles T Bressler LR Fadul CE Knox C le-Lindqwister N Gilman PB Shapiro CL Alliance for Clinical Trials in Oncology Effect of duloxetine on pain, function, and quality of life among patients with chemotherapy-induced painful peripheral neuropathy: a randomized clinical trial JAMA 2013 309 1359 1367 10.1001/jama.2013.2813 23549581 \n27. Yamamoto T Murai T Ueda M Clinical features of paclitaxel-induced peripheral neuropathy and role of Gosya-jinki-gan JPN J Cancer Chemother 2009 36 89 92 \n28. Hanai A Ishiguro H Sozu T Tsuda M Yano I Nakagawa T Imai S Hamabe Y Toi M Arai H Tsuboyama T Effects of cryotherapy on objective and subjective symptoms of paclitaxel-induced neuropathy: prospective self-controlled trial J Natl Cancer Inst 2018 110 141 148 10.1093/jnci/djx178 29924336 \n29. McClure NS Sayah FA Xie F Luo N Johnson JA Instrument-defined estimates of the minimally important difference for EQ-5D-5L index scores Value Health 2017 20 644 650 10.1016/j.jval.2016.11.015 28408007 \n30. Costa WA Monteiro MN Queiroz JF Pain and quality of life in breast cancer patients Clinics (Sao Paulo) 2017 72 758 763 10.6061/clinics/2017(12)07 29319722 \n31. Temel JS Greer JA Muzikansky A Gallagher ER Admane S Jackson VA Dahlin CM Blinderman CD Jacobsen J Pirl WF Billings JA Lynch TJ Early palliative care for patients with metastatic non-small-cell lung cancer N Engl J Med 2010 363 733 742 10.1056/NEJMoa1000678 20818875\n\n",
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"abstract": "An immunocompetent, 25-year-old gentleman with bilateral chronic uveitis presented to various uveitis clinics at different points of time with documented typical clinical features of Toxoplasma Chorioretinitis (Headlight in fog appearance), Behcet's Disease (Hypopyon with peripheral retinal vasculitis), and Presumed Ocular Tuberculosis (Granulomatous Intermediate Uveitis with positive Interferon-gamma release assay) and had been treated with anti-toxoplasma drugs, oral prednisolone, and immunomodulation with oral Mycophenolate/oral Azathioprine to no avail. After cytological examination of vitreous aspirate, he was found to have non-Langerhans cell Histiocytosis which responded to chemotherapy with Vinblastine and Cyclophosphamide.",
"affiliations": "Department of Ophthalmology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India.;Department of Ophthalmology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India.;Department of Ophthalmology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India.;Department of Pathology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India.;Department of Oncology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India.",
"authors": "Moreker|Mayur R|MR|;Dudani|Ajay I|AI|;Sharma|Tanuj R|TR|;Patel|Keyuri|K|;Smruti|B K|BK|",
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"fulltext": "\n==== Front\nIndian J Ophthalmol\nIndian J Ophthalmol\nIJO\nIndian Journal of Ophthalmology\n0301-4738 1998-3689 Wolters Kluwer - Medknow India \n\n32823479\nIJO-68-2054\n10.4103/ijo.IJO_565_20\nCase Reports\nIsolated intraocular histiocytosis—A rarely reported entity masquerading clinically as uveitis\nMoreker Mayur R Dudani Ajay I Sharma Tanuj R Patel Keyuri 1 Smruti B K 2 Department of Ophthalmology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India\n1 Department of Pathology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India\n2 Department of Oncology, Bombay Hospital Institute of Medical Sciences, Mumbai, Maharashtra, India\n\nCorrespondence to: Dr. Mayur R Moreker, 4th Floor, New Wing, Bombay Hospital, 12, New Marine Lines, Mumbai - 400 020, Maharashtra, India. E-mail: eyeinflammation@gmail.com\n9 2020 \n20 8 2020 \n68 9 2054 2056\n16 3 2020 15 4 2020 12 5 2020 Copyright: © 2020 Indian Journal of Ophthalmology2020This is an open access journal, and articles are distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 4.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as appropriate credit is given and the new creations are licensed under the identical terms.An immunocompetent, 25-year-old gentleman with bilateral chronic uveitis presented to various uveitis clinics at different points of time with documented typical clinical features of Toxoplasma Chorioretinitis (Headlight in fog appearance), Behcet's Disease (Hypopyon with peripheral retinal vasculitis), and Presumed Ocular Tuberculosis (Granulomatous Intermediate Uveitis with positive Interferon-gamma release assay) and had been treated with anti-toxoplasma drugs, oral prednisolone, and immunomodulation with oral Mycophenolate/oral Azathioprine to no avail. After cytological examination of vitreous aspirate, he was found to have non-Langerhans cell Histiocytosis which responded to chemotherapy with Vinblastine and Cyclophosphamide.\n\nIntraocular histiocytosisnon-langerhans histiocytosisuveitis masquerades\n==== Body\n”Intraocular Histiocytosis” is a very rarely reported entity; with isolated case reports in literature and masquerades as “Hypopyon Uveitis” and presents with clinical features typical of other common forms of uveitis. It may be steroid responsive; but relapsing and requires intervention and treatment with an oncologist to achieve control of disease activity.\n\nCase Report\nAn immunocompetent, 25-year-old gentleman with bilateral chronic uveitis presented to various uveitis clinics over 2 years at different points of time with typical clinical features of Toxoplasma Chorioretinitis (Headlight in fog appearance), Behcet's disease (Hypopyon with peripheral retinal vasculitis); Presumed Ocular Tuberculosis (Granulomatous intermediate uveitis with positive Interferon-gamma release assay).\n\nHe had been extensively investigated prior to presentation with us (complete blood count with Erythrocyte Sedimentation Rate, Mantoux test, Serum Angiotensin Converting Enzyme, TORCH titers, HLA B5, HLA B51, Anti-nuclear antibody, Antineutrophil cytoplasmic antibody, MRI Brain with Orbit - All inconclusive) and treated with anti-Toxoplasma drugs, oral prednisolone, and immunomodulation variously with oral Mycophenolate/oral Azathioprine to no avail.\n\nOn presentation with us; he had best corrected visual acuity of 20/20, N6 in right eye with intraocular pressure of 14 mm Hg and 20/60 in left eye with posterior subcapsular cataract and an intraocular pressure of 16 mm Hg with sloping optic nerve rims. He had vitreous cells in both eyes (left more than right) with vitritis and cystoid macular odema in the left eye. The clinical picture on presentation to us was of Intermediate Uveitis in both eyes (left eye more than right eye) and being most commensurate with presumed ocular tuberculosis (normal High-Resolution CT Scan of the Chest done as requested by us and with a previously positive Interferon-gamma release assay); treatment with anti-tuberculosis drugs (AKT) was started; with only a partial response to treatment and relapses while tapering oral Prednisolone.\n\nAfter 4 months of AKT with multiple relapses; the clinical picture changed with some relapses mimicking Ocular Toxoplasmosis [Fig. 1a and b] (Headlight in fog appearance); and a need for a vitreous biopsy was felt. Cytology smears and cell block from an undiluted vitreous sample obtained by vitreous biopsy and transported immediately to the laboratory showed Histiocyte predominance on microscopy [Fig. 1c]. These histiocytes were confirmed to be of non-Langerhans type by immunohistochemistry with CD 68 highlighting Histiocytes, and CD 1a and S - 100 protein not expressed. Microbiology sampling of the vitreous showed no organisms on microscopy (Grams Stain and KOH Mount), no growth on bacterial (Nutrient Broth) and fungal (Sabouraud Dextrose Broth) cultures. The Xpert MTB/RIF which detects DNA sequences specific for Mycobacterium tuberculosis and rifampicin resistance by polymerase chain reaction was negative.\n\nFigure 1 (a) Shows parafoveal reactivation. (b) shows peripheral reactivation while tapering treatment. (c) shows microscopy image of cytological examination of vitreous with Histiocyte predominance (Reniform nuclei and Longitudinal grooves). (d) shows resolution of disease after chemotherapy with Vinblastine\n\nPatient was screened by an oncologist who ruled out other organ involvement by a systemic clinical examination, X-Ray of the skull, cervical spine, dorsal spine, lumbosacral spine, pelvis, a Tc-MDP Bone scan, Contrast Enhanced CT Scan of the chest, abdomen and pelvis and with normal liver and renal function tests and Lactate Dehydrogenase levels. He was put on chemotherapy with injection Vinblastine over 3 months with a good response with disease activity relenting [Fig. 1d] to only 1+ vitreous cells and no vitritis in both eyes with a best corrected visual acuity of 20/20 in right eye and 20/60 in left eye with posterior subcapsular cataracts in both eyes; allowing taper of oral steroids to 2.5 mg alternate day within 6 months.\n\nIn the course of his treatment, he developed raised intraocular pressures in both eyes with associated glaucomatous disc changes in the left eye which were treated medically. Because there was no associated rise in intraocular inflammation and no peripheral anterior synechiae; this bilateral rise in intraocular pressure was considered to be induced by use of oral and topical steroids; as he had not been treated with any periocular or intraocular steroids. Six months on 2.5 mg of Prednisolone alternate day, he developed a rhegmatogenous retinal detachment with an inferotemporal horse-shoe tear in the left eye which required vitrectomy with silicon oil injection. The patient was not a myope and had no other risk factors for a retinal detachment. Within 1-month post-surgery, inflammation again became unstable in both eyes which was treated with oral steroids. In the next 8 months, he had migration of silicon oil in the anterior chamber and secondary uncontrolled intraocular pressures with a cataract in the left eye which necessitated cataract extraction with PCIOL implantation with silicon oil removal and later trabeculectomy with Mitomycin C to stabilize intraocular pressure. Further reactivations were attempted to be controlled initially with 35 mg of oral methotrexate per week as per oncologist for 10 weeks and later with pulsed IV Cyclophosphamide 750 mg. Six such pulses over 6 months achieved good control of inflammation. This was followed up with six 3-monthly pulses of IV Cyclophosphamide 750 mg with self-limiting minor peripheral reactivations.\n\nAt last follow-up; being 22 months in quiescence with 3.75 mg of oral prednisolone per day, he maintains a best corrected visual acuity of 20/20, N6 in right eye with an intraocular pressure of 10 mm Hg and CF at 3 meter in the left eye with an intraocular pressure of 10 mm Hg on combination of Timolol Maleate and Brimonidine with Brinzolamide eye drops with a visually significant posterior capsular opacification and foveal retinal thinning in addition to a glaucomatous optic nerve cupping being the cause of loss of best corrected visual acuity.\n\nDiscussion\n”Intraocular Histiocytosis” is a rare clinical entity[12] which masquerades as “Hypopyon Uveitis” and clinical features typical of other forms of uveitis.\n\nHistiocytosis in the form of either Langerhans cell histiocytosis or non-Langerhans cell histiocytosis, is characterized by histiocyte proliferation and may involve various organs and tissues. Among lesions in other organs, characterized by skin disorders, lymphadenopathy, bone lesions, hepatosplenomegaly, lung disease and central nervous system lesions; the eyeball with its adnexa may also be affected, as is the case in Juvenile Xanthogranuloma, Rosai-Dorfman disease or Letterer-Siwe disease.\n\nThis rare entity of Intraocular Histiocytosis in an isolated form without systemic disease has been reported rarely in literature. A previously reported case is of a 12-year-old girl[1] who was additionally HLA B 51 positive and had Langerhans Cell Histiocytosis (LCH) unlike our patient who was HLA B 51 negative and had non-Langerhans Cell Histiocytosis. Another patient, a 49-year-old gentleman with choroidal Langerhans cell histiocytosis and no evidence of systemic lesions has also been previously reported.[2] He had been diagnosed to have choroidal melanoma based on clinical studies and angiographic findings and underwent enucleation of his right eyeball with immunohistochemical studies including S-100 and CD 68 staining showing characteristic features of Langerhans' cell histiocytosis. In literature, the other reported patients had systemic involvement; one with hemorrhagic uveitis and systemic involvement[3] and other with unilateral anterior segment inflammation and iris nodule where the bone marrow aspirate confirmed recurrent, active LCH[4] previously called Histiocytosis X.[5] Isolated Ocular Rosai-Dorfman Disease has also been recently reported[6] to present as a solitary choroidal mass with clinical features overlapping with a Uveal Melanoma.\n\nConclusion\nThe take home message from these cases would be that knowledge of this entity is important to any ophthalmologist. Our patient requiring treatment over 8 years and his follow-up over 5 years with us emphasizes; the all-important need for an initial through review of the clinical reports of all previous treating clinicians on first presentation as the same uveitis entity may have presented to various clinics in various different clinical patterns.\n\nFurther this entity is steroid responsive but relapsing on steroid taper. Cytological examination of the vitreous sample with immunohistochemistry as a diagnostic modality is of paramount importance. Treatment by an oncologist using chemotherapeutic agents to achieve control of disease activity would help us have better visual outcomes.\n\nDeclaration of patient consent\nThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\nReceived a Travel Grant Award for presentation at 15th Annual Meet of the Uveitis Society of India, Pondicherry, 2015.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nAcknowledgements\nThe Authors wish to acknowledge Dr. Avinash Pathengay, Dr. Anita Borges, Dr. Rajul Parekh, Dr. S. N. Amin for technical help in management of the patient.\n==== Refs\n1 Sikic J Vukojevic N Popovic-Suic S Katusic D Intraocular histiocytosis in a 12-year –old girl without systemic disease Coll Antropol 2005 29 Suppl 1 119 21 16193692 \n2 Kim IT Lee SM Choroidal langerhans' cell histiocytosis Acta Ophthalmol Scand 2000 78 97 100 10726800 \n3 Sitaula RK Khatri A Langerhans cell histiocytosis with hemorrhagic uveitis and exudative retinal detachment Int Med Case Rep J 2018 11 65 8 29618940 \n4 Tsai JH Galaydh F Ching SS Anterior uveitis and iris nodules that are associated with Langerhans cell histiocytosis Am J Ophthalmol 2005 140 1143 5 16376670 \n5 Moore AT Pritchard J Taylor DS Histiocytosis X: An ophthalmological review Br J Ophthalmol 1985 69 7 14 3871158 \n6 Fogt F Rüediger T Augustin AJ Frank DM Rosenwald A Wellmann A Isolated intraocular rosai-dorfman disease Ocul Oncol Pathol 2019 5 418 23 31768365\n\n",
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"medicinalproduct": "AZATHIOPRINE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Retinal tear",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Rhegmatogenous retinal detachment",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Intraocular pressure increased",
"reactionmeddraversionpt": "23.1",
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}
],
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},
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"literaturereference": "MOREKER MR, DUDANI AI, SHARMA TR.. ISOLATED INTRAOCULAR HISTIOCYTOSIS?A RARELY REPORTED ENTITY MASQUERADING CLINICALLY AS UVEITIS. INDIAN J OPHTHALMOL. 2020?68:2054?6",
"literaturereference_normalized": "isolated intraocular histiocytosis a rarely reported entity masquerading clinically as uveitis",
"qualification": "1",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20200909",
"receivedate": "20200909",
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},
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},
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"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
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},
{
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{
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"medicinalproduct": "PREDNISOLONE."
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"activesubstancename": "AZATHIOPRINE"
},
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"medicinalproduct": "AZATHIOPRINE."
}
],
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"patientonsetage": "25",
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"reaction": [
{
"reactionmeddrapt": "Tuberculosis of eye",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Eye infection toxoplasmal",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Behcet^s syndrome",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "MOREKER M, DUDANI A, SHARMA T, PATEL K, ET.AL. ISOLATED INTRAOCULAR HISTIOCYTOSIS?A RARELY REPORTED ENTITY MASQUERADING CLINICALLY AS UVEITIS. INDIAN JOURNAL OF OPHTHALMOLOGY. 2020?68(9):2054?6",
"literaturereference_normalized": "isolated intraocular histiocytosis a rarely reported entity masquerading clinically as uveitis",
"qualification": "1",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20200922",
"receivedate": "20200922",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
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"sendertype": "2"
},
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"seriousnessother": 1,
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}
] |
{
"abstract": "OBJECTIVE\nTacrolimus is very effective at inducing remission in patients with refractory ulcerative colitis. However, the optimal time-point for the discontinuation of tacrolimus is controversial because administration of tacrolimus for > 3 months is currently not approved for insurance reimbursement in Japan. We conducted this study to determine the optimal time of discontinuation of tacrolimus in patients with ulcerative colitis.\n\n\nMETHODS\nOf 38 patients who received tacrolimus as remission induction therapy for refractory active ulcerative colitis between 2009 and 2018, this study included 21 patients who received tacrolimus for ≥ 3 months before being switched to thiopurines. These patients were divided into two groups for analysis: the confirmed switch (CS) group (n = 13), in which tacrolimus was switched to azathioprine after endoscopic confirmation of mucosal improvement, and the mandatory switch (MS) group (n = 8), in which tacrolimus was switched to a thiopurine agent without endoscopic confirmation of improvement.\n\n\nRESULTS\nThe relapse rates after the switch to azathioprine were 23% and 88% in the CS and MS groups, respectively (p = 0.0075). No patient of the CS group underwent surgery, while 50% of patients of the MS group underwent surgery (p = 0.0117). The cumulative event-free rates at 6 months, 1 year, and 2 years were 92%, 92%, and 65%, respectively, in the CS group and 15%, 15%, and 0%, respectively, in the MS group (p < 0.0001). The incidence rate of adverse reactions was 31% in the CS group and 13% in the MS group, but there were no serious adverse reactions.\n\n\nCONCLUSIONS\nIt seems preferable to discontinue tacrolimus after endoscopic confirmation of mucosal healing. However, attention should be paid to the potential occurrence of adverse reactions associated with long-term tacrolimus therapy.",
"affiliations": "Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama, 330-8503, Japan. s.w.himananon@ac.auone-net.jp.;Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama, 330-8503, Japan.;Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama, 330-8503, Japan.;Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama, 330-8503, Japan.;Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama, 330-8503, Japan.;Department of Gastroenterology, Saitama Medical Center, Jichi Medical University, 1-847 Amanuma, Omiya, Saitama, 330-8503, Japan.",
"authors": "Matsumoto|Satohiro|S|https://orcid.org/0000-0001-7802-3980;Otake|Haruka|H|;Sekine|Masanari|M|;Uehara|Takeshi|T|;Miyatani|Hiroyuki|H|;Mashima|Hirosato|H|",
"chemical_list": "D007166:Immunosuppressive Agents; D016559:Tacrolimus",
"country": "New Zealand",
"delete": false,
"doi": "10.1007/s40261-019-00795-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1173-2563",
"issue": "39(8)",
"journal": "Clinical drug investigation",
"keywords": null,
"medline_ta": "Clin Drug Investig",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D003093:Colitis, Ulcerative; D005260:Female; D006801:Humans; D007166:Immunosuppressive Agents; D007564:Japan; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction; D012720:Severity of Illness Index; D016559:Tacrolimus; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9504817",
"other_id": null,
"pages": "737-744",
"pmc": null,
"pmid": "31065933",
"pubdate": "2019-08",
"publication_types": "D016428:Journal Article",
"references": "10361877",
"title": "Appropriate Timing of Discontinuation of Tacrolimus Therapy for Refractory Ulcerative Colitis.",
"title_normalized": "appropriate timing of discontinuation of tacrolimus therapy for refractory ulcerative colitis"
} | [
{
"companynumb": "PHHY2019JP191743",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
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{
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}
],
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"reaction": [
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"reactionmeddrapt": "Cellulitis",
"reactionmeddraversionpt": "22.0",
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},
{
"reactionmeddrapt": "Product use in unapproved indication",
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}
],
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},
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},
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},
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},
{
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},
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"medicinalproduct": "PREDNISOLONE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.0",
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},
{
"reactionmeddrapt": "Device related infection",
"reactionmeddraversionpt": "22.0",
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}
],
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},
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"literaturereference": "MATSUMOTO S, OTAKE H, SEKINE M, UEHARA T, MIYATANI H, MASHIMA H. APPROPRIATE TIMING OF DISCONTINUATION OF TACROLIMUS THERAPY FOR REFRACTORY ULCERATIVE COLITIS. CLINICAL DRUG INVESTIGATION. 2019?39 (8):737-44",
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},
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}
] |
{
"abstract": "Kaposi's sarcoma (KS) is a malignant vascular tumor widely known as a complication of acquired immunodeficiency syndrome (AIDS) but also related to immunosupression in renal transplants, and less frequently, to other diseases. We describe a case of KS in a patient affected by anti-synthetase syndrome treated with steroids.",
"affiliations": "Servicio de Medicina Interna, Hospital Universitario Príncipe de Asturias, Alcalá de Henares, Madrid, España.",
"authors": "Bragado|Laura|L|;Ruiz Gutiérrez|Lucía|L|;Cuende|Eduardo|E|;López González|José Luis|JL|",
"chemical_list": "D005938:Glucocorticoids; D011241:Prednisone",
"country": "Spain",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1699-258X",
"issue": "9(4)",
"journal": "Reumatologia clinica",
"keywords": "Anti-synthetase syndrome; Corticoides; Corticosteroids; Kaposi's sarcoma; Sarcoma de Kaposi; Síndrome antisintetasa",
"medline_ta": "Reumatol Clin",
"mesh_terms": "D000368:Aged; D005938:Glucocorticoids; D006801:Humans; D008297:Male; D009220:Myositis; D011241:Prednisone; D012514:Sarcoma, Kaposi",
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"pages": "243-5",
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"pmid": "23271139",
"pubdate": "2013",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Kaposi's sarcoma in a steroid-treated antisynthethase antibody syndrome patient.",
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{
"abstract": "We investigated early outcomes for patients receiving chemotherapy followed by consolidative proton therapy (PT) for the treatment of Hodgkin lymphoma (HL).\nFrom June 2008 through August 2015, 138 patients with HL enrolled on either IRB-approved outcomes tracking protocols or registry studies received consolidative PT. Patients were excluded due to relapsed or refractory disease. Involved-site radiotherapy field designs were used for all patients. Pediatric patients received a median dose of 21 Gy(RBE) [range 15-36 Gy(RBE)]; adult patients received a median dose of 30.6 Gy(RBE) [range, 20-45 Gy(RBE)]. Patients receiving PT were young (median age, 20 years; range 6-57). Overall, 42% were pediatric (≤18 years) and 93% were under the age of 40 years. Thirty-eight percent of patients were male and 62% female. Stage distribution included 73% with I/II and 27% with III/IV disease. Patients predominantly had mediastinal involvement (96%) and bulky disease (57%), whereas 37% had B symptoms. The median follow-up was 32 months (range, 5-92 months).\nThe 3-year relapse-free survival rate was 92% for all patients; it was 96% for adults and 87% for pediatric patients (P = 0.18). When evaluated by positron emission tomography/computed tomography scan response at the end of chemotherapy, patients with a partial response had worse 3-year progression-free survival compared with other patients (78% versus 94%; P = 0.0034). No grade 3 radiation-related toxicities have occurred to date.\nConsolidative PT following standard chemotherapy in HL is primarily used in young patients with mediastinal and bulky disease. Early relapse-free survival rates are similar to those reported with photon radiation treatment, and no early grade 3 toxicities have been observed. Continued follow-up to assess late effects is critical.",
"affiliations": "Department of Radiation Oncology, University of Florida College of Medicine, Gainesville.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia.;Department of Radiation Oncology, University of Washington, Seattle.;Department of Radiation Oncology, University of Florida College of Medicine, Gainesville.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia.;Proton Collaborative Group Registry Membership Site, Warrenville.;Department of Radiation Oncology, University of Florida College of Medicine, Gainesville.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia.;Proton Collaborative Group Registry Membership Site, Warrenville.;Department of Radiation Oncology, University of Pennsylvania, Philadelphia.",
"authors": "Hoppe|B S|BS|;Hill-Kayser|C E|CE|;Tseng|Y D|YD|;Flampouri|S|S|;Elmongy|H M|HM|;Cahlon|O|O|;Mendenhall|N P|NP|;Maity|A|A|;McGee|L A|LA|;Plastaras|J P|JP|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/annonc/mdx287",
"fulltext": "\n==== Front\nAnn OncolAnn. OncolannoncAnnals of Oncology0923-75341569-8041Oxford University Press 2891109310.1093/annonc/mdx287mdx287Original ArticlesHaematologic MalignanciesConsolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma Hoppe B. S. 12Hill-Kayser C. E. 3Tseng Y. D. 456Flampouri S. 1Elmongy H. M. 3Cahlon O. 578Mendenhall N. P. 12Maity A. 3McGee L. A. 59Plastaras J. P. 3\n1 Department of Radiation Oncology, University of Florida College of Medicine, Gainesville;\n2 University of Florida Health Proton Therapy Institute, Jacksonville;\n3 Department of Radiation Oncology, University of Pennsylvania, Philadelphia;\n4 Department of Radiation Oncology, University of Washington, Seattle;\n5 Proton Collaborative Group Registry Membership Site, Warrenville;\n6 Seattle Cancer Care Alliance Proton Therapy Center, Seattle;\n7 Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York;\n8 Procure Proton Therapy Center, Somerset;\n9 Mayo Clinic, Scottsdale, USA * Correspondence to: Dr Bradford S. Hoppe, Department of Radiation Oncology, University of Florida College of Medicine, 2015 North Jefferson Street, Jacksonville, FL 32206, USA. Tel: (904) 588-1800; E-mail: bhoppe@ufl.edu.9 2017 09 8 2017 09 8 2017 28 9 2179 2184 © The Author 2017. Published by Oxford University Press on behalf of the European Society for Medical Oncology.2017This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.comAbstract\nBackground\nWe investigated early outcomes for patients receiving chemotherapy followed by consolidative proton therapy (PT) for the treatment of Hodgkin lymphoma (HL).\n\nPatients and methods\nFrom June 2008 through August 2015, 138 patients with HL enrolled on either IRB-approved outcomes tracking protocols or registry studies received consolidative PT. Patients were excluded due to relapsed or refractory disease. Involved-site radiotherapy field designs were used for all patients. Pediatric patients received a median dose of 21 Gy(RBE) [range 15–36 Gy(RBE)]; adult patients received a median dose of 30.6 Gy(RBE) [range, 20–45 Gy(RBE)]. Patients receiving PT were young (median age, 20 years; range 6–57). Overall, 42% were pediatric (≤18 years) and 93% were under the age of 40 years. Thirty-eight percent of patients were male and 62% female. Stage distribution included 73% with I/II and 27% with III/IV disease. Patients predominantly had mediastinal involvement (96%) and bulky disease (57%), whereas 37% had B symptoms. The median follow-up was 32 months (range, 5–92 months).\n\nResults\nThe 3-year relapse-free survival rate was 92% for all patients; it was 96% for adults and 87% for pediatric patients (P = 0.18). When evaluated by positron emission tomography/computed tomography scan response at the end of chemotherapy, patients with a partial response had worse 3-year progression-free survival compared with other patients (78% versus 94%; P = 0.0034). No grade 3 radiation-related toxicities have occurred to date.\n\nConclusion\nConsolidative PT following standard chemotherapy in HL is primarily used in young patients with mediastinal and bulky disease. Early relapse-free survival rates are similar to those reported with photon radiation treatment, and no early grade 3 toxicities have been observed. Continued follow-up to assess late effects is critical.\n\nHodgkin lymphomaradiotherapyproton therapychemotherapy\n==== Body\nKey Message\n\nProton therapy is predominantly used in patients with Hodgkin lymphoma that are at greatest risk of developing late toxicity. Early results demonstrate excellent relapse-free survival with a favorable acute toxicity profile including very low rates of pneumonitis. \n\n\n\n\nIntroduction\nCombination chemotherapy and radiation therapy provides the best relapse-free survival among patients with Hodgkin lymphoma (HL) [1, 2]. Unfortunately, survivors of HL are at high risk of developing late side-effects with ∼50% of survivors developing a grade 3 or higher toxicity within 30 years of treatment [3]. These late side-effects are mostly due to cardiovascular complications and secondary malignancies. \n\nA well-established linear relationship has been observed between radiation dose to most organs and subsequent toxicity. By reducing the dose, treatment volumes, or a combination of both, radiation oncologists can modify their radiation treatment to reduce late effects while maintaining the best chances of cure. Indeed, field reduction from the larger mantle field to the smaller involved-field radiation therapy (IFRT) was associated with reduced secondary breast cancer risk [4]. More recently, lower prescription radiation doses and additional field reductions with involved-node radiation therapy and involved-site radiation therapy (ISRT) have been implemented to further reduce late toxicity. \n\nAnother important approach in the reduction of radiation morbidity is the use of more conformal radiation techniques, such as intensity-modulated radiation therapy (IMRT) and proton therapy (PT). These treatments are included in the National Comprehensive Cancer Network (NCCN) guidelines for HL and non-HL and are allowed to be used on current International collaborative HL studies [Children’s Oncology Group (COG) study AHOD 1331 (NCT02166463) and Euronet-PHL-C2 (NCT02684708)].\n\nYet these newer treatments, which can help reduce the radiation dose to different organs, are more expensive and not widely available. Furthermore, concerns have been raised regarding the potential increased risk of relapse due to the steeper dose gradient.\n\nUtilizing prospective academic and community registry data, we report current patterns-of-care and early outcomes among patients with HL receiving PT.\n\nPatients and methods\nPatients diagnosed with HL and treated with chemotherapy followed by consolidative PT between June 2008 and August 2015 were prospectively enrolled on one of the following institutional review board-approved protocols: the University of Florida outcomes tracking protocol (n = 39), the University of Pennsylvania Adult or Pediatric proton registry (n = 54), or the Proton Collaborative Group (PCG) registry (n = 45). Patients were excluded if they had refractory or relapsed HL, if they received PT as a boost following photon radiation, or if they had composite HL/non-HL.\n\nBaseline patient, disease, and treatment characteristics are included in Table 1. As erythrocyte sedimentation rate and all sites of involvement were not routinely reported, risk group stratification included favorable early-stage (stage IA or IIA non-bulky), unfavorable early-stage (stage I or II with either B symptoms or bulky disease), or advanced stage (stage IIB bulky and all stage III and IV patients) disease. Positron emission tomography (PET)/computed tomography (CT) imaging to assess chemotherapy response was available for most patients (94%); however, standard reporting was not carried out across institutions. For the purpose of this study, a complete response (CR) by PET/CT scan was considered if the report stated a complete metabolic response or a Deauville 1, 2, or 3 score, while a partial response by PET/CT scan was considered if the report stated an incomplete or partial metabolic response or a Deauville 4 or 5 score at the end of chemotherapy. Immobilization and simulation techniques varied across patients and institutions. In general, motion management was carried out using four-dimensional CT planning with the creation of an internal target volume as an expansion of the clinical target volumes. Some patients underwent the deep inspiration breath-hold technique for motion management.\nTable 1. Patient, disease, and treatment characteristics (N = 138)a\n\nCharacteristic\tNo. of patients\t%\t\nSex\t\n Male\t53\t38.4\t\n Female\t85\t61.6\t\nAge (years)\t\n 5–10\t6\t4.3\t\n 11–18\t53\t38.4\t\n 19–30\t50\t36.2\t\n 31–40\t20\t14.5\t\n >40\t9\t6.5\t\nStage\t\n I\t7\t5.1\t\n II\t93\t67.4\t\n III\t21\t15.2\t\n IV\t17\t12.3\t\nB symptoms\t\n Yes\t51\t37.0\t\n No\t86\t62.3\t\n Unknown\t1\t0.7\t\nBulky disease\t\n Yes\t78\t57.4\t\n No\t58\t42.0\t\n Unknown\t2\t0.7\t\nMediastinal\t\n Yes\t132\t95.7\t\n No\t6\t4.3\t\nRisk\t\n Favorable (I/II A, non-bulky)\t41\t29.7\t\n Unfavorable (I/II with B or bulky)\t39\t28.2\t\n High (I/II B bulky, III, or IV)\t58\t42.0\t\nChemotherapy\t\n ABVDx2–3\t9\t6.5\t\n ABVDx4\t34\t24.6\t\n ABVDx5–6\t32\t22.5\t\n ABVE-PCx3–4\t39\t28.3\t\n ABVE-PCx5\t7\t5.1\t\n ABVE-PCx4 + (DECA or IV)\t6\t4.3\t\n Other\t11\t8.0\t\nPET/CT response to chemotherapy\t\n Complete response\t115\t83.3%\t\n Partial response\t15\t10.9%\t\n Not clearly defined\t8\t5.8%\t\nProton dose Gy (RBE)\t\n 15–25.9\t62\t44.9\t\n 26–30.9\t58\t42.0\t\n 31–36.9\t14\t10.1\t\n 37–45\t4\t2.9\t\na Median age for the cohort was 20 years (range 6–57 years). Pediatric patients received a median dose of 21 Gy(RBE) [range 15–36 Gy(RBE)]; adult patients received a median dose of 30.6 Gy(RBE) [range 20–45 Gy(RBE)].\n\nABVD, adriamycin, bleomycin, vinblastine, dacarbazine; ABVE-PC, adriamycin, bleomycin, vincristine sulfate, etoposide, prednisone, cyclophosphamide; DECA, dexamethasone, etoposide, cisplatin, and cytarabine; IE, ifosfamide, etoposide.\n\n\n\nPT was delivered using ISRT [5] or similar fields based on modern radiation treatment planning concepts of omission of uninvolved nodes and volumetric target delineation including INRT, with the addition of a boost to high-risk sites based on the physicians’ discretion [6, 7]. The median dose was 21 Gy(RBE) for pediatric patients [range 15–36 Gy(RBE)] and 30.6 Gy(RBE) for adult patients [range 20–45 Gy(RBE)] and was delivered with either passive-scatter (n = 64), uniform-scanning (n = 57), or pencil-beam scanning (n = 17) techniques [8]. Twenty-one patients treated with a mediastinal proton field matched to a photon neck plan at the University of Pennsylvania were included.\n\nAt each weekly on-treatment and follow-up visit, patients were assessed for radiation toxicity and disease progression using the Common Terminology Criteria for Adverse Events, version 4, in addition to a physical examination and periodic imaging. The median follow-up was 32 months (range 5–92 months). The Kaplan-Meier method was used to assess relapse-free survival from the time of diagnosis and log-rank test for univariate analysis.\n\nResults\nPatient-, disease-, and treatment-related characteristics are listed in Table 1. The median age for the cohort was 20 years (range 6–57 years); 42% and 93% were under 19 years old (pediatric) and under 40 years old adolescent/young adult (AYA), respectively. Most patients in the cohort were female (62%). Stage distribution included 73% of patients with I/II and 27% with III/IV. Patients predominantly had mediastinal involvement (96%) and bulky disease (57%), while 37% had B symptoms. Risk-group stratification as previously described included 30% favorable early-stage, 28% unfavorable early-stage disease, and 42% advanced-stage.\n\nPediatric patients were typically treated with ABVE-PC (adriamycin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide)-based chemotherapy (84%) with three to four cycles (n = 37), five cycles (n = 7), two additional cycles of DECA (dexamethasone, etoposide, cisplatin, cytarabine), or IV (ifosfamide, vinorelbine) (n = 5). Most adult patients (90%) received ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) chemotherapy for two to three cycles (n = 7), four cycles (n = 33), or five to six cycles (n = 32). Response to chemotherapy by PET/CT scan included 115 patients with a complete response, 15 patients with a partial response (PR), and 8 patients with an unknown response. Dose escalation for PR at the physician’s discretion was done for 10 of the patients, including doses up to 30–36 Gy for four patients ≤19 year old for whom the standard dose is 21 Gy, and to 36–45 Gy for six adult patients. The remaining patients who did not receive dose escalation were 3 ≤19 years old treated to 21 Gy and two adults treated to 30 Gy.\n\nThe 3-year relapse-free survival rate was 92% (Figure 1A) and by age group it was 96% for adults and 87% (P = 0.18) for pediatric patients (Figure 1B). According to risk group stratification, the 3-year relapse-free survival rates for favorable early-stage, unfavorable early-stage, and advanced-stage disease were: 97%, 88%, and 92% (P = 0.33), and by age group they were 97%, 93%, and 96% (P = 0.64) for adult patients and 100%, 83%, and 87% (P = 0.64) for pediatric patients (Figure 1C and D). When relapse-free survival was evaluated by PET/CT response to chemotherapy, patients who experienced a PR had a statistically significant higher risk of relapse compared with the patients who experienced a complete or unknown response to treatment (3-year relapse-free survival, 78% versus 94%; P = 0.0034; Figure 1E). \n\n\nFigure 1. Relapse-free survival curves for the entire cohort (A), by age group stratification (B) and by risk group stratification for (C) adults and (D) pediatrics patients and according to favorable early-stage (Fav), unfavorable early-stage (Inter), and advanced-stage (High) disease. (E) Relapse-free survival rates by positron emission tomography/computed tomography response to chemotherapy. CR, complete response; PR, partial response.\n\nTen recurrences developed, including six in-field, one in-field and out-of-field, and three out-of-field in immediately adjacent nodal regions. Six of the seven recurrences (86%) with an in-field component developed in pediatric patients treated to <30 Gy(RBE), including two with a PR treated to 21 Gy. All in-field recurrences occurred in the middle of the radiation field. There were no marginal recurrences at the edge of the proton field that could be attributed to proton range uncertainties. The three out-of-field recurrences developed immediately inferiorly or superior to the ISRT-defined PTV, including in two patients without prechemotherapy PET/CT imaging previously described [9]. \n\nNo grade 3 toxicities were observed during follow-up among the patients in our cohort. Grade 1 and 2 toxicities are reported in Table 2 and separated by institution. No clinically meaningful pneumonitis was reported in the cohort.\nTable 2. Grade 1 and 2 toxicity reporting according to institution\n\n\tUF (n = 39)\tPCG (n = 45)\tUP (n = 54)\t\nToxicity\tGrade1\tGrade 2\tGrade 1\tGrade 2\tGrade 1\tGrade 2\t\nAnorexia\t5\t1\t2\t2\t9\t1\t\nAnxiety/depression/agitation\t14\t1\t\t\t5\t0\t\nConstipation\t\t\t1\t0\t11\t0\t\nCough\t27\t1\t11\t0\t15\t1\t\nDiarrhea\t\t\t1\t0\t2\t0\t\nDry Mouth\t17\t1\t1\t0\t9\t0\t\nDyspepsia\t\t\t2\t2\t9\t0\t\nDyspnea\t19\t0\t\t\t11\t0\t\nEsophagitis\t21\t7\t14\t8\t13\t10\t\nFatigue\t27\t4\t11\t1\t30\t2\t\nHoarseness\t\t\t11\t0\t5\t0\t\nHypothyroidism\t0\t3\t\t\t\t\t\nMucositis\t\t\t\t\t2\t0\t\nNausea\t13\t3\t3\t0\t13\t1\t\nPain\t18\t1\t4\t0\t\t\t\nPerformance status\t7\t1\t\t\t\t\t\nPulmonary (fibrosis/pneumonitis/effusion)\t6\t0\t\t\t0\t0\t\nRadiation dermatitis\t33\t2\t34\t3\t28\t3\t\nVomiting\t6\t2\t\t\t2\t0\t\nPCG, Proton Collaborative Group; UF, University of Florida; UP, University of Pennsylvania.\n\n\n\nDiscussion\nThe present study is the first proton outcomes study to merge data from three separate IRB-approved registry studies and demonstrates the feasibility and benefits of collaborating to attain a meaningful number of patients with HL managed with PT. Collaboration among proton centers has been encouraged by the American Society for Radiation Oncology (ASTRO) in their Model Policy on PT in order to facilitate evidence development for using proton therapy. Furthermore, the importance of this collaborative effort is even more impressive based on a recent National Cancer Database (NCDB) study that reported on radiation techniques utilized for patients with HL; only 40 patients were treated with PT, which was considered too small a number to report outcomes [10].\n\nIn the present study, most patients who received PT for HL as part of first-line therapy were those with the highest risk of developing late toxicities, including younger patients with longer life expectancies in survivorship, female patients with a higher risk of developing a second cancer because of the breast cancer risk, and patients with bulky mediastinal disease adjacent to the lung, heart, and breasts. Although difficult to compare due to differences in data collection between studies, the results contrast with findings from a patterns-of-care analysis from the NCDB, which evaluated the use of three-dimensional (3D) conformal radiation therapy (CRT) and IMRT [10]. IMRT was predominantly used among older patients (>40 years old, 55%), males (59%), and those with head-and-neck involvement compared with patients with mediastinal disease (38% versus 13%, respectively) [10]. Compared with IMRT, 3D-CRT was more commonly delivered to females (48% versus 41%), patients stage III/IV disease (15% versus 8%), and to the mediastinum/chest (30% versus 13%). The difference in patterns of care may be due to the concern of a low-dose radiation bath from IMRT, which can increase the risk of second cancers in younger female patients with mediastinal disease or, alternatively, increased insurance coverage for head and neck sites for salivary gland sparing [11].\n\nThe predominant use of PT for mediastinal involvement is not surprising considering the thirteen published dosimetric studies, including a prospective clinical trial, evaluating the use of PT in HL. These studies have demonstrated the potential dose reduction to the heart, lung, breast, and esophagus among patients with mediastinal disease compared with either CRT or IMRT [12–15] and the consistent reduction in integral dose (whole-body radiation exposure) by 40%–50% with PT [13]. Although, the magnitude of benefit in some patients might be low for the difference in dose to the organs, the integral dose (whole body exposure) is always substantially reduced in all patients (40%–50%). Consequently, when following the ALARA (as low as reasonably achievable) principle, PT would be the treatment of choice, especially in young adult, adolescent, and pediatric patients. Data have emerged over the last two decades that a radiation dose–response relationship exists between mean doses to the heart and coronary heart disease [16] and valvular disease [17] in survivors of HL. Furthermore, similar associations of radiation dose to the lungs, breast, and body and risk of lung cancer, breast cancer, and sarcomas have been demonstrated [18]. Although these rates are expected to fall, owing to smaller radiation treatment fields and lower prescription doses, PT has the potential to further reduce these risks. Importantly, these dose reductions are expected to lower the risk of second cancers and cardiovascular complications, which translates into an overall survival advantage with PT over volumetric arc therapy or 3D CRT [19].\n\nAlthough these results are preliminary, they represent excellent 3-year outcomes, especially considering most patients (70%) had unfavorable early-stage or advanced-stage disease. Despite the adverse risk factors in our cohort of PT patients (i.e. risk group, PET/CT response, bulky disease, and B symptoms), our results compare favorably to the only three published clinical outcomes studies of IMRT for Hodgkin lymphoma, which altogether comprise 140 patients treated with IMRT [20–22]. A post-chemotherapy partial response on PET/CT was associated with inferior outcomes, notwithstanding consolidation with PT. Finally, although the worse relapse free-survival was among these partial responders, many remained in remission following PT and avoided salvage regimens and stem cell transplant, and their associated toxicities.\n\nThe predominant pattern of failure in this study was in-field recurrences after lower doses of radiation [<30 Gy(RBE)]. Similar patterns of recurrence have been reported by the Children’s Oncology Group for pediatric HL treated to 21 Gy, in which >85% of relapses occurred with an in-field component [23]. Importantly, neither marginal relapses attributed to the dramatic dose fall-off observed with PT nor end-of-range uncertainty was observed, confirming the effectiveness of PT in consolidation after chemotherapy in HL. In this study, marginal relapses were more likely owing to inadequate radiation field design, which has been reported in radiation quality assessments in clinical trials [24]. Although modern radiation fields utilizing ISRT concepts were used in the study, we could not evaluate the quality of target volumes (since they were either too big or too small) for most patients because of the lack of baseline PET/CT imaging data, which is a limitation of the study.\n\nNo acute grade 3 toxicities were observed during follow-up among the patients in our cohort. This finding is not surprising given the rarity of acute grade 3 radiation-related toxicities with the relatively low dose of radiation used in HL. While grade 2 esophagitis is to be expected, the lack of any grade 2 pneumonitis was surprising given the 7% rate of grade 3 pneumonitis (using the RTOG scale) reported by investigators at MD Anderson Cancer Center (Houston, TX) among mediastinal lymphoma patients receiving IMRT [25]. Their group determined that the strongest predictor for pneumonitis was >55% of the lung receiving 5 Gy or more (V5); thus, the absence of a low-dose proton bath may mitigate the risk of clinically meaningful pneumonitis. Overall, the lack of clinically significant toxicity in this proton cohort is encouraging.\n\nNo late grade 3 toxicities developed in the cohort, which is unsurprising given the decades of follow-up needed to observe significant late toxicities, such as cardiac morbidity and secondary cancers. Although the present study is unable to provide evidence for reducing late toxicity from treatment, investigators at Massachusetts General Hospital (MGH; Boston, MA) reported on development of second cancers after PT [26]. In their study, patients treated at MGH with PT were matched to similar patients from the Surveillance, Epidemiology, and End Results (SEER) registry treated with photon radiation. Compared with patients treated with photons, there was a 50% reduction in second cancers among those treated with PT at MGH (HR 0.52; 95% CI 0.32–0.85; P = 0.009). This finding suggests that the reduction in integral dose allowed by PT translates into a clinically meaningful difference in second cancer reduction.\n\nThe present study is subject to the weaknesses of any observational study. Treatment techniques, including chemotherapy regimen, PT technique, and motion management strategies were not standardized across the cohort; nevertheless, such heterogeneity can also be considered a strength as it makes the study more pragmatic and demonstrates the feasibility of delivering PT safely and effectively across different institutions, including community and academic hospitals. A strength of the present collaboration was our ability to extract additional relevant data, such as post-chemotherapy PET/CT response, bulky disease, and patterns of relapse, with respect to radiation treatment field, which cannot be done with other larger cancer registries (SEER, NCDB).\n\nIn conclusion, PT is predominantly used in patients with HL that are at greatest risk of developing late toxicity, including young patients, female patients, and those with mediastinal involvement. Early results with PT demonstrate excellent relapse-free survival with a favorable acute toxicity profile including very low rates of pneumonitis. These results are encouraging and support continued treatment of patients with HL with PT in a registry setting, which permits long-term follow-up and potential confirmation of decreased late toxicity.\n\nAcknowledgements\nWe would like to thank Jessica Kirwan and Judy Tran for assisting with editing and preparing the manuscript for submission, Robin Toton for coordinating the research project, and the Particle Therapy Cooperative Group lymphoma subcommittee for assistance in the collaboration.\n\nFunding\nNone declared.\n\nDisclosure\nThe authors have declared no conflicts of interest.\n==== Refs\nReferences\n1 \nWolden SL , Chen L , Kelly KM \n\nLong-term results of CCG 5942: a randomized comparison of chemotherapy with and without radiotherapy for children with Hodgkin's lymphoma—a report from the Children's Oncology Group . J Clin Oncol 2012 ; 30 : 3174 –3180 .22649136 \n2 \nRaemaekers JM , Andre MP , Federico M \n\nOmitting radiotherapy in early positron emission tomography-negative stage I/II Hodgkin lymphoma is associated with an increased risk of early relapse: clinical results of the preplanned interim analysis of the randomized EORTC/LYSA/FIL H10 trial . J Clin Oncol 2014 ; 32 : 1188 –1194 .24637998 \n3 \nOeffinger KC , Mertens AC , Sklar CA \n\nChronic health conditions in adult survivors of childhood cancer . N Engl J Med 2006 ; 355 : 1572 –1582 .17035650 \n4 \nConway JL , Connors JM , Tyldesley S \n\nSecondary breast cancer risk by radiation volume in women with Hodgkin lymphoma . Int J Radiat Oncol Biol Phys 2017 ; 97 : 35 –41 .27979454 \n5 \nSpecht L , Yahalom J , Illidge T \n\nModern radiation therapy for Hodgkin lymphoma: field and dose guidelines from the international lymphoma radiation oncology group (ILROG) . Int J Radiat Oncol Biol Phys 2014 ; 89 : 854 –862 .23790512 \n6 \nGirinsky T , van der Maazen R , Specht L \n\nInvolved-node radiotherapy (INRT) in patients with early Hodgkin lymphoma: concepts and guidelines . Radiother Oncol 2006 ; 79 : 270 –277 .16797755 \n7 \nHoppe RT. \nHodgkin lymphoma In Halperin EC , Wazer DE , Perez CA , Brady LW (eds), Principles and Practice of Radiation Oncology , 6th edition. Edition Philadelphia, PA : \nLippincott Williams & Wilkins 2008 ; 1717 –1738 .\n8 \nZeng C , Plastaras JP , James P \n\nProton pencil beam scanning for mediastinal lymphoma: treatment planning and robustness assessment . Acta Oncol 2016 ; 55 : 1 –7 .\n9 \nFigura N , Flampouri S , Mendenhall NP \n\nImportance of baseline PET/CT imaging on radiation field design and relapse rates in patients with Hodgkin lymphoma . Adv Radiat Oncol 2017 ; 2 : 197 –203 .28740932 \n10 \nParikh RR , Grossbard ML , Harrison LB , Yahalom J. \nAssociation of intensity-modulated radiation therapy on overall survival for patients with Hodgkin lymphoma . Radiother Oncol 2016 ; 118 : 52 –59 .26522061 \n11 \nWeber DC , Johanson S , Peguret N \n\nPredicted risk of radiation-induced cancers after involved field and involved node radiotherapy with or without intensity modulation for early-stage Hodgkin lymphoma in female patients . Int J Radiat Oncol Biol Phys 2011 ; 81 : 490 –497 .20800383 \n12 \nMaraldo MV , Specht L. \nA decade of comparative dose planning studies for early-stage Hodgkin lymphoma: what can we learn? \nInt J Radiat Oncol Biol Phys \n2014 ; 90 : 1126 –1135 .25539371 \n13 \nHoppe BS , Flampouri S , Zaiden R \n\nInvolved-node proton therapy in combined modality therapy for Hodgkin lymphoma: results of a phase 2 study . Int J Radiat Oncol Biol Phys 2014 ; 89 : 1053 –1059 .24928256 \n14 \nHoppe BS , Flampouri S , Su Z \n\nConsolidative involved-node proton therapy for stage IA-IIIB mediastinal Hodgkin lymphoma: preliminary dosimetric outcomes from a phase II study . Int J Radiat Oncol Biol Phys 2012 ; 83 : 260 –267 .22014950 \n15 \nTseng YD , Cutter DJ , Plastara JP \n\nEvidence-based review on the utilization of proton therapy in lymphoma from the Particle Therapy Cooperative Group Lymphoma Subcommittee . Int J Rad Oncol Biol Phys 2017 .\n16 \nvan Nimwegen FA , Schaapveld M , Cutter DJ \n\nRadiation dose–response relationship for risk of coronary heart disease in survivors of Hodgkin lymphoma . J Clin Oncol 2016 ; 34 : 235 –243 .26573075 \n17 \nCutter DJ , Schaapveld M , Darby SC \n\nRisk of valvular heart disease after treatment for Hodgkin lymphoma . J Natl Cancer Inst 2015 ; 107 : djv008 .25713164 \n18 \nInskip PD , Sigurdson AJ , Veiga L \n\nRadiation-related new primary solid cancers in the childhood cancer survivor study: comparative radiation dose response and modification of treatment effects . Int J Radiat Oncol Biol Phys 2016 ; 94 : 800 –807 .26972653 \n19 \nMaraldo MV , Brodin NP , Aznar MC \n\nEstimated risk of cardiovascular disease and secondary cancers with modern highly conformal radiotherapy for early-stage mediastinal Hodgkin lymphoma . Ann Oncol 2013 ; 24 : 2113 –2118 .23619032 \n20 \nFilippi AR , Ciammella P , Piva C \n\nInvolved-site image-guided intensity modulated versus 3D conformal radiation therapy in early stage supradiaphragmatic Hodgkin lymphoma . Int J Radiat Oncol Biol Phys 2014 ; 89 : 370 –375 .24613810 \n21 \nLu NN , Li YX , Wu RY \n\nDosimetric and clinical outcomes of involved-field intensity-modulated radiotherapy after chemotherapy for early-stage Hodgkin's lymphoma with mediastinal involvement . Int J Radiat Oncol Biol Phys 2012 ; 84 : 210 –216 .22436783 \n22 \nPaumier A , Khodari W , Beaudre A \n\n[Intensity-modulated radiotherapy and involved-node concept in patients with Hodgkin lymphoma: experience of the Gustave-Roussy Institute] . Cancer Radiother 2011 ; 15 : 709 –715 .22116023 \n23 \nDharmarajan KV , Friedman DL , Schwartz CL \n\nPatterns of relapse from a phase 3 Study of response-based therapy for intermediate-risk Hodgkin lymphoma (AHOD0031): a report from the Children's Oncology Group . Int J Radiat Oncol Biol Phys 2015 ; 92 : 60 –66 .25542311 \n24 \nKriz J , Baues C , Engenhart-Cabillic R \n\nQuality control of involved field radiotherapy in the HD 13 and HD 14 trials: report of the radiotherapy panel of the German Hodgkin Study Group (GHSG) . Strahlenther Onkol 2017 ; 193 : 109 –115 .27596217 \n25 \nPinnix CC , Smith GL , Milgrom S \n\nPredictors of radiation pneumonitis in patients receiving intensity modulated radiation therapy for Hodgkin and non-Hodgkin lymphoma . Int J Radiat Oncol Biol Phys 2015 ; 92 : 175 –182 .25863764 \n26 \nChung CS , Yock TI , Nelson K \n\nIncidence of second malignancies among patients treated with proton versus photon radiation . Int J Radiat Oncol Biol Phys 2013 ; 87 : 46 –52 .23778197\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0923-7534",
"issue": "28(9)",
"journal": "Annals of oncology : official journal of the European Society for Medical Oncology",
"keywords": "Hodgkin lymphoma; chemotherapy; proton therapy; radiotherapy",
"medline_ta": "Ann Oncol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D059248:Chemoradiotherapy; D002648:Child; D005260:Female; D006689:Hodgkin Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D064847:Multimodal Imaging; D049268:Positron-Emission Tomography; D061766:Proton Therapy; D014057:Tomography, X-Ray Computed; D055815:Young Adult",
"nlm_unique_id": "9007735",
"other_id": null,
"pages": "2179-2184",
"pmc": null,
"pmid": "28911093",
"pubdate": "2017-09-01",
"publication_types": "D016428:Journal Article",
"references": "26573075;26522061;28740932;22014950;20800383;27979454;24637998;25539371;23790512;27596217;22116023;16797755;25713164;17035650;28943076;22649136;22436783;23778197;23619032;25863764;24928256;26972653;25542311;24613810;27332881",
"title": "Consolidative proton therapy after chemotherapy for patients with Hodgkin lymphoma.",
"title_normalized": "consolidative proton therapy after chemotherapy for patients with hodgkin lymphoma"
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"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HODGKIN^S DISEASE",
"drugintervaldosagedefinition": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ETOPOSIDE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
"drugenddate": null,
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"drugindication": "HODGKIN^S DISEASE",
"drugintervaldosagedefinition": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "IFOSFAMIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"medicinalproduct": "IFOSFAMIDE."
}
],
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"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hypothyroidism",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Mucosal inflammation",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Agitation",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dyspnoea",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Oesophagitis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pulmonary fibrosis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "General physical health deterioration",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Anxiety",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Constipation",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cough",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dyspepsia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dysphonia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pleural effusion",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Depression",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumonitis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Decreased appetite",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dry mouth",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pain",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HOPPE BS, HILL-KAYSER CE, TSENG YD, FLAMPOURI S, ELMONGY HM, CAHLON O, ET AL. CONSOLIDATIVE PROTON THERAPY AFTER CHEMOTHERAPY FOR PATIENTS WITH HODGKIN LYMPHOMA. ANNALS OF ONCOLOGY 2017;28 (9):2179-2184.",
"literaturereference_normalized": "consolidative proton therapy after chemotherapy for patients with hodgkin lymphoma",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20171017",
"receivedate": "20171017",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14098334,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180321"
}
] |
{
"abstract": "OBJECTIVE\nDirect acting antivirals (DAA) are extremely effective to treat chronic hepatitis C. The aim of this study was to evaluate, by using objective variables, the safety of DAA combinations under clinical practice conditions.\n\n\nMETHODS\nA retrospective study was carried out in mono-infected patients with chronic hepatitis C treated with DAA between January and December 2015 in our centre. Discontinuations, treatment modifications, deaths and laboratory parameters were studied (liver function tests, hemoglobin, creatinine and lipid profile at baseline, weeks 4, 8 and post 12). Temporal variation of laboratory parameters was analyzed by t-test for paired data, and comparison between groups was made by t-test for independent samples and ANOVA.\n\n\nRESULTS\n227 patients were included (40.5% cirrhotic). Sustained virological response (SVR) was achieved in 97.3% of patients. In only one case was the antiviral medication suspended due to toxicity, and there were no voluntary treatment discontinuations. The use of ribavirin (RBV) was associated with mild transient hyperbilirubinemia (41.2%) and anemia (32.6%, with RBV dose reduction in 7.9% of cases). There was an elevation in total cholesterol and LDL-cholesterol (LDL-C) during and after treatment: mean increase of 23 mg/dL (0.59 mmol/L) and 22 mg/dL (0.57 mmol/L), respectively in post 12 (p < .0001). An increment of 20% of patients with cholesterol levels over optimal figures was observed after DAA completion.\n\n\nCONCLUSIONS\nDAA have an optimum safety profile in real life conditions, with infrequent discontinuation and minor laboratory alterations.",
"affiliations": "a Department of Pharmacy , Complejo Hospitalario de Navarra , Pamplona , Spain.;d Liver Unit, Department of Gastroenterology , Complejo Hospitalario de Navarra , Pamplona , Spain.;c Instituto de Investigación Sanitaria de Navarra (IdiSNA) , Pamplona , Spain.;d Liver Unit, Department of Gastroenterology , Complejo Hospitalario de Navarra , Pamplona , Spain.;c Instituto de Investigación Sanitaria de Navarra (IdiSNA) , Pamplona , Spain.;c Instituto de Investigación Sanitaria de Navarra (IdiSNA) , Pamplona , Spain.;b CIBER Epidemiología y Salud Pública (CIBERESP) , Madrid , Spain.;a Department of Pharmacy , Complejo Hospitalario de Navarra , Pamplona , Spain.",
"authors": "Juanbeltz|Regina|R|;Goñi Esarte|Silvia|S|;Úriz-Otano|Juan Isidro|JI|;Martínez Echeverría|Ana|A|;Elizalde|Inmaculada|I|;Zozaya|José Manuel|JM|;Castilla|Jesús|J|;San Miguel|Ramón|R|",
"chemical_list": "D000998:Antiviral Agents; D004338:Drug Combinations",
"country": "England",
"delete": false,
"doi": "10.1080/00325481.2017.1311197",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0032-5481",
"issue": "129(4)",
"journal": "Postgraduate medicine",
"keywords": "Antiviral agents; cholesterol; chronic hepatitis C; direct acting antiviral; drug monitoring; drug safety; ribavirin",
"medline_ta": "Postgrad Med",
"mesh_terms": "D000284:Administration, Oral; D000998:Antiviral Agents; D004338:Drug Combinations; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005260:Female; D005838:Genotype; D019698:Hepatitis C, Chronic; D006801:Humans; D008103:Liver Cirrhosis; D008111:Liver Function Tests; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013030:Spain; D016896:Treatment Outcome",
"nlm_unique_id": "0401147",
"other_id": null,
"pages": "476-483",
"pmc": null,
"pmid": "28343408",
"pubdate": "2017-05",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Safety of oral direct acting antiviral regimens for chronic hepatitis C in real life conditions.",
"title_normalized": "safety of oral direct acting antiviral regimens for chronic hepatitis c in real life conditions"
} | [
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"activesubstance": {
"activesubstancename": "LEDIPASVIR\\SOFOSBUVIR"
},
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"drugindication": "CHRONIC HEPATITIS C",
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}
],
"patientagegroup": "5",
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"reaction": [
{
"reactionmeddrapt": "Nephrotic syndrome",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "JUANBELTZ R., ET AL. SAFETY OF ORAL DIRECT ACTING ANTIVIRAL REGIMENS FOR CHRONIC HEPATITIS C IN REAL LIFE CONDITIONS. POSTGRADUATE MEDICINE. 2017;UNK:UNK",
"literaturereference_normalized": "safety of oral direct acting antiviral regimens for chronic hepatitis c in real life conditions",
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},
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},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
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},
{
"companynumb": "ES-GILEAD-2017-0273592",
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],
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"reaction": [
{
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"reactionmeddraversionpt": "20.0",
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},
{
"reactionmeddrapt": "Drug ineffective",
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}
],
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},
"primarysource": {
"literaturereference": "JUANBELTZ R., ET AL. SAFETY OF ORAL DIRECT ACTING ANTIVIRAL REGIMENS FOR CHRONIC HEPATITIS C IN REAL LIFE CONDITIONS. POSTGRADUATE MEDICINE. 2017;UNK:UNK",
"literaturereference_normalized": "safety of oral direct acting antiviral regimens for chronic hepatitis c in real life conditions",
"qualification": "2",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20170613",
"receivedate": "20170613",
"receiver": {
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},
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"safetyreportid": 13647627,
"safetyreportversion": 1,
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},
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"transmissiondate": "20170830"
},
{
"companynumb": "ES-GILEAD-2017-0273593",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "JUANBELTZ R., ET AL. SAFETY OF ORAL DIRECT ACTING ANTIVIRAL REGIMENS FOR CHRONIC HEPATITIS C IN REAL LIFE CONDITIONS. POSTGRADUATE MEDICINE. 2017;UNK:UNK",
"literaturereference_normalized": "safety of oral direct acting antiviral regimens for chronic hepatitis c in real life conditions",
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"reportercountry": "ES"
},
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},
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"sendertype": "2"
},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170830"
},
{
"companynumb": "ES-GILEAD-2017-0273594",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
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{
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"activesubstance": {
"activesubstancename": "LEDIPASVIR\\SOFOSBUVIR"
},
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}
],
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"reactionoutcome": "5"
},
{
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"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "JUANBELTZ R., ET AL. SAFETY OF ORAL DIRECT ACTING ANTIVIRAL REGIMENS FOR CHRONIC HEPATITIS C IN REAL LIFE CONDITIONS. POSTGRADUATE MEDICINE. 2017;UNK:UNK",
"literaturereference_normalized": "safety of oral direct acting antiviral regimens for chronic hepatitis c in real life conditions",
"qualification": "2",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20170613",
"receivedate": "20170613",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 13647660,
"safetyreportversion": 1,
"sender": {
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},
"serious": 1,
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"seriousnessother": 1,
"transmissiondate": "20170830"
}
] |
{
"abstract": "We report a case of a 24-year-old liver transplant recipient who developed hepatic artery thrombosis and graft failure, which was complicated by subphrenic abscess and persistent Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae bacteremia. Ceftazidime-avibactam treatment led to emergence of resistance, and alternative combination therapy failed due to persistent infection and toxicity. The infection resolved after initiation of meropenem-vaborbactam, which created a bridge to retransplantation. Treatment-emergent ceftazidime-avibactam resistance is increasingly recognized, suggesting a role for meropenem-vaborbactam.",
"affiliations": "Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio, USA Vasilios.Athans@uphs.upenn.edu ajm5b@virginia.edu.;Department of Pharmacy, Cleveland Clinic, Cleveland, Ohio, USA.;Department of Infectious Diseases, Cleveland Clinic, Cleveland, Ohio, USA.;Department of Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio, USA.;Department of Laboratory Medicine, Cleveland Clinic, Cleveland, Ohio, USA.;JMI Laboratories, North Liberty, Iowa, USA.;Department of Infectious Diseases, Cleveland Clinic, Cleveland, Ohio, USA.;Division of Infectious Disease and International Health, Department of Medicine, University of Virginia Health System, Charlottesville, Virginia, USA Vasilios.Athans@uphs.upenn.edu ajm5b@virginia.edu.",
"authors": "Athans|Vasilios|V|;Neuner|Elizabeth A|EA|;Hassouna|Habiba|H|;Richter|Sandra S|SS|;Keller|George|G|;Castanheira|Mariana|M|;Brizendine|Kyle D|KD|;Mathers|Amy J|AJ|",
"chemical_list": "D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D001897:Boronic Acids; D004338:Drug Combinations; D006573:Heterocyclic Compounds, 1-Ring; C000595613:avibactam, ceftazidime drug combination; C000654127:meropenem and vaborbactam; D002442:Ceftazidime; D001618:beta-Lactamases; C063912:carbapenemase; D000077731:Meropenem",
"country": "United States",
"delete": false,
"doi": "10.1128/AAC.01551-18",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0066-4804",
"issue": "63(1)",
"journal": "Antimicrobial agents and chemotherapy",
"keywords": "Klebsiella pneumoniae carbapenemase; carbapenem-resistant Enterobacteriaceae\n; carbapenemase-producing Klebsiella pneumoniae\n; ceftazidime-avibactam; meropenem-vaborbactam",
"medline_ta": "Antimicrob Agents Chemother",
"mesh_terms": "D000900:Anti-Bacterial Agents; D053961:Azabicyclo Compounds; D016470:Bacteremia; D001425:Bacterial Outer Membrane Proteins; D001426:Bacterial Proteins; D001897:Boronic Acids; D000073182:Carbapenem-Resistant Enterobacteriaceae; D002442:Ceftazidime; D004338:Drug Combinations; D024901:Drug Resistance, Multiple, Bacterial; D006499:Hepatic Artery; D006573:Heterocyclic Compounds, 1-Ring; D006801:Humans; D007710:Klebsiella Infections; D007711:Klebsiella pneumoniae; D016031:Liver Transplantation; D008297:Male; D000077731:Meropenem; D008826:Microbial Sensitivity Tests; D016879:Salvage Therapy; D013927:Thrombosis; D055815:Young Adult; D001618:beta-Lactamases",
"nlm_unique_id": "0315061",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "30578403",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19506063;27313268;29089425;28461318;23290507;29456043;29377998;25900159;29507064;29263067;28031201;28223379;25957381;29510189;23221186;24514083;27624958;29038260;27107460;29566151;29020404;29486041",
"title": "Meropenem-Vaborbactam as Salvage Therapy for Ceftazidime-Avibactam-Resistant Klebsiella pneumoniae Bacteremia and Abscess in a Liver Transplant Recipient.",
"title_normalized": "meropenem vaborbactam as salvage therapy for ceftazidime avibactam resistant klebsiella pneumoniae bacteremia and abscess in a liver transplant recipient"
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{
"abstract": "Sphincter of Oddi spasm from opioids has been documented, presenting as severe epigastric pain and potentially overlooked in a differential diagnosis. We present a case of sphincter of Oddi spasm from periarticular morphine in a patient under spinal anesthesia, causing severe distress and treated effectively with glucagon. It is important for anesthesiologists using opioids to consider it as a cause of perioperative pain and be familiar with treatment as it may be refractory by conventional use of opioids for pain relief. It is also important to consider the systemic effects of periarticular absorption, as evident by our case.",
"affiliations": "From the Department of Anesthesiology and Perioperative Medicine, Queen's University, Kingston General Hospital, Kingston, Ontario, Canada.",
"authors": "Koumpan|Yuri|Y|;Engen|Dale|D|;Tanzola|Robert|R|;Saha|Tarit|T|",
"chemical_list": "D000701:Analgesics, Opioid; D009020:Morphine",
"country": "United States",
"delete": false,
"doi": "10.1213/XAA.0000000000000372",
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"issn_linking": "2325-7237",
"issue": "7(7)",
"journal": "A & A case reports",
"keywords": null,
"medline_ta": "A A Case Rep",
"mesh_terms": "D000368:Aged; D000701:Analgesics, Opioid; D000775:Anesthesia, Spinal; D001919:Bradycardia; D002358:Cartilage, Articular; D005260:Female; D006801:Humans; D009020:Morphine; D010146:Pain; D012720:Severity of Illness Index; D013035:Spasm; D009803:Sphincter of Oddi",
"nlm_unique_id": "101637720",
"other_id": null,
"pages": "152-4",
"pmc": null,
"pmid": "27513967",
"pubdate": "2016-10-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Periarticular Morphine-Induced Sphincter of Oddi Spasm Causing Severe Pain and Bradycardia in an Awake Patient Under Spinal Anesthesia: An Important Diagnostic Consideration.",
"title_normalized": "periarticular morphine induced sphincter of oddi spasm causing severe pain and bradycardia in an awake patient under spinal anesthesia an important diagnostic consideration"
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},
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},
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] |
{
"abstract": "5-fluorouracil (5-FU) is an important component of chemotherapy for metastatic colon cancer and can be administered as an intravenous infusion or bolus. Coronary vasospasm is a known complication of infusional and bolus 5-FU administration. In patients who experience coronary vasospasm, 5-FU is often discontinued. Several cases of successful re-challenge with bolus 5-FU, utilizing calcium channel blockers (CCBs) and nitrates to prophylaxis against coronary vasospasm recurrence, have been reported in the literature. However, since there is increased variability of time to symptom onset with infusional 5-FU, re-challenge with infusional 5-FU has not been widely studied. Given potential differences in the toxicity profile and exposure time, infusional may be more appropriate than bolus for some patients. Here we report successful re-challenge with infusional 5-FU, following coronary vasospasm during the first cycle of 5-FU plus leucovorin plus oxaliplatin chemotherapy, in a patient with metastatic colon cancer and coronary artery disease (CAD). The 5-FU re-challenge plan included dose reduction, CCB and nitrate prophylaxis, and telemetry monitoring.",
"affiliations": "Genitourinary Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Department of Medicine, Inova Fairfax Medical Campus, Falls Church, VA, USA.;Cardiology Consult Service, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.;Cardiology Consult Service, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA.;Genitourinary Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Genitourinary Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Genitourinary Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Genitourinary Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.;Genitourinary Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.",
"authors": "Redman|Jason M|JM|;Rhea|Logan P|LP|;Brofferio|Alessandra|A|;Whelpley|Margaret|M|;Gulley|James L|JL|;Gatti-Mays|Margaret E|ME|;McMahon|Sheri|S|;Cordes|Lisa M|LM|;Strauss|Julius|J|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.21037/jgo.2019.07.04",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2078-6891",
"issue": "10(5)",
"journal": "Journal of gastrointestinal oncology",
"keywords": "5-fluorouracil (5-FU); 5-fluorouracil rechallenge (5-FU rechallenge); FOLFOX; coronary vasospasm; metastatic colon cancer",
"medline_ta": "J Gastrointest Oncol",
"mesh_terms": null,
"nlm_unique_id": "101557751",
"other_id": null,
"pages": "1010-1014",
"pmc": null,
"pmid": "31602339",
"pubdate": "2019-10",
"publication_types": "D002363:Case Reports",
"references": "15855175;14665611;8391384;9440757;14657227;17636329;2278719;12070449;9807986;2466960;15939922;25870182;12775730;23582737;26701613;15033676;10623704;30396850;9704726;29299356;9053508;27113369;23042307;22939579",
"title": "Successful 5-fluorouracil (5-FU) infusion re-challenge in a metastatic colorectal cancer patient with coronary artery disease who experienced symptoms consistent with coronary vasospasm during first 5-FU infusion.",
"title_normalized": "successful 5 fluorouracil 5 fu infusion re challenge in a metastatic colorectal cancer patient with coronary artery disease who experienced symptoms consistent with coronary vasospasm during first 5 fu infusion"
} | [
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{
"abstract": "Graft-versus-host disease (GVHD) of the central nervous system is a rare complication following allogeneic haematopoietic stem cell transplant (HSCT). It is a challenging disease process to confirm as biopsies of the involved tissues can be difficult to obtain safely, the clinical presentation can be non-specific and the differential diagnosis includes infection, drug toxicities, metabolic encephalopathy and disease relapse. We report a case of meningeal graft-versus-host disease in a young woman with relapsed acute myeloid leukaemia after a sibling allogeneic HSCT. The GVHD responded to immunosuppression with resolution of the clinical symptoms and radiological findings and has remained quiescent after a second allogeneic HSCT from an unrelated matched donor.",
"affiliations": "Department of Haematology and Transfusion Medicine, Royal North Shore Hospital, Sydney, Australia, torypechey@gmail.com.",
"authors": "Pechey|Victoria|V|;Parratt|John|J|;Vo|Linh|L|;Stevenson|William|W|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-014-1704-x",
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"issn_linking": "0925-5710",
"issue": "101(2)",
"journal": "International journal of hematology",
"keywords": null,
"medline_ta": "Int J Hematol",
"mesh_terms": "D000328:Adult; D001921:Brain; D005260:Female; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007166:Immunosuppressive Agents; D015470:Leukemia, Myeloid, Acute; D008279:Magnetic Resonance Imaging; D008578:Meninges; D012008:Recurrence; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "203-6",
"pmc": null,
"pmid": "25416235",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11320189;8493865;12499502;17994117;19915632;20846944;14715632;17099715;15760882;19667266;11509085;10436117;2390633;16398660;24652969;17502894;23299314;9516171;3550805;19687597",
"title": "Successful treatment of meningeal graft-versus-host disease in a haematopoietic stem cell transplant recipient.",
"title_normalized": "successful treatment of meningeal graft versus host disease in a haematopoietic stem cell transplant recipient"
} | [
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},
{
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],
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"literaturereference": "PECHEY V, PARRATT J, VO, L, STEVENSON W.. SUCCESSFUL TREATMENT OF MENINGEAL GRAFT-VERSUS-HOST DISEASE IN A HAEMATOPOIETIC STEM CELL TRANSPLANT RECIPIENT.. INTERNATIONAL JOURNAL OF HEMATOLOGY. 2015;101:203-206",
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{
"abstract": "We report a case of metformin-associated lactic acidosis (MALA) in the setting of normal renal function and review the relevant medical literature. A 77-year-old female diagnosed with type 2 diabetes mellitus previously treated with insulin and gliclazide MR was started on metformin. A few weeks later, she was found to have lactic acidosis. Renal function was normal, and no severe underlying illness was identified. Metformin was discontinued, and lactate levels normalized within 4 days, suggesting metformin was a reversible precipitant of the lactic acidosis. MALA can occur in the absence of renal impairment, systemic hypoperfusion or severe liver disease. A possible mechanism is a genetically determined alteration in metformin pharmacokinetics. Metformin is beneficial and safe in patients with normal renal function, but the development of MALA, although rare, should be kept in mind to prevent potentially life-threatening toxicity.",
"affiliations": "Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.;Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada.;Chronic Disease Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada; Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada; Department of Biochemistry, Microbiology & Immunology, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: asorisky@ohri.ca.",
"authors": "Omar|Ahmed|A|;Ellen|Ruth|R|;Sorisky|Alexander|A|",
"chemical_list": "D019344:Lactic Acid; D008687:Metformin",
"country": "Canada",
"delete": false,
"doi": null,
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"issn_linking": "1499-2671",
"issue": "40(4)",
"journal": "Canadian journal of diabetes",
"keywords": "acidose lactique; agent antihyperglycémiant oral; diabète de type 2; fonction rénale; lactic acidosis; metformin; metformine; oral antihyperglycemia agent; renal function; type 2 diabetes",
"medline_ta": "Can J Diabetes",
"mesh_terms": "D000140:Acidosis, Lactic; D000368:Aged; D003924:Diabetes Mellitus, Type 2; D005260:Female; D006801:Humans; D007677:Kidney Function Tests; D019344:Lactic Acid; D008687:Metformin",
"nlm_unique_id": "101148810",
"other_id": null,
"pages": "280-1",
"pmc": null,
"pmid": "27197687",
"pubdate": "2016-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Metformin-Associated Lactic Acidosis in a Patient with Normal Renal Function.",
"title_normalized": "metformin associated lactic acidosis in a patient with normal renal function"
} | [
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{
"abstract": "OBJECTIVE\nAlthough docetaxel plus ramucirumab has shown superior treatment efficacy over docetaxel monotherapy for patients with non-small cell lung cancer (NSCLC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to validate the primary prophylactic use of pegfilgrastim with docetaxel and ramucirumab treatment in Japanese patients with NSCLC.\n\n\nMETHODS\nPatients with NSCLC with progression after at least one round of chemotherapy were enrolled and administered docetaxel (60 mg/m2) plus ramucirumab (10 mg/kg) intravenously on day 1, followed by pegylated-granulocyte colony-stimulating factor (3.6 mg) on day 2 of a 21-day treatment cycle. The primary study endpoint was the percentage of patients who developed FN. Secondary endpoints included overall survival, progression-free survival, overall response rate, and safety.\n\n\nRESULTS\nOverall, 20 patients (15 men and 5 women) were enrolled, of whom one developed FN, resulting in an overall FN rate of 5%. The response and disease control rates were 40% and 85%, respectively. The median progression-free survival was 6.6 (95% confidence interval [CI], 0.5-NR) months. The median overall survival was 18.4 (95% CI, 2.2-11.0) months. Six patients aged over 75 years were included in this study, and although most adverse events were durable, ramucirumab-associated adverse events occurred more frequently in these patients.\n\n\nCONCLUSIONS\nWe observed a 5% FN rate using primary prophylactic pegylated-granulocyte colony-stimulating factor with docetaxel plus ramucirumab in Japanese patients with NSCLC. While most adverse events were durable, elderly patients should be closely monitored.",
"affiliations": "Innovative Medical Research Center, Gunma University Hospital, Maebashi, Gunma, 371-8511, Japan. m14702016@gunma-u.ac.jp.;Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.;Department of Respiratory Medicine, Shibukawa Medical Center, Shibukawa, Gunma, Japan.;Department of Respiratory Medicine, Hidaka Hospital, Takasaki, Gunma, Japan.;Division of Respiratory Medicine, Gunma Prefectural Cancer Center, Ota, Gunma, Japan.;Department of Respiratory Medicine, Shibukawa Medical Center, Shibukawa, Gunma, Japan.;Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.;Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.;Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.;Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.;Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.;Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.;Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.;Oncology Center, Gunma University Hospital, Maebashi, Gunma, Japan.;Clinical Research Center, Shizuoka Cancer Center, Nagaizumi, Shizuoka, Japan.;Department of Respiratory Medicine, Comprehensive Cancer Center, International Medical Center, Saitama Medical University, Hidaka, Saitama, Japan.;Department of Respiratory Medicine, Gunma University Graduate School of Medicine, Maebashi, Gunma, Japan.;Innovative Medical Research Center, Gunma University Hospital, Maebashi, Gunma, 371-8511, Japan.;Graduate School of Health Sciences, Gunma University, Maebashi, Gunma, Japan.",
"authors": "Kasahara|Norimitsu|N|;Sunaga|Noriaki|N|;Kuwako|Tomohito|T|;Naruse|Ichiro|I|;Imai|Hisao|H|;Jingu|Asuka|A|;Tsukagoshi|Yusuke|Y|;Masuda|Tomomi|T|;Kitahara|Shinsuke|S|;Tsurumaki|Hiroaki|H|;Yatomi|Masakiyo|M|;Hara|Kenichiro|K|;Koga|Yasuhiko|Y|;Sakurai|Reiko|R|;Mori|Keita|K|;Kaira|Kyoichi|K|;Maeno|Toshitaka|T|;Asao|Takayuki|T|;Hisada|Takeshi|T|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000077143:Docetaxel; C455861:pegfilgrastim; D011092:Polyethylene Glycols; C543333:ramucirumab; D000069585:Filgrastim",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00520-020-05317-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-4355",
"issue": "28(10)",
"journal": "Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer",
"keywords": "Docetaxel; Febrile neutropenia; Non-small cell lung cancer; Pegylated-granulocyte colony-stimulating factor; Ramucirumab",
"medline_ta": "Support Care Cancer",
"mesh_terms": "D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung; D064146:Chemotherapy-Induced Febrile Neutropenia; D018450:Disease Progression; D000077143:Docetaxel; D005260:Female; D000069585:Filgrastim; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols",
"nlm_unique_id": "9302957",
"other_id": null,
"pages": "4825-4831",
"pmc": null,
"pmid": "31982960",
"pubdate": "2020-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "29313949;20573926;19692680;28586279;26028407;26412456;20048182;27565938;20715160;1711156;15078138;15718314;25576433;27072050;29963237;30859745;22173662",
"title": "Administration of docetaxel plus ramucirumab with primary prophylactic pegylated-granulocyte colony-stimulating factor for pretreated non-small cell lung cancer: a phase II study.",
"title_normalized": "administration of docetaxel plus ramucirumab with primary prophylactic pegylated granulocyte colony stimulating factor for pretreated non small cell lung cancer a phase ii study"
} | [
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"abstract": "BACKGROUND\nChoroidal detachment is a major postoperative complication of trabeculectomy. Postoperative choroidal detachment occurs with low intraocular pressure (IOP), and is naturally resolved by elevation of IOP. We report a case of chronic chorioretinal detachment (CRD) in the eye with uveitic glaucoma after trabeculectomy which persisted with normal IOP resistant for medication and required surgery.\nA 63-year-old man was referred to our department with uncontrolled uveitic glaucoma in his right eye. At first presentation, IOP was 62 mm Hg in the right eye with opened angle, and active ocular inflammation was presented by moderate cell infiltration to the anterior chamber.\n\n\nMETHODS\nUveitic glaucoma.\n\n\nMETHODS\nTrabeculectomy with mitomycin-C combined with phacoemulsification were performed without any surgical trouble. Postoperative inflammation in the anterior segment was mild, and IOP decreased to the middle-teen.\n\n\nRESULTS\nAt 19 days after surgery, the depth of the anterior chamber changed to shallow and CRD occurred in the inferior quadrant area. This complication could not be resolved by additional systemic corticosteroid medication and scleral fenestration. Although IOP was maintained in middle-teen range, suture fixation of the sclera flap and additional scleral fenestration were necessary to resolve CRD at 191 days after primary surgery.\n\n\nCONCLUSIONS\nIn uveitic eye with uncontrolled ocular hypertension, severe CRD after trabeculectomy is able to occur even with normal IOP, which requires surgical procedure in addition to the medical treatment.",
"affiliations": "Department of Ophthalmology, National Defense Medical College, Tokorozawa, Saitama, Japan.",
"authors": "Sakurai|Yutaka|Y|;Takayama|Kei|K|;Abe|Tatsuhiro|T|;Takeuchi|Masaru|M|",
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"fulltext": "\n==== Front\nMedicine (Baltimore)Medicine (Baltimore)MEDIMedicine0025-79741536-5964Wolters Kluwer Health 31914050MD-D-19-0303910.1097/MD.0000000000018652186525800Research ArticleClinical Case ReportChronic chorioretinal detachment under normal intraocular pressure in eye with uveitic glaucoma after trabeculectomy A case reportSakurai Yutaka MDTakayama Kei MD, PhDAbe Tatsuhiro MDTakeuchi Masaru MD, PhD∗NA. Department of Ophthalmology, National Defense Medical College, Tokorozawa, Saitama, Japan.∗ Correspondence: Masaru Takeuchi, Department of Ophthalmology, National Defense Medical College, 3-2 Namiki, Tokorozawa, 359-8513 Saitama, Japan (e-mail: masatake@ndmc.ac.jp).1 2020 10 1 2020 99 2 e1865218 4 2019 7 11 2019 4 12 2019 Copyright © 2020 the Author(s). Published by Wolters Kluwer Health, Inc.2020This is an open access article distributed under the Creative Commons Attribution License 4.0 (CCBY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. http://creativecommons.org/licenses/by/4.0Abstract\nRationale:\nChoroidal detachment is a major postoperative complication of trabeculectomy. Postoperative choroidal detachment occurs with low intraocular pressure (IOP), and is naturally resolved by elevation of IOP. We report a case of chronic chorioretinal detachment (CRD) in the eye with uveitic glaucoma after trabeculectomy which persisted with normal IOP resistant for medication and required surgery.\n\nPatient concerns:\nA 63-year-old man was referred to our department with uncontrolled uveitic glaucoma in his right eye. At first presentation, IOP was 62 mm Hg in the right eye with opened angle, and active ocular inflammation was presented by moderate cell infiltration to the anterior chamber.\n\nDiagnosis:\nUveitic glaucoma.\n\nInterventions:\nTrabeculectomy with mitomycin-C combined with phacoemulsification were performed without any surgical trouble. Postoperative inflammation in the anterior segment was mild, and IOP decreased to the middle-teen.\n\nOutcomes:\nAt 19 days after surgery, the depth of the anterior chamber changed to shallow and CRD occurred in the inferior quadrant area. This complication could not be resolved by additional systemic corticosteroid medication and scleral fenestration. Although IOP was maintained in middle-teen range, suture fixation of the sclera flap and additional scleral fenestration were necessary to resolve CRD at 191 days after primary surgery.\n\nLessons:\nIn uveitic eye with uncontrolled ocular hypertension, severe CRD after trabeculectomy is able to occur even with normal IOP, which requires surgical procedure in addition to the medical treatment.\n\nKeywords\nchoroidal detachmentcomplicationglaucomasurgeryuveitisOPEN-ACCESSTRUE\n==== Body\n1 Introduction\nOcular hypertension (OH) is a common complication in any type of uveitis, which occurs at any time during the course of disease.[1] Antiglaucoma agents, such as topical prostaglandin analogs, β-blockers, carbonic anhydrase inhibitors, and rho-kinase inhibitor are often used to reduce OH.[2] However, when medication therapy is not sufficient, surgical procedure should be necessary, but the rates of postoperative complications in eyes with uveitis are higher than those without uveitis, and become more severe condition.[3]\n\nChoroidal detachment is a major postoperative complication of trabeculectomy.[4] In general, postoperative choroidal detachment occurs with low intraocular pressure (IOP) and is naturally resolved by elevation of IOP.[5] Severe choroidal detachment is often accompanied with serous retinal detachment and is known as chorioretinal detachment (CRD). For CRD, systemic corticosteroid medication is used as the first line, and surgical procedures including scleral fenestration, or re-suturing of scleral flap, are performed if necessary. We report a case of chronic severe CRD persistent with normal IOP after trabeculectomy in the eye with uveitic glaucoma which needed scleral fenestration and re-suturing of scleral flap.\n\n2 Case report\nA 63-year-old man with uncontrolled uveitic glaucoma in the right eye was referred to our department. He had 10-years history of diabetes mellitus and 16-years history of anterior granulomatous uveitis and had been treated with topical antiglaucoma and corticosteroid agents, systemic corticosteroid medication (15 mg/day of prednisolone), and immunosuppressive agents. Systemic examination and polymerase chain reaction test in the aqueous humor could not detect the etiology of uveitis. At the first presentation, visual acuity and IOP were 20/20 and 62 mm Hg, and active ocular inflammation presented by moderate cell infiltration to the anterior chamber and peripheral anterior synechia of approximately 50% of total angle were observed in the right eye, Additional oral carbonic anhydrase inhibitor was initiated but IOP was still 47 mm Hg, and trabeculectomy with mitomycin-C (MMC) combined with phacoemulsification were performed without any surgical trouble. Postoperative 19 days, the depth of the anterior chamber with slight inflammation became shallow, and choroidal detachment occurred in the inferior quadrant area within middle-teen IOP (15 mm Hg) in the right eye. Additional systemic corticosteroid medication (40 mg/d of prednisolone) was initiated; however, choroidal detachment was worsened and developed to CRD (Fig. 1A and B ). From postoperative 120 days, scleral fenestrations were performed 3 times with monthly intervals, but the complications were not resolved. During the procedure, IOP was maintained in middle-teen range. At postoperative 191 days, re-suturing of the sclera flap and additional scleral fenestration were performed. IOP was elevated to 40 mm Hg and resolved these complications (Fig. 1C). Thereafter, IOP was reduced by hypotensive agents and subconjunctival needling and was maintained in high-teen range. Visual acuity was not changed during the course of treatment (20/20) and inflammation in the anterior segment was resolved by systemic immunosuppressive agents and topical/systemic corticosteroid, although optic disc changed to pallor (Fig. 1D) and visual field was defected (Fig. 2A and B).\n\nFigure 1 Microscopic examination, ultrasound examination, color fundus photo. Microscopic examination detected detached retina behind the lens (A). Ultrasound examination detected choroidal detachment (white allow) and serous retinal detachment (yellow allow) at postoperative 19 d (B) and these complications were resolved after additional treatment (C). Optic disc was changed to pallor (D).\n\nFigure 2 Changes of visual field. Visual field at first presentation (A) and at last visit (B). The visual field was measured by Humphrey Field Analyzer 30-2.\n\n3 Discussion\nSurgical management of uveitis-associated glaucoma is often challenging and the rates of postoperative complications are high and the condition became severe, particularly in eyes with active inflammation.[3] Multiple complicating factors are associated. Firstly, there is higher propensity for postoperative hypotony due to dysfunction of ciliary body impaired by chronic and relapsing ocular inflammation.[6] Second, the use of antimetabolite such as MMC to inhibit the scarring responses causes further increase of the risk of hypotony.[7] Third, postoperative inflammation is more accelerated in uveitic eyes following ocular surgery.[8] For these reasons, previous studies have shown lower surgical success rates of trabeculectomy with antimetabolite in uveitic glaucoma compared with primary open angle glaucoma.[9] In the present case, surgical procedure was performed in emergency because of severe OH resistant to anti-inflammatory medication. After trabeculectomy, although ocular inflammation was controlled by topical corticosteroid medication and systemic immunosuppressive agents, CRD occurred with normal ocular tension. Since additional systemic corticosteroid medication failed to resolve CRD, it is considered that noninflammatory factors associated with impaired production, outflow, and/or circulation of the aqueous humor would cause these complications.[10] For treating chronic CD, systemic steroids do not appear to be effective, and surgical decompression of the vortex veins as they pass through the sclera has been described, but the most common treatment is full thickness sclerectomies to provide an exit for choroidal fluid.[10] Therefore, scleral fenestration and elevating IOP by re-suturing were performed, although visual field was defected largely.\n\nIn the eye with uncontrolled uveitic glaucoma, severe CRD after trabeculectomy is able to occur even with normal IOP, which requires surgical procedures in addition to controlling inflammation.\n\nAuthor contributions\nConceptualization: Masaru Takeuchi.\n\nData curation: Yutaka Sakurai.\n\nResources: Tatsuhiro Abe.\n\nSupervision: Masaru Takeuchi.\n\nValidation: Kei Takayama.\n\nWriting – original draft: Kei Takayama.\n\nWriting – review and editing: Masaru Takeuchi.\n\nAbbreviations: CRD = chorioretinal detachment, IOP = intraocular pressure, MMC = mitomycin-C, OH = ocular hypertension.\n\nHow to cite this article: Sakurai Y, Takayama K, Abe T, Takeuchi M. Chronic chorioretinal detachment under normal intraocular pressure in eye with uveitic glaucoma after trabeculectomy: A case report. Medicine. 2020;99:2(e18652).\n\nWritten informed consent has been provided by the patient for the publication of his case details and images.\n\nThe authors have no funding and conflicts of interest to disclose.\n==== Refs\nReferences\n[1] Kanda T Shibata M Taguchi M \nPrevalence and aetiology of ocular hypertension in acute and chronic uveitis . Br J Ophthalmol \n2014 ;98 :932 –6 .24682184 \n[2] Takeuchi M Kanda T Taguchi M \nEvaluation of efficacy and safety of latanoprost/timolol versus travoprost/timolol fixed combinations for ocular hypertension associated with uveitis . Ocul Immunol Inflamm \n2017 ;25 :105 –10 .26799307 \n[3] Sng CC Ang M Barton K \nUveitis and glaucoma: new insights in the pathogenesis and treatment . Prog Brain Res \n2015 ;221 :243 –69 .26518082 \n[4] Arimura S Takihara Y Miyake S \nRandomized clinical trial for early postoperative complications of Ex-PRESS implanttion versus trabeculectomy: complications postoperatively of Ex-PRESS versus trabeculectomy Study (CPETS) . Sci Rep \n2016 ;6 :26080 .27184606 \n[5] Migdal C Hitchings R \nMorbidity following prolonged postoperative hypotony after trabeculectomy . Ophthalmic Surg \n1988 ;19 :865 –7 .3231411 \n[6] Shimizu A Maruyama K Yokoyama Y \nCharacteristics of uveitic glaucoma and evaluation of its surgical treatment . Clin Ophthalmol \n2014 ;8 :2383 .25473265 \n[7] Iwao K Inatani M Seto T \nLong-term outcomes and prognostic factors for trabeculectomy with mitomycin C in eyes with uveitic glaucoma: a retrospective cohort study . J Glaucoma \n2014 ;23 :88 –94 .22895522 \n[8] Ophir A Ticho U \nDelayed filtering bleb encapsulation . Ophthalmic Surg \n1992 ;23 :38 –9 .1574265 \n[9] Iverson SM Bhardwaj N Shi W \nSurgical outcomes of inflammatory glaucoma: a comparison of trabeculectomy and glaucoma-drainage-device implantation . Jpn J Ophthalmol \n2015 ;59 :179 –86 .25688057 \n[10] Elagouz M Stanescu-Segall D Jackson TL \nUveal effusion syndrome . Surv Ophthalmol \n2010 ;55 :134 –45 .20159229\n\n",
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"abstract": "OBJECTIVE\nWe aimed to compare the efficacy of combined immunosuppression in terms of mucosal healing in paediatric patients with moderate-to-severe luminal Crohn's disease receiving infliximab according to either an 'escalated combined immunosuppression' or an 'early combined immunosuppression' strategy.\n\n\nMETHODS\nIn this prospective observational study, the efficacy of combined immunosuppression was evaluated in terms of mucosal healing at weeks 14 and 54 from baseline infliximab infusion. Comparison was performed between the escalated combined immunosuppression group [group A] and the early combined immunosuppression group [group B]. Factors associated with mucosal healing at weeks 14 and 54 from baseline infliximab infusion were also investigated.\n\n\nRESULTS\nSeventy-six patients initiated infliximab with concomitant azathioprine [group A = 28; group B = 48]. Comparison of baseline characteristics revealed a significantly longer duration from initial diagnosis to infliximab infusion in group A [median 8.1 vs. 0.7 months; p < 0.001]. Mucosal healing was achieved in 32% of patients in group A and 51% in group B at week 14 [p = 0.121], and in 42% in group A and 74% in group B at week 54 [p = 0.007]. Group B was also positively associated with mucosal healing at week 54 on multivariate logistic regression [odds ratio = 6.216, 95% confidence interval = 1.782-21.686, p = 0.004].\n\n\nCONCLUSIONS\nMucosal healing during combined immunosuppression is more effectively achieved by treatment with an early combined immunosuppression strategy without corticosteroid induction administered within 1 month rather than escalating to receive combination therapy later during the course. The therapeutic window of opportunity in early Crohn's disease may be shorter than generally thought, especially in children.",
"affiliations": "Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Biostatistics and Clinical Epidemiology Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.;Biostatistics and Clinical Epidemiology Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.;Department of Pediatrics, Kyung Hee University Graduate School of Medicine, Seoul, Korea.;Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea i101016@skku.edu.",
"authors": "Kang|Ben|B|;Choi|So Yoon|SY|;Kim|Hye Seung|HS|;Kim|Kyunga|K|;Lee|Yoo Min|YM|;Choe|Yon Ho|YH|",
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}
] |
{
"abstract": "Darkening of the tongue and oral mucosa is a reaction pattern that can be related to a number of physiologic, metabolic, and toxic disorders, and medications and exogenous substances. Black discoloration of the tongue should be distinguished from black \"hairy\" tongue, which is characterized by hypertrophy of the filiform papillae. We report a case of a 42-year-old man presented with a black discoloration of his tongue during treatment with linezolid for spondylodiscitis. So in conclusion, tongue discoloration is a benign and reversible condition and a probable adverse event associated with linezolid. We present this case to increase clinicians' awareness of a new potential adverse effect of linezolid.",
"affiliations": "Infectious Diseases Unit, Hospital Clínico Universitario de San Juan, Alicante, Spain. fjoverdiaz@coma.es",
"authors": "Jover-Diaz|Francisco|F|;Cuadrado-Pastor|Jose-Maria|JM|;Talents-Bolos|Amparo|A|;Martin-Gonzalez|Coral|C|",
"chemical_list": "D000081:Acetamides; D000890:Anti-Infective Agents; D023303:Oxazolidinones; D000069349:Linezolid",
"country": "United States",
"delete": false,
"doi": "10.1097/MJT.0b013e3181a59bcd",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-2765",
"issue": "17(4)",
"journal": "American journal of therapeutics",
"keywords": null,
"medline_ta": "Am J Ther",
"mesh_terms": "D000081:Acetamides; D000328:Adult; D000890:Anti-Infective Agents; D015299:Discitis; D006801:Humans; D000069349:Linezolid; D008297:Male; D023303:Oxazolidinones; D014059:Tongue",
"nlm_unique_id": "9441347",
"other_id": null,
"pages": "e115-7",
"pmc": null,
"pmid": "20634649",
"pubdate": "2010",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Black tongue associated with linezolid.",
"title_normalized": "black tongue associated with linezolid"
} | [
{
"companynumb": "US-ALKEM LABORATORIES LIMITED-US-ALKEM-2018-09496",
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}
],
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"patientonsetage": "65",
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"reaction": [
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"reactionmeddrapt": "Trichoglossia",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Tongue discolouration",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
}
],
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},
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"literaturereference": "JOVER-DIAZ F, CUADRADO-PASTOR JM, TALENTS-BOLOS A AND MARTIN-GONZALEZ C. BLACK TONGUE ASSOCIATED WITH LINEZOLID. AMERICAN JOURNAL OF THERAPEUTICS. 2010?17:E115?E117",
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"qualification": "1",
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},
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},
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},
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190417"
},
{
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},
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}
],
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}
],
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},
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},
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},
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},
"serious": 2,
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"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190417"
}
] |
{
"abstract": "Several kinds of pediatric hematological and/or malignant diseases are treated with chemotherapy regimens including ifosfamide (IFO). IFO-induced encephalopathy (IIE) is one of the serious side effects, but there is not enough evidence regarding the clinical features of IIE in children.\n\n\n\nWe performed a retrospective study on pediatric patients treated with chemotherapy regimens, including IFO, at a single center. We recorded the clinical characteristics of all patients; we compared the clinical characteristics between patients who developed IIE and those who did not.\n\n\n\nIn total, 88 patients received a chemotherapy regimen including IFO. IIE developed in seven patients (8.0%). The median age of patients at the time of IIE development was 4.3 (range 1.4-6.5) years in the younger population. Six of seven patients with IIE improved with supportive therapy only; however, one patient died due to heart failure. Overall survival was not different between the two groups. Multivariable analysis revealed that the co-administration of cisplatin (CDDP) or carboplatin (CBDCA) was a significant risk factor associated with IIE. Although there was no significant difference in laboratory data between the groups before chemotherapy, patients who developed IIE showed exacerbation in several laboratory tests, including those for renal and liver functions.\n\n\n\nRenal dysfunction caused by the combination of nephrotoxic agents (IFO and CDDP/CBDCA) seems to be important for the development of pediatric IIE. It was thought to be difficult to predict IIE onset based on laboratory data before the initiation of chemotherapy regimens; however, careful observation of laboratory data during IFO chemotherapy regimens may help predict IIE onset and facilitate early treatment.",
"affiliations": "Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.;Life Science Research Center, Nagano Children's Hospital, Matsumoto, Japan.;Life Science Research Center, Nagano Children's Hospital, Matsumoto, Japan.;Department of Hematology and Oncology, Nagano Children's Hospital, Azumino, Japan.;Life Science Research Center, Nagano Children's Hospital, Matsumoto, Japan.;Life Science Research Center, Nagano Children's Hospital, Matsumoto, Japan.;Department of Laboratory Medicine, Shinshu University Hospital, Matsumoto, Japan.",
"authors": "Ide|Yuichiro|Y|;Yanagisawa|Ryu|R|0000-0003-4012-0958;Kubota|Noriko|N|;Sakashita|Kazuo|K|;Tozuka|Minoru|M|;Nakamura|Tomohiko|T|;Honda|Takayuki|T|",
"chemical_list": "D016190:Carboplatin; D002945:Cisplatin; D007069:Ifosfamide",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.27996",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "66(12)",
"journal": "Pediatric blood & cancer",
"keywords": "children; ifosfamide; ifosfamide-related encephalopathy; nephrotoxicity; neurotoxicity",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D001927:Brain Diseases; D016190:Carboplatin; D002648:Child; D002675:Child, Preschool; D002945:Cisplatin; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007069:Ifosfamide; D007223:Infant; D008297:Male; D009369:Neoplasms; D011379:Prognosis; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e27996",
"pmc": null,
"pmid": "31535455",
"pubdate": "2019-12",
"publication_types": "D016430:Clinical Trial; D016428:Journal Article",
"references": null,
"title": "Analysis of the clinical characteristics of pediatric patients who experience ifosfamide-induced encephalopathy.",
"title_normalized": "analysis of the clinical characteristics of pediatric patients who experience ifosfamide induced encephalopathy"
} | [
{
"companynumb": "JP-TEVA-2019-JP-1156560",
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"patient": {
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{
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"activesubstancename": "ETOPOSIDE"
},
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"drugindication": "CLEAR CELL SARCOMA OF THE KIDNEY",
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{
"actiondrug": "1",
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"activesubstancename": "IFOSFAMIDE"
},
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},
{
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},
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}
],
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"reaction": [
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}
],
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},
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"literaturereference": "IDE Y, YANAGISAWA R, KUBOTA N, SAKASHITA K, TOZUKA M, NAKAMURA T, ET AL. ANALYSIS OF THE CLINICAL CHARACTERISTICS OF PEDIATRIC PATIENTS WHO EXPERIENCE IFOSFAMIDE-INDUCED ENCEPHALOPATHY. PEDIATR-BLOOD-CANCER 2019?66:NO. 12.",
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},
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"medicinalproduct": "IFOSFAMIDE."
},
{
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},
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},
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{
"abstract": "We report a case of pharmacologic management of pediatric paroxysmal sympathetic hyperactivity (PSH) in a patient who experienced symptomatic resolution with dexmedetomidine and propranolol. Following a blunt traumatic subdural hematoma and diffuse axonal injury, an 8-year-old male developed PSH on approximately day 5 of the hospitalization. PSH symptoms identified in this patient were hyperthermia, tachycardia, posturing, and hypertension with associated elevations in intracranial pressure. Episodes of PSH continued to be observed despite appropriate titration of opiates, sedatives, and traditional blood pressure management. Dexmedetomidine and propranolol were subsequently initiated to attenuate acute episodes of PSH. A reduction in sedative requirements and improvement in symptoms followed, which facilitated successful extubation. The combination of propranolol and dexmedetomidine was followed by a decrease in the frequency and severity of acute episodes of PSH. After utilization of multiple treatment modalities to control PSH episodes in our patient, propranolol and dexmedetomidine may have helped attenuate PSH signs and symptoms.",
"affiliations": "Department of Pharmacy, UF Health Jacksonville, Jacksonville, Florida, United States.;Department of Pharmacy, UF Health Jacksonville, Jacksonville, Florida, United States.;Department of Pharmacy, UF Health Jacksonville, Jacksonville, Florida, United States.;Department of Pharmacy, Wesley Medical Center, Wichita, Kansas, United States.",
"authors": "Branstetter|Joshua W|JW|0000-0002-6637-625X;Ohman|Kelsey L|KL|;Johnson|Donald W|DW|;Gilbert|Brian W|BW|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0039-1698758",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2146-4626",
"issue": "9(1)",
"journal": "Journal of pediatric intensive care",
"keywords": "dexmedetomidine; paroxysmal sympathetic hyperactivity; pediatrics; propranolol; traumatic brain injury",
"medline_ta": "J Pediatr Intensive Care",
"mesh_terms": null,
"nlm_unique_id": "101592756",
"other_id": null,
"pages": "64-69",
"pmc": null,
"pmid": "31984161",
"pubdate": "2020-03",
"publication_types": "D002363:Case Reports",
"references": "30489486;24731076;22150061;27752785;19345772;1973880;22304785;3037994;27654000;12218525;25506508;17603760;26352612;10849235;26700947;18212567;28978176;25310291;2180636;17583440;26167316;22712762;26380574;20695005;15195790",
"title": "Management of Paroxysmal Sympathetic Hyperactivity with Dexmedetomidine and Propranolol Following Traumatic Brain Injury in a Pediatric Patient.",
"title_normalized": "management of paroxysmal sympathetic hyperactivity with dexmedetomidine and propranolol following traumatic brain injury in a pediatric patient"
} | [
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},
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},
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},
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "Branstetter JW, Ohman KL, Johnson DW, Gilbert BW. Management of paroxysmal sympathetic hyperactivity with dexmedetomidine and propranolol following traumatic brain injury in a pediatric patient. J Pediatr Intensive Care. 2020;9:64-69",
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"qualification": "3",
"reportercountry": "US"
},
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"receiptdate": "20220614",
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},
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},
"serious": 2,
"seriousnesscongenitalanomali": 2,
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"transmissiondate": "20220720"
}
] |
{
"abstract": "BACKGROUND\nThe antiangiogenic monoclonal antibody aflibercept in association with fluorouracil and irinotecan improves the survival of patients with metastatic colorectal cancer (mCRC) treated previously with oxaliplatin-based therapy. Multiple reports raised the hypothesis that the concomitant use of antiresorptive drugs and antiangiogenic drugs may increase the risk of osteonecrosis of the jaw (ONJ). Some reports have been published regarding cases of ONJ during treatment with bevacizumab for mCRC.\n\n\nMETHODS\nHere we describe the first reported case of ONJ occurring in a 64-year-old woman with untreated periodontitis and episodic previous pyorrhea occurring during treatment with aflibercept plus FOLFIRI during the expanded-access program.\n\n\nCONCLUSIONS\nThis case report warrants further investigation into the potential association between the use of anti-VEGF agents and ONJ. Given the serious nature of ONJ, we recommend that particular attention be paid to the oral district prior to treating patients and during treatment with chemotherapy and targeted agents, especially anti-VEGF agents. Such measures could also be useful in reducing the incidence of stomatitis.",
"affiliations": "Colorectal Cancer Unit, Division of Medical Oncology 1, San Giovanni Battista Hospital, Città della Salute e della Scienza, Turin - Italy.;Colorectal Cancer Unit, Division of Medical Oncology 1, San Giovanni Battista Hospital, Città della Salute e della Scienza, Turin - Italy.;Colorectal Cancer Unit, Division of Medical Oncology 1, San Giovanni Battista Hospital, Città della Salute e della Scienza, Turin - Italy.;Colorectal Cancer Unit, Division of Medical Oncology 1, San Giovanni Battista Hospital, Città della Salute e della Scienza, Turin - Italy.;Colorectal Cancer Unit, Division of Medical Oncology 1, San Giovanni Battista Hospital, Città della Salute e della Scienza, Turin - Italy.;Colorectal Cancer Unit, Division of Medical Oncology 1, San Giovanni Battista Hospital, Città della Salute e della Scienza, Turin - Italy.;Colorectal Cancer Unit, Division of Medical Oncology 1, San Giovanni Battista Hospital, Città della Salute e della Scienza, Turin - Italy.;Colorectal Cancer Unit, Division of Medical Oncology 1, San Giovanni Battista Hospital, Città della Salute e della Scienza, Turin - Italy.",
"authors": "Ponzetti|Agostino|A|;Pinta|Francesco|F|;Spadi|Rosella|R|;Mecca|Caterina|C|;Fanchini|Laura|L|;Zanini|Marcello|M|;Ciuffreda|Libero|L|;Racca|Patrizia|P|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D000077146:Irinotecan; D040262:Receptors, Vascular Endothelial Growth Factor; D005472:Fluorouracil; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": "10.5301/tj.5000405",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8916",
"issue": "102(Suppl. 2)",
"journal": "Tumori",
"keywords": null,
"medline_ta": "Tumori",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D002166:Camptothecin; D015179:Colorectal Neoplasms; D017809:Fatal Outcome; D005260:Female; D005472:Fluorouracil; D006801:Humans; D000077146:Irinotecan; D007571:Jaw Diseases; D008875:Middle Aged; D010020:Osteonecrosis; D040262:Receptors, Vascular Endothelial Growth Factor; D011993:Recombinant Fusion Proteins; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0111356",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26350200",
"pubdate": "2016-11-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Jaw osteonecrosis associated with aflibercept, irinotecan and fluorouracil: attention to oral district.",
"title_normalized": "jaw osteonecrosis associated with aflibercept irinotecan and fluorouracil attention to oral district"
} | [
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{
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}
],
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"reaction": [
{
"reactionmeddrapt": "Osteonecrosis of jaw",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Deep vein thrombosis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Periodontal disease",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stomatitis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PONZETTI A, PINTA F, SPADI R, MECCA C, FANCHINI L, ZANINI M ET AL.. JAW OSTEONECROSIS ASSOCIATED WITH AFLIBERCEPT, IRINOTECAN AND FLUOROURACIL: ATTENTION TO ORAL DISTRICT. TUMORI. 2016;102(2):S74-S77",
"literaturereference_normalized": "jaw osteonecrosis associated with aflibercept irinotecan and fluorouracil attention to oral district",
"qualification": "3",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20171003",
"receivedate": "20171003",
"receiver": {
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},
"reporttype": "1",
"safetyreportid": 14031574,
"safetyreportversion": 1,
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"sendertype": "2"
},
"serious": 1,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180321"
},
{
"companynumb": "IT-MYLANLABS-2016M1058010",
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Osteonecrosis of jaw",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Deep vein thrombosis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stomatitis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Periodontal disease",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PONZETTI A, PINTA F, SPADI R, MECCA C, FANCHINI L, ZANINI M, ET AL. JAW OSTEONECROSIS ASSOCIATED WITH AFLIBERCEPT, IRINOTECAN AND FLUOROURACIL: ATTENTION TO ORAL DISTRICT. TUMORI 2016;102 (SUPPL. 2):S74-S77.",
"literaturereference_normalized": "jaw osteonecrosis associated with aflibercept irinotecan and fluorouracil attention to oral district",
"qualification": "3",
"reportercountry": "IT"
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},
{
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},
{
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},
{
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{
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{
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{
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},
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{
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}
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] |
{
"abstract": "Anti-tumor necrosis factor-alpha (TNF-α) blockade is so far the most effective therapy for extensive pediatric Crohn disease (CD), but loss of response is frequently encountered. We describe here the use of golimumab (Simponi) in 6 pediatric CD patients with antibody formation/loss of response to infliximab and adalimumab. Most patients had undergone surgery but had poor disease control. After introduction of golimumab, the levels of inflammatory markers and fecal calprotectin declined at first, but the response was not sustained. Each patient needed dose escalation of golimumab from 4 to 2 week intervals, to maintain response and to increase trough levels. Importantly, most patients were able to attend school when undergoing golimumab therapy. As with other anti-TNFα drugs, follow-up of drug levels is advisable. Although golimumab therapy failed in most patients, it is an alternate treatment option in pediatric patients with severe CD. The therapeutic response, however, is suboptimal in anti-TNFα exposed patients.",
"affiliations": "Children's Hospital, Helsinki University Hospital and University of Helsinki, Helsinki, Finland.",
"authors": "Merras-Salmio|Laura|L|;Kolho|Kaija-Leena|KL|",
"chemical_list": "D000911:Antibodies, Monoclonal; D007155:Immunologic Factors; D014409:Tumor Necrosis Factor-alpha; C529000:golimumab; D000069285:Infliximab; D000068879:Adalimumab",
"country": "United States",
"delete": false,
"doi": "10.1097/MPG.0000000000001165",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-2116",
"issue": "63(3)",
"journal": "Journal of pediatric gastroenterology and nutrition",
"keywords": null,
"medline_ta": "J Pediatr Gastroenterol Nutr",
"mesh_terms": "D000068879:Adalimumab; D000293:Adolescent; D000911:Antibodies, Monoclonal; D002648:Child; D003424:Crohn Disease; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D000069285:Infliximab; D008297:Male; D056687:Off-Label Use; D012720:Severity of Illness Index; D017211:Treatment Failure; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8211545",
"other_id": null,
"pages": "344-7",
"pmc": null,
"pmid": "26963940",
"pubdate": "2016-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Golimumab Therapy in Six Patients With Severe Pediatric Onset Crohn Disease.",
"title_normalized": "golimumab therapy in six patients with severe pediatric onset crohn disease"
} | [
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}
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{
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}
],
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{
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},
{
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug effect decreased",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug specific antibody present",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Stoma closure",
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},
{
"reactionmeddrapt": "Growth retardation",
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Crohn^s disease",
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"reactionoutcome": "6"
}
],
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},
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},
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],
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},
{
"reactionmeddrapt": "Large intestinal stenosis",
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{
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ADALIMUMAB"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "AZATHIOPRINE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "103772",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "LYOPHILIZED POWDER",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CROHN^S DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "INFLIXIMAB, RECOMBINANT"
}
],
"patientagegroup": "4",
"patientonsetage": "15",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": "39",
"reaction": [
{
"reactionmeddrapt": "Crohn^s disease",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Therapeutic response decreased",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Delayed puberty",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Body height decreased",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MERRAS-SALMIO L, KOLHO K. GOLIMUMAB THERAPY IN SIX PATIENTS WITH SEVERE PEDIATRIC ONSET CROHN DISEASE. JOURNAL OF PEDIATRIC GASTROENTEROLOGY + NUTRITION 2016;63 (3):344-347.",
"literaturereference_normalized": "golimumab therapy in six patients with severe pediatric onset crohn disease",
"qualification": "1",
"reportercountry": "FI"
},
"primarysourcecountry": "FI",
"receiptdate": "20160919",
"receivedate": "20160831",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12703600,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20161109"
},
{
"companynumb": "FI-JNJFOC-20160822314",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": "103772",
"drugbatchnumb": "UNKNOWN",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "LYOPHILIZED POWDER",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CROHN^S DISEASE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "INFLIXIMAB"
}
],
"patientagegroup": "3",
"patientonsetage": "10",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Crohn^s disease",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Jejunectomy",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Therapeutic response unexpected",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Therapeutic response decreased",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug specific antibody present",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MERRAS-SALMIO L, KAIJA-LEENA K. GOLIMUMAB THERAPY IN SIX PATIENTS WITH SEVERE PEDIATRIC ONSET CROHN DISEASE. JOURNAL OF PEDIATRIC GASTROENTEROLOGY + NUTRITION 2016;63 (3):344-7.",
"literaturereference_normalized": "golimumab therapy in six patients with severe pediatric onset crohn disease",
"qualification": "1",
"reportercountry": "FI"
},
"primarysourcecountry": "FI",
"receiptdate": "20160923",
"receivedate": "20160901",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12706651,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20161109"
},
{
"companynumb": "FI-ORION CORPORATION ORION PHARMA-REMS2018-0001",
"fulfillexpeditecriteria": "1",
"occurcountry": "FI",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugindication": "CROHN^S DISEASE",
"drugintervaldosagedefinition": null,
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"drugrecurrence": null,
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"medicinalproduct": "INFLIXIMAB"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "METHOTREXATE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
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"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHOTREXATE."
}
],
"patientagegroup": null,
"patientonsetage": "16",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug intolerance",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug effect incomplete",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug specific antibody",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MERRAS-SALMIO L,KOLHO K. GOLIMUMAB THERAPY IN SIX PATIENTS WITH SEVERE PEDIATRIC ONSET CROHN DISEASE. J PEDIATR GASTROENTEROL NUTR. 63(3):344-7.",
"literaturereference_normalized": "golimumab therapy in six patients with severe pediatric onset crohn disease",
"qualification": "1",
"reportercountry": "FI"
},
"primarysourcecountry": "FI",
"receiptdate": "20180119",
"receivedate": "20180119",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14409881,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180509"
}
] |
{
"abstract": "OBJECTIVE\nTo investigate the efficacy and safety of the treatment of the newly diagnosed multiple myeloma (MM) with or without renal impairment receiving the therapy of bortezomib, dexamethasone plus thalidomide (BTD) regimen in order to analyze the effects of BTD regimen on the prognosis of the MM patients with renal impairment compared with the patients without renal impairment.\n\n\nMETHODS\nSeventy-two newly diagnosed MM patients entered into our study and all the patients belonged to International Stage System (ISS) 3 in which transplantation patients were excluded or the patients refused receiving transplantation therapy. According to the level of serum creatinine (Scr), the patients were divided into two groups including group 1 (n=42) (Scr <2 mg/dL) and group 2 (n=30) (Scr ≥2 mg/dL). All the patients received the therapy of BTD regimen as induction therapy, and the median treatment time was 5 (range, 2-8) cycles. The outcome was analyzed retrospectively.\n\n\nRESULTS\nThe overall remission (OR) rates were 81.0% (group 1) and 80.0% (group 2). There was no statistical difference between the two groups (P>0.05). In group 2, 10 patients (33.3%) got renal function reversal, 14 patients (46.7%) got improved renal function and the median time to renal function reversal was 1.4 (range, 0.7-3.0) months. Among 12 patients with hemodialysis at diagnosis, 8 patients got rid of hemodialysis after median 4 cycles of therapy (range, 3-6 cycles). After a median follow-up period of 16 (range, 2-31) months, 5 patients (11.9%) in group 1 died and 9 patients (30.0%) in group 2 died (P=0.056). The 2-year estimate of overall survival was 77.3% in group 1 and 63.8% in group 2, respectively (P=0.188). During a median follow-up time of 13.0 months (range, 2-25 months), 15 patients (35.7%) in group 1 progressed and 13 patients (43.3%) in group 2 progressed (P=0.513). The 2-year estimate of response duration was 50.6% in group 1 and 42.1% in group 2, respectively (P=1). The main toxicities in the two groups included thrombocytopenia, peripheral neuropathy (PN), infection, herpes zoster and so on. The incidence of grade 3 and 4 adverse events was low.\n\n\nCONCLUSIONS\nBTD regimen may become the front-line therapy for the newly diagnosed MM patients with renal impairment because BTD regimen can improve the prognosis of the patients with renal impairment as good as the patients without renal impairment.",
"affiliations": "Department of Hematology & Multiple Myeloma Research Center of Beijing, Beijing Chaoyang Hospital Affiliated to Capital Medical University, Beijing 100020, China.",
"authors": "Yang|Guangzhong|G|;Chen|Wenming|W|;Wu|Yin|Y|",
"chemical_list": null,
"country": "China",
"delete": false,
"doi": "10.3978/j.issn.1000-9604.2013.03.07",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1000-9604",
"issue": "25(2)",
"journal": "Chinese journal of cancer research = Chung-kuo yen cheng yen chiu",
"keywords": "Myeloma; bortezomib; renal impairment",
"medline_ta": "Chin J Cancer Res",
"mesh_terms": null,
"nlm_unique_id": "9315242",
"other_id": null,
"pages": "155-60",
"pmc": null,
"pmid": "23592895",
"pubdate": "2013-04",
"publication_types": "D016428:Journal Article",
"references": "12528874;15690325;15953004;17488666;16855634;18464107;20823423;19252175;19767634;15809451;18528426;18569958;17975015;19930441;9759684;15953001;2383164;16275935;17768111;12903007;11007053;16772605",
"title": "Bortezomib, dexamethasone plus thalidomide for treatment of newly diagnosed multiple myeloma patients with or without renal impairment.",
"title_normalized": "bortezomib dexamethasone plus thalidomide for treatment of newly diagnosed multiple myeloma patients with or without renal impairment"
} | [
{
"companynumb": "CN-TAKEDA-2017MPI006816",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": "1",
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "200 MG, UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PLASMA CELL MYELOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "200",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "THALIDOMIDE"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "BORTEZOMIB"
},
"drugadditional": "1",
"drugadministrationroute": "040",
"drugauthorizationnumb": "021602",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": "1.3 MG/M2, UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PLASMA CELL MYELOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1.3",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VELCADE"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "DEXAMETHASONE"
},
"drugadditional": "1",
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "40 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PLASMA CELL MYELOMA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "40",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DEXAMETHASONE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Neutropenia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pneumonia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Tonsillitis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pharyngitis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rhinitis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Febrile bone marrow aplasia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Respiratory tract infection bacterial",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Herpes zoster",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Bronchitis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Upper respiratory tract infection",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Urinary tract infection",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nasopharyngitis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rash",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Gastrointestinal disorder",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neuropathy peripheral",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "YANG G, CHEN W, WU Y.. BORTEZOMIB, DEXAMETHASONE PLUS THALIDOMIDE FOR TREATMENT OF NEWLY DIAGNOSED MULTIPLE MYELOMA PATIENTS WITH OR WITHOUT RENAL IMPAIRMENT. CHINESE JOURNAL OF CANCER RESEARCH. 2013;25/2:155-160",
"literaturereference_normalized": "bortezomib dexamethasone plus thalidomide for treatment of newly diagnosed multiple myeloma patients with or without renal impairment",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20170809",
"receivedate": "20170809",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13849693,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20171127"
}
] |
{
"abstract": "Anaphylaxis continues to cause significant morbidity and mortality. Healthcare providers struggle to promptly recognize and appropriately treat anaphylaxis patients. The goal of this study was to characterize anaphylaxis-related malpractice lawsuits.\nWe collected jury verdicts, settlements, and court opinions regarding alleged medical malpractice involving anaphylaxis from May 2011 through May 2016 from an online legal database (Thomson Reuters Westlaw). Data were abstracted onto a standardized data form.\nWe identified 30 anaphylaxis-related malpractice lawsuits. In 80% of cases, the trigger was iatrogenic (40% intravenous [IV] contrast, 33% medications, 7% latex). Sixteen (53%) cases resulted in death, 7 (23%) in permanent cardiac and/or neurologic damage, and 7 (23%) in less severe outcomes. Fourteen (47%) of the lawsuits were related to exposure to a known trigger. Delayed recognition or treatment was cited in 12 (40%) cases and inappropriate IV epinephrine dosing was reported in 5 (17%) cases. Defendants were most commonly physicians (n=15, 50%) and nurses (n=5, 17%). The most common physician specialties named were radiology and primary care (n=3, 10% each), followed by emergency medicine, anesthesiology, and cardiology (n=2, 7% each). Among the 30 cases, 14 (47%) favored the defendant, 8 (37%) resulted in findings of negligence, 3 (10%) cases settled, and 5 (17%) had an unknown legal outcome.\nAdditional anaphylaxis education, provision of epinephrine autoinjectors or other alternatives to reduce dosing errors, and stronger safeguards to prevent administration of known allergens would all likely reduce anaphylaxis-related patient morbidity and mortality and providers' legal vulnerability to anaphylaxis-related lawsuits.",
"affiliations": "Mayo Clinic, Department of Emergency Medicine, Rochester, Minnesota.;Mayo Clinic, Department of Emergency Medicine, Rochester, Minnesota.;Mayo Clinic, Department of Emergency Medicine, Phoenix, Arizona.;Mayo Clinic, Department of Emergency Medicine, Rochester, Minnesota.;Mayo Clinic, Department of Emergency Medicine, Rochester, Minnesota.;Mayo Clinic, Department of Emergency Medicine, Rochester, Minnesota.",
"authors": "Lindor|Rachel A|RA|;McMahon|Erika M|EM|;Wood|Joseph P|JP|;Sadosty|Annie T|AT|;Boie|Eric T|ET|;Campbell|Ronna L|RL|",
"chemical_list": "D004837:Epinephrine",
"country": "United States",
"delete": false,
"doi": "10.5811/westjem.2018.4.37453",
"fulltext": "\n==== Front\nWest J Emerg MedWest J Emerg MedWestJEMWestern Journal of Emergency Medicine1936-900X1936-9018Department of Emergency Medicine, University of California, Irvine School of Medicine 10.5811/westjem.2018.4.37453wjem-19-693Legal MedicineOriginal ResearchAnaphylaxis-related Malpractice Lawsuits Lindor Rachel A. MD, JD*McMahon Erika M. MD*Wood Joseph P. MD, JD†Sadosty Annie T. MD*Boie Eric T. MD*Campbell Ronna L. MD, PhD*\n* Mayo Clinic, Department of Emergency Medicine, Rochester, Minnesota\n† Mayo Clinic, Department of Emergency Medicine, Phoenix, ArizonaAddress for Correspondence: Ronna L. Campbell, MD, PhD, Mayo Clinic, Department of Emergency Medicine, 200 1st Street SW, Rochester, MN 55905. Email: campbell.ronna@mayo.edu.7 2018 04 6 2018 19 4 693 700 04 1 2018 26 2 2018 16 4 2018 Copyright: © 2018 Lindor et al.2018This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/Introduction\nAnaphylaxis continues to cause significant morbidity and mortality. Healthcare providers struggle to promptly recognize and appropriately treat anaphylaxis patients. The goal of this study was to characterize anaphylaxis-related malpractice lawsuits.\n\nMethods\nWe collected jury verdicts, settlements, and court opinions regarding alleged medical malpractice involving anaphylaxis from May 2011 through May 2016 from an online legal database (Thomson Reuters Westlaw). Data were abstracted onto a standardized data form.\n\nResults\nWe identified 30 anaphylaxis-related malpractice lawsuits. In 80% of cases, the trigger was iatrogenic (40% intravenous [IV] contrast, 33% medications, 7% latex). Sixteen (53%) cases resulted in death, 7 (23%) in permanent cardiac and/or neurologic damage, and 7 (23%) in less severe outcomes. Fourteen (47%) of the lawsuits were related to exposure to a known trigger. Delayed recognition or treatment was cited in 12 (40%) cases and inappropriate IV epinephrine dosing was reported in 5 (17%) cases. Defendants were most commonly physicians (n=15, 50%) and nurses (n=5, 17%). The most common physician specialties named were radiology and primary care (n=3, 10% each), followed by emergency medicine, anesthesiology, and cardiology (n=2, 7% each). Among the 30 cases, 14 (47%) favored the defendant, 8 (37%) resulted in findings of negligence, 3 (10%) cases settled, and 5 (17%) had an unknown legal outcome.\n\nConclusion\nAdditional anaphylaxis education, provision of epinephrine autoinjectors or other alternatives to reduce dosing errors, and stronger safeguards to prevent administration of known allergens would all likely reduce anaphylaxis-related patient morbidity and mortality and providers’ legal vulnerability to anaphylaxis-related lawsuits.\n==== Body\nINTRODUCTION\nAnaphylaxis is most simply understood as a multisystem and potentially life-threatening allergic reaction.1 Although no universal definition for anaphylaxis exists, diagnostic criteria have been developed to help medical providers promptly recognize and initiate treatment in patients experiencing severe allergic reactions or anaphylaxis.1 These criteria suggest treatment is appropriate for patients who develop hypotension after exposure to a known trigger or in patients who rapidly develop symptoms involving multiple organ systems, with or without confirmed exposure to a trigger.1 Initial treatment of anaphylaxis requires administration of epinephrine intramuscularly (IM), with use of intravenous (IV) epinephrine reserved for cases that are refractory to IM epinephrine and IV fluids. Other medications, such as antihistamines and steroids, are recommended as adjunctive, second-line therapies. Timely treatment is exceedingly important as the median time between exposure to cardiopulmonary arrest in fatal cases ranges from just five minutes in cases of medication reactions, to 15 minutes for insect stings, and 30 minutes for food.2\n\nAlthough the dangers of anaphylaxis have been well recognized for over a century, patients with anaphylaxis are consistently underdiagnosed and inappropriately treated.3 Providers frequently fail to both recognize anaphylaxis and to treat patients with the correct dose of epinephrine, often struggling with the different formulations of epinephrine.4, 5 This has been best studied among radiologists and emergency physicians, who manage the majority of acute cases, but is almost certainly true for a broader range of medical providers.3, 6, 7 These delayed diagnoses and inappropriate treatments contribute to the estimated 1,500 deaths caused by anaphylaxis each year in the United States alone.7\n\nThis study seeks to characterize the incidence, patient characteristics, and legal outcomes of cases in which healthcare providers were sued for their alleged mismanagement of patients with anaphylaxis. Our goal was to highlight these legal risks to serve as additional evidence for providers that knowledge of anaphylaxis diagnosis and management is essential in a broad range of clinical specialties and settings.\n\nMETHODS\nStudy Design\nWe searched an online subscription legal database (Thomson Reuters Westlaw) for all relevant court opinions, jury verdicts, and settlements, using a Boolean search of malpractice cases with the query terms starting with “anaphyla-,” or “allergi-.” We excluded cases with the term “Eighth amendment” as there were a significant number of cases not relevant to this study involving prisoners’ claims that their Eighth Amendment rights had been violated due to failure to provide accommodations for their allergies. We included in this study all cases reported in the five-year period from May 15, 2011, through May 15, 2016. No medical records were accessed. This search strategy was similar to that used in previous legal case series and was exempted from review by the institutional review board.8, 9\n\nData Collection and Primary Data Analysis\nOf the 327 unique cases identified in the initial search, most cases were excluded because they were unrelated to an allergic reaction or anaphylaxis. The most common reasons for exclusion were cases involving adverse rather than allergic reactions (n=32), allergic reactions that occurred outside of the medical context such as in restaurants or schools (n=22), or mild allergic reactions that did not qualify as anaphylaxis (n=15). Overall, the search yielded 30 unique cases alleging medical malpractice against providers regarding cases of anaphylaxis.\n\nPer recognized chart-review methods,10 we created a standardized data collection form to record patient and provider demographics, nature of the trigger, clinical management, and medical and legal outcomes. Two primary abstractors (RAL, EMM) piloted the data collection form by independently abstracting five full cases. Ambiguities in data collection were clarified with the entire investigative team. The two abstractors then independently abstracted the information for all 30 cases, with a senior investigator (RLC) adjudicating any disagreements or ambiguous data. Categorical data are presented as frequency of occurrence, and continuous data are summarized as means and ranges.\n\nPopulation Health Research Capsule\nWhat do we already know about this issue?\n\nPatients with anaphylaxis are frequently underdiagnosed and inappropriately treated in many healthcare settings.\n\nWhat was the research question?\n\nWhat are the causes and outcomes of anaphylaxis related medical malpractice lawsuits?\n\nWhat was the major finding of the study?\n\nDelayed recognition, inappropriate treatment, and known allergen exposures are major causes of anaphylaxis related lawsuits.\n\nHow does this improve population health?\n\nAdditional provider education, use of epinephrine autoinjectors, and safeguards to prevent known trigger exposure would decrease anaphylaxis-related patient morbidity and mortality.\n\nRESULTS\nTable 1 summarizes the 30 cases involving malpractice lawsuits related to anaphylaxis. Additional details are found in Table 2.\n\nPatient Characteristics and Outcomes\nThe majority of patients were females (n=22; 73%). Three (10%) of the cases involved pediatric patients. The most common inciting trigger was IV contrast, which was involved in 12 (40%) of the cases. Medications were the second most common trigger, resulting in anaphylaxis in 10 (33%) of the cases. The vast majority of the cases involved severe reactions with poor outcomes. Sixteen (53%) of the cases resulted in death, five (17%) in permanent neurologic damage, four (13%) in an intensive care unit (ICU) admission, and four (13%) in non-fatal cardiac arrest. Seven of the 16 deaths (44%) were related to exposure to a trigger to which the patient had a known allergy (three IV contrast, two food, one medication, one latex). The remaining nine deaths (56%) were attributed to delayed or inadequate treatment or inadequate pre-treatment for IV contrast. There were no deaths attributed to inappropriate administration of IV epinephrine; however, two of the five patients who received inappropriate doses of IV epinephrine had permanent cardiac dysfunction, one patient had both permanent cardiac and neurologic dysfunction, and two patients required ICU admission without reported long-term morbidity.\n\nLegal case characteristics and outcomes\nNearly half of the lawsuits (n=14; 47%) were related to exposure to a known trigger. Delayed recognition and treatment was cited in 12 (40%) cases, and inappropriate epinephrine dosing was reported in five (17%) cases. All of the cases of inappropriate epinephrine dosing were due to IV rather than IM administration of epinephrine. In one case the patient received 10 times the recommended dose of epinephrine as a result of confusion over route and concentration.\n\nAmong the 30 cases, 14 (47%) were decided in favor of the defendant, 8 (27%) resulted in findings of negligence, 3 (10%) cases settled, and 5 (n=17%) had an unknown legal outcome. The mean award amount in cases ending in findings of negligence was $1.4 million, compared to just over $375,000 for cases that settled. The most commonly named defendants were physicians (n=15, 50%) and nurses (n=5, 17%). The most common physician specialties named were radiology and primary care (n=3, 10% each), followed by emergency medicine, anesthesiology, and cardiology (n=2, 7% each).\n\nDISCUSSION\nIn this review of five years of case law, we identified 30 lawsuits against healthcare providers related to anaphylaxis. The most common cause of the lawsuits was exposure to a known trigger followed by delayed recognition or treatment of anaphylaxis and inappropriate use of IV epinephrine, including both over- and under-dosing errors. Seventy-seven percent of the cases resulted in death or permanent neurologic or cardiac dysfunction. The healthcare providers involved in the lawsuits were from multiple specialties and healthcare settings, demonstrating the need for all providers to know how to recognize and treat anaphylaxis.\n\nMany cases in this series (40%) revolved around providers’ failure to recognize and treat anaphylaxis in a timely manner. The difficulty in diagnosing anaphylaxis in the acute setting has been well recognized for many years, exacerbated by previous definitions that focused largely on underlying mechanisms and physiological responses rather than clinical signs and symptoms.11 The difficulty in applying these definitions to patients in acute care settings led to the development of clinical criteria to help providers identify patients with anaphylaxis within the first few minutes of assessment.1 Despite the fact that these clinical criteria were endorsed over a decade ago and accompanied by clear instructions for management, evidence continues to demonstrate that anaphylaxis remains under-recognized and under-treated.12 Our results suggest that this may be the case in a broad range of healthcare settings and highlights the need for all healthcare providers to be able to recognize and treat anaphylaxis expeditiously.\n\nBeyond recognition of anaphylaxis, the appropriate administration of epinephrine has proven to be an additional and pervasive challenge for providers. Providers’ discomfort with epinephrine dosing has been demonstrated in multiple countries and specialties including radiology, internal medicine, emergency medicine, and pediatrics.6, 13, 14, 15 In the emergency department (ED) setting, for example, among patients with severe allergic reactions or anaphylaxis—all of whom should receive epinephrine as first-line treatment—less than one quarter actually received any epinephrine in any form.16, 3 In a survey of over 250 North American radiologists, no radiologist was able to correctly identify the preferred dose and route of administration of epinephrine for patients with anaphylaxis, and only 11% knew which concentration of epinephrine was available to them in their own institution.6 These numbers suggest a need to prioritize epinephrine-related education for providers, especially for those who routinely oversee the administration of medications and IV contrast.\n\nEqually problematic to inadequate epinephrine dosing is the use of overly aggressive IV epinephrine dosing. In a literature review of complications of epinephrine administration in an ED setting, all identified cases involved IV rather than IM epinephrine, with most of these resulting in cardiac injury.17 In our study, 17% of the lawsuits were related to inappropriate administration of IV epinephrine complicated by non-fatal cardiac arrest as well as permanent cardiac and neurologic dysfunction. The use of IV bolus epinephrine in patients presenting to an ED has been shown to be associated with a 61 times higher risk of overdose when compared to IM administration; furthermore, three-fourths of the IV epinephrine overdoses were associated with adverse cardiovascular events including cardiac ischemia and ventricular tachycardia.5 Notably, the majority of these epinephrine overdoses occurred prior to ED arrival, including in post-operative areas, infusion therapy centers, and by prehospital emergency medical responders.5 Radiologists have also demonstrated difficulty with epinephrine dosing; those surveyed about appropriate management of contrast-induced anaphylaxis selected epinephrine dosing that would have been a significant overdose in 17% of cases,6 and in another study 42% of patients actually treated with IV epinephrine for a contrast reaction received an overdose.18\n\nThe availability of epinephrine autoinjectors may be one option to mitigate provider reluctance to administer epinephrine and decrease dosing errors. The introduction of epinephrine autoinjectors along with an anaphylaxis management order set was shown to increase the use of epinephrine in a study of ED anaphylaxis management.19 In addition, a recent survey study of ED healthcare providers demonstrated that autoinjector administration of epinephrine was preferred to manual epinephrine injection and believed to reduce the risk of dosing errors.20 The use of prefilled epinephrine syringes has also been suggested as an alternative to the more costly commercially manufactured autoinjectors, and the stability and sterility of the epinephrine has been demonstrated at three months after the preparation.21\n\nInadvertent exposure to a known allergen was the leading cause of lawsuits and the leading cause of patient death in this study. Exposures to triggers to which a patient has a known allergy represent avoidable medical errors, and healthcare institutions must continue to implement systems to avoid these errors. Specific systems designed to address these avoidable errors are beyond the scope of this paper. Medications, including IV contrast, have been demonstrated to be a leading cause of fatal anaphylaxis, as they were in this study.2, 22, 23 This is likely due to a more rapid onset of cardiopulmonary arrest with medication exposure, with a median time of five minutes in cases of fatal anaphylaxis, compared to 15 and 30 minutes for food and insect stings, respectively.2 This underscores the need for healthcare facilities, particularly radiology departments, to have protocols in place to rapidly and safely treat iatrogenic anaphylaxis.\n\nLIMITATIONS\nThis study is limited based on its reliance on court opinions as the primary source of data. No medical records were accessed. Court opinions are written by judges, court reporters, or other employees of the court with no standardized reporting formats, and therefore they include widely varying amounts of detail. As a result, certain pieces of information that may be relevant to clinicians were often not available in these reports and are missing from our data. In addition, although the legal database used contains tens of thousands of cases, it is not a comprehensive database of all legal cases; no such data source exists. Instead, the database is a combination of cases that have been appealed and a selection of trial court cases and settlements chosen for inclusion by individual court reporters. Consequently, the cases here provide descriptive data for a subset of anaphylaxis-related cases, not a comprehensive list of all lawsuits that occurred during our study period.\n\nCONCLUSION\nOur data suggest several possible lessons for moving forward. First, despite significant progress in the development of clinical criteria to facilitate prompt recognition and treatment of patients with anaphylaxis, providers continue to struggle in this realm, suggesting the need for additional education on this topic. The diversity of provider types and range of affected specialties are compelling, emphasizing the need for this education to be directed at a similarly broad range of providers, specifically to help them quickly identify when epinephrine is needed. Second, the inappropriate use and consequent morbidity and mortality associated with IV epinephrine in this study reflect the dangers of IV epinephrine demonstrated in previous studies; this leads us to echo prior recommendations to make epinephrine autoinjectors or other lower cost alternatives available, rather than relying on providers to navigate the different epinephrine formulations found in many acute care settings.\n\nFinally, exposure to known triggers was a common problem in our cases and highlights the need for continued systems improvements to reduce these avoidable errors. These three interventions—additional provider education in a broad range of healthcare settings regarding recognition and management of anaphylaxis; provision of epinephrine autoinjectors or other alternatives to reduce doing errors; and stronger safeguards to prevent exposure to known triggers—would all likely decrease the patient morbidity and mortality associated with anaphylaxis as well as reduce providers’ legal vulnerability to anaphylaxis-related lawsuits.\n\nSection Editor: Greg P. Moore, MD, JD\n\nFull text available through open access at http://escholarship.org/uc/uciem_westjem\n\nConflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. No author has professional or financial relationships with any companies that are relevant to this study. There are no conflicts of interest or sources of funding to declare.\n\nTable 1 Characteristics of cases, patients, and outcomes of 30 lawsuits related to anaphylaxis.\n\n\tN (%)\t\nPatient demographics\t\n Female\t22 (73%)\t\n Male\t8 (27%)\t\n Pediatric patient (age <18 yrs)\t3 (10%)\t\nInciting trigger\t\n IV contrast\t12 (40%)\t\n Latex\t2 (7%)\t\n Cephalosporin\t2 (7%)\t\n Other medication\t8 (27%)\t\n Food\t2 (7%)\t\n Insect sting\t2 (7%)\t\n Not reported\t2 (7%)\t\nPatient outcomea\t\n Death\t16 (53%)\t\n Permanent neurologic damageb\t5 (17%)\t\n Permanent cardiac dysfunction\t4 (13%)\t\n Non-fatal cardiac arrest\t4 (13%)\t\n ICU admission\t4 (13%)\t\n Other severe reaction (hospitalization, long-term consequences)\t3 (10%)\t\nDefendant named in lawsuitc\t\n Physician\t15 (50%)\t\n Hospital\t13(43%)\t\n Nurse\t5 (17%)\t\n Other (clinic, radiology technician, school, EMS, rehab facility)\t6 (20%)\t\nPhysician specialty (if specified)c\t\n Radiology\t3 (10%)\t\n Primary care (internal medicine, family medicine)\t3 (10%)\t\nEmergency medicine\t2 (7%)\t\n Anesthesiology\t2 (7%)\t\n Cardiology\t2 (7%)\t\n Other (plastic surgery, otolaryngology, urology, ophthalmology, neurology, obstetrics)\t6 (20%)\t\nReason for lawsuitd\t\n Exposure to known trigger\t14 (47%)\t\n Delayed diagnosis/inadequate treatment\t12 (40%)\t\n Inappropriate administration of IV epinephrine\t5 (17%)\t\n Inadequate pretreatment for contrast\t3 (10%)\t\nOutcome of lawsuit\t\n No liability\t14 (47%)\t\n Negligence\t8 (27%)\t\n Settlement\t3 (10%)\t\n Unknown\t5 (17%)\t\n Amount of settlement/judgment\tMean (range)\t\n Cases ending in finding of negligence\t$1,407,368 ($27,500 – 4,500,000)\t\n Cases ending in settlement\t$376,667 ($250,000 – 440,000)\t\nIV, intravenous; ICU, intensive care unit; EMS, emergency medical services.\n\na Some patients had more than one outcome.\n\nb Includes case in which permanent neurologic injury was caused to baby in utero allegedly from maternal hypotension leading to fetal hypoxia.\n\nc Some cases named more than one defendant or specialty.\n\nd Some cases had more than one reason for the lawsuit.\n\nTable 2 Summary table of Individual legal cases related to anaphylaxis.\n\nYear of report\tLegal outcome ($ amount)\tTrigger\tDefendant\tPatient outcome\tReason(s) for lawsuit\t\n2016\tNo Liability\tMedication (cephalosporin)\tHospital\tAnaphylaxis and hospitalization\taExposure (prior cephalosporin allergic reaction)\t\n2015\tNo Liability\tMedication (ranitidine)\tHospital\tbHypoxic brain injury of fetus resulting in permanent neurologic dysfunction\tExposure (known allergy)\t\n2015\tNo Liability\tIV Contrast\tHospital and radiology technician\tDeath\tFailure to identify risk factors for allergic reaction\t\n2015\tNegligence ($3,615,000)\tIV Contrast\tED physicians, OB physician, and hospital\tPermanent neurologic dysfunction\tExposure (known allergy)\t\n2015\tNegligence ($842,340)\tIV Contrast\tRadiologist\tFall, disfigurement, and disability\tInadequate treatment\t\n2014\tNo Liability\tIV Contrast\tRadiologist\tCardiac arrest, permanent cardiac and neurologic dysfunction\tInadequate treatment (delayed)\t\n2014\tNo Liability\tMedication (cephalosporin)\tClinic and provider\tDeath\tInadequate treatment (delayed)\t\n2014\tNegligence ($4,500,000)\tIV Contrast (MRI)\tNeurologist\tDeath\tExposure (known allergy) and inadequate treatment\t\n2014\tUnknown\tBee sting\tHospital and emergency department nurse\tPermanent cardiac dysfunction\tInappropriate IV epinephrine\t\n2014\tNo Liability\tNot reported\tSchool district and nurse\tDeath\tInadequate treatment (no epinephrine)\t\n2014\tUnknown\tLatex\tHospital, otolaryngologist, anesthesiologist\tICU admission\tExposure (known allergy)\t\n2014\tNo Liability\tMedication (acetaminophen)\tHospital\tICU admission\tInappropriate IV epinephrine\t\n2014\tNo Liability\tMedication (morphine)\tEmergency medical services company\tDeath\tInadequate treatment (epinephrine after cardiac arrest)\t\n2013\tUnknown\tIV Contrast\tHospital, physician\tDeath\tExposure (known allergy)\t\n2013\tNo Liability\tFood (blueberries)\tSchool nurse, school, city\tDeath\tExposure (known allergy), inadequate treatment (epinephrine delayed)\t\n2013\tUnknown\tMedication (methylprednisolone)\tHome infusion nurse\tDeath\tInadequate treatment (no epinephrine available)\t\n2013\tNegligence ($375,000)\tIV Contrast\tFamily med physician/clinic\tDeath\tInadequate treatment (delayed)\t\n2013\tNo Liability\tIV Contrast\tOphthalmologist\tDeath\tFailure to premedicate patient with “iodine allergy,” inadequate treatment\t\n2013\tNegligence ($430,000)\tMedication (Vicodin)\tUrologist and hospital\tDeath\tExposure (to oxycodone) and inadequate treatment (delayed)\t\n2013\tSettlement ($440,000)\tNot reported\tNot reported\tCardiac arrest, permanent neurologic and cardiac dysfunction\tInappropriate IV epinephrine\t\n2012\tSettlement ($250,000)\tFood (chocolate)\tRehabilitation facility\tDeath\tExposure (known allergy)\t\n2012\tNegligence ($1,000,000)\tIV Contrast\tCardiologist\tDeath\tExposure (inadequate pretreatment for known contrast allergy)\t\n2012\tSettlement ($440,000)\tIV Contrast\tRadiologist\tCardiac arrest, permanent cardiomyopathy\tInappropriate IV epinephrine\t\n2012\tUnknown\tIV Contrast\tInternist, cardiologist, hospital\tDeath\tFailure to premedicate patient with shellfish allergy\t\n2012\tNo Liability\tIV Contrast\tHospital\tDebilitating fatigue\tExposure (known allergy)\t\n2012\tNegligence ($27,500)\tBee sting\tHospital\tICU admission\tInappropriate IV epinephrine\t\n2011\tNegligence ($4,691,000)\tLatex\tHospital and surgical nurses\tDeath\tExposure (known allergy)\t\n2011\tNo Liability\tMedication (NSAID)\tEmergency physician\tICU admission\tExposure (known allergy)\t\n2011\tNo Liability\tMedication (lidocaine)\tPlastic surgeon\tCardiac arrest, permanent cardiac and neurologic damage\tExposure (known allergy)\t\n2011\tNo Liability\tMedication (not specified)\tAnesthesiologist\tDeath\tDelayed airway intervention\t\nIV, intravenous; ICU, intensive care unit; MRI, magnetic resonance imaging; ED, emergency department; OB, obstetrics; NSAID, nonsteroidal anti-inflammatory drug.\n\na Patient’s prior medication allergy had been inappropriately documented.\n\nb Secondary to maternal hypotension.\n\nExposure indicates exposure to substance to which the patient had had a prior allergic reaction.\n==== Refs\nREFERENCES\n1 Sampson HA Munoz-Furlong A Campbell RL Second symposium on the definition and management of anaphylaxis: summary report—Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium J Allergy Clin Immunol 2006 117 2 391 7 16461139 \n2 Pumphrey RSH Lessons for management of anaphylaxis from a study of fatal reactions Clin Exp Allergy 2000 20 1144 50 \n3 Campbell RL Li JTC Nicklas RA Emergency department diagnosis and treatment of anaphylaxis: a practice parameter Ann Allergy Asthma Immunol 2014 113 599 608 25466802 \n4 Kanwar M Irvin CB Frank JJ Confusion about epinephrine dosing leading to iatrogenic overdose: a life-threatening problem with a potential solution Ann Emerg Med 2010 55 4 341 4 20031267 \n5 Campbell RL Bellolio MF Knutson BD Epinephrine in anaphylaxis: higher risk of cardiovascular complications and overdose after administration of intravenous bolus epinephrine compared with intramuscular epinephrine J Allergy Clin Immunol 2015 3 1 76 80 \n6 Lightfoot CB Abraham RJ Mammen T Survey of radiologists’ knowledge regarding management of severe contrast material-induced allergic reactions Radiology 2009 251 3 691 6 19474374 \n7 Nowak R Farrar JR Brenner BE Customizing anaphylaxis guidelines for emergency medicine J Emerg Med 2013 45 2 299 306 23643240 \n8 Liang BA Zivin JA Empirical characteristics of litigation involving tissue plasminogen activator and ischemic stroke Ann Emerg Med 2008 52 2 160 4 18313798 \n9 Lindor RA Campbell RL Pines JM EMTALA and patients with psychiatric emergencies: a review of relevant case law Ann Emerg Med 2014 64 5 439 44 24491351 \n10 Kaji AH Schriger D Green S Looking through the retrospectoscope: reducing bias in emergency medicine chart review studies Ann Emerg Med 2014 64 3 292 8 24746846 \n11 The American Heart Association in collaboration with the International Liaison Committee on Resuscitation Guidelines 2000 for Cardiopulmonary Resuscitation and Emergency Cardiovascular Care. Part 8: advanced challenges in resuscitation: section 3L special challenges in ECC Circulation 2000 102 Suppl 8 1241 3 \n12 Sclar DA Lieberman PL Anaphylaxis: underdiagnosed, underreported, and undertreated Am J Med 2014 127 Suppl 1 S1 5 \n13 Krugman SD Chiaramonte DR Matsui EC Diagnosis and management of food-induced anaphylaxis: a national survey of pediatricians Pediatrics 2006 118 3 e554 60 16950947 \n14 Ferreira MB Alves RR Are general practitioners alert to anaphylaxis diagnosis and treatment? Eur Ann Allergy Clin Immunol 2006 38 3 83 6 16752692 \n15 Campbell RL Hagan JB Manivannan V Evaluation of National Institute of Allergy and Infectious Diseases/Food Allergy and Anaphylaxis Network criteria for the diagnosis of anaphylaxis in emergency department patients J Allergy Clin Immunol 2012 129 3 748 52 22051698 \n16 Clark S Bock SA Gaeta TJ Multicenter study of emergency department visits for food allergies J Allergy Clin Immunol 2004 113 2 347 52 14767453 \n17 Wood JP Traub SJ Lipinski C Safety of epinephrine for anaphylaxis in the emergency department setting World J Emerg Med 2013 4 4 245 51 25215127 \n18 Wang CL Cohan RH Ellis JH Frequency, outcome, and appropriateness of treatment of nonionic iodinated contrast media reactions AJR Am J Roentgenol 2008 191 2 409 15 18647910 \n19 Manivannan V Hess EP Bellamkonda VR A multi-faceted intervention for patients with anaphylaxis increases epinephrine use in adult emergency department J Allergy Clin Immunol Pract 2014 2 3 294 9.e1 24811020 \n20 Campbell RL Bellolio MF Motosue MS Autoinjectors preferred for intramuscular epinephrine in anaphylaxis and allergic reactions West J Emerg Med 2016 17 6 775 82 27833688 \n21 Kerddonfak S Manuyakorn W Kamchaisatian W The stability and sterility of epinephrine prefilled syringe Asian Pac J Allergy Immunol 2010 28 1 53 7 20527517 \n22 Pumphrey RSH Roberts SD Postmortem findings after fatal anaphylactic reactions J Clin Pathol 2000 53 273 76 10823122 \n23 Greenberger PA Rotskoff BD Lifschultz B Fatal anaphylaxis: postmortem findings and associated comorbid disease Ann Allergy Asthma Immunol 2007 98 3 252 7 17378256\n\n",
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"abstract": "Evans syndrome is an uncommon disease characterized by a combination of autoimmune hemolytic anemia and autoimmune thrombocytopenia concomitantly or sequentially with a positive direct Coombs test in the absence of any underlying known cause. Here, we present a case of an adult patient who underwent living-donor liver transplant that was preceded by bone marrow transplant 20 years earlier from the same HLA identical donor and who received a single-agent immunosuppressive therapy for only 2 months as prophylaxis against graft-versus-host disease. Two months after transplant, he developed Evans syndrome with severe anemia and thrombocytopenia. After administration of steroids and intravenous immunoglobulin, the patient's anemia and thrombocytopenia improved dramatically. Through the 7 years of follow-up, the patient has not developed graft-versus-host disease or acute or chronic rejection. This case demonstrates a rare complication posttransplant and the possibility of functional tolerance of liver grafts after a combined liver and bone marrow transplant from the same donor.",
"affiliations": ">From the Hepato-Biliary-Pancreatic Surgery and Transplantation Department, Kyoto University, Kyoto, Japan; and the General Surgery Department, Alexandria University, Alexandria, Egypt.",
"authors": "Badawy|Amr|A|;Kaido|Toshimi|T|;Atsushi|Yoshizawa|Y|;Yagi|Shintaro|S|;Hata|Koichiro|K|;Kamo|Naoko|N|;Fukumitsu|Ken|K|;Okajima|Hideaki|H|;Uemoto|Shinji|S|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.2018.0005",
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"issue": "18(2)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000744:Anemia, Hemolytic, Autoimmune; D016026:Bone Marrow Transplantation; D003298:Coombs Test; D006648:Histocompatibility; D006801:Humans; D007166:Immunosuppressive Agents; D016031:Liver Transplantation; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D013921:Thrombocytopenia; D023001:Transplantation Tolerance; D016896:Treatment Outcome",
"nlm_unique_id": "101207333",
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"pages": "258-260",
"pmc": null,
"pmid": "29911962",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Evans Syndrome After Successful Immunosuppressant-Free Living-Donor Liver Transplant.",
"title_normalized": "evans syndrome after successful immunosuppressant free living donor liver transplant"
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"literaturereference": "BADAWY A, KAIDO T, YOSHIZAWA A, YAGI S, HATA K, KAMO N, ET AL.. EVANS SYNDROME AFTER SUCCESSFUL IMMUNOSUPPRESSANT-FREE LIVING-DONOR LIVER TRANSPLANT. EXPERIMENTAL AND CLINICAL TRANSPLANTATION. 2020?18(2):258-60",
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"abstract": "BACKGROUND\nEvidence from clinical trials shows rivaroxaban to be effective for the treatment of deep vein thrombosis. Switching to rivaroxaban following failure of indirect anticoagulants in deep vein thrombosis has not been demonstrated in a real-life setting.\n\n\nMETHODS\nA 43-year-old white woman was switched from warfarin to rivaroxaban for the treatment of thrombosis of her right common femoral vein after saphenectomy. The reason for the switch was due to the instability of anti-coagulation therapy with vitamin K antagonists over a period of 3 months during which she did not reach the \"therapeutic range\" of prothrombin time-international normalized ratio. The ineffectiveness of the conventional oral anticoagulant was confirmed by persistence of moderate-high values of fibrin D dimers (780 ng/ml) and by residual vein thrombosis at an ultrasound examination. Objectively, her right leg appeared to be still edematous and warm and pain was elicited by deep palpation. Rivaroxaban was administered after warfarin discontinuation (prothrombin time-international normalized ratio = 1.43) at a dosage of 15 mg every 12 hours for 3 weeks, followed by 20 mg once daily for 3 months. After this period, her objective symptoms significantly improved, with reduction of edema of her lower limb and pain relief. Her fibrin D dimer values returned to normal (210 ng/ml). An ultrasound showed recanalization of the obstructed venous segment.\n\n\nCONCLUSIONS\nIn this case report, a switch to rivaroxaban from warfarin was shown to be effective and safe for the treatment of postoperative deep vein thrombosis, whereas standard oral anticoagulation therapy, which required dose adjustments over a period of 3 months, was not able to stabilize the therapeutic range of prothrombin time-international normalized ratio nor improve our patient's outcome.",
"affiliations": "Department of Internal Medicine Hospital, Hemophilia and Rare Coagulopathies Centre, \"I. Veris Delli Ponti\", 73020, Scorrano, Azienda Sanitaria Locale di Lecce, Italy. marioschiavoni@gmail.com.;Department of Internal Medicine Hospital, Hemophilia and Rare Coagulopathies Centre, \"I. Veris Delli Ponti\", 73020, Scorrano, Azienda Sanitaria Locale di Lecce, Italy.",
"authors": "Schiavoni|Mario|M|;Coluccia|Antonella|A|",
"chemical_list": "D000925:Anticoagulants; D014859:Warfarin; D000069552:Rivaroxaban",
"country": "England",
"delete": false,
"doi": "10.1186/s13256-016-1058-5",
"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 105810.1186/s13256-016-1058-5Case ReportSuccessful use of rivaroxaban in postoperative deep vein thrombosis of the lower limb following instability with warfarin: a case report Schiavoni Mario +390836420677marioschiavoni@gmail.com Coluccia Antonella antonellacoluccia40@gmail.com Department of Internal Medicine Hospital, Hemophilia and Rare Coagulopathies Centre, “I. Veris Delli Ponti”, 73020 Scorrano, Azienda Sanitaria Locale di Lecce Italy 5 10 2016 5 10 2016 2016 10 2769 6 2016 7 9 2016 © The Author(s). 2016\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nEvidence from clinical trials shows rivaroxaban to be effective for the treatment of deep vein thrombosis. Switching to rivaroxaban following failure of indirect anticoagulants in deep vein thrombosis has not been demonstrated in a real-life setting.\n\nCase presentation\nA 43-year-old white woman was switched from warfarin to rivaroxaban for the treatment of thrombosis of her right common femoral vein after saphenectomy. The reason for the switch was due to the instability of anti-coagulation therapy with vitamin K antagonists over a period of 3 months during which she did not reach the “therapeutic range” of prothrombin time-international normalized ratio.\n\nThe ineffectiveness of the conventional oral anticoagulant was confirmed by persistence of moderate-high values of fibrin D dimers (780 ng/ml) and by residual vein thrombosis at an ultrasound examination. Objectively, her right leg appeared to be still edematous and warm and pain was elicited by deep palpation. Rivaroxaban was administered after warfarin discontinuation (prothrombin time-international normalized ratio = 1.43) at a dosage of 15 mg every 12 hours for 3 weeks, followed by 20 mg once daily for 3 months. After this period, her objective symptoms significantly improved, with reduction of edema of her lower limb and pain relief. Her fibrin D dimer values returned to normal (210 ng/ml). An ultrasound showed recanalization of the obstructed venous segment.\n\nConclusions\nIn this case report, a switch to rivaroxaban from warfarin was shown to be effective and safe for the treatment of postoperative deep vein thrombosis, whereas standard oral anticoagulation therapy, which required dose adjustments over a period of 3 months, was not able to stabilize the therapeutic range of prothrombin time-international normalized ratio nor improve our patient’s outcome.\n\nKeywords\nRivaroxabanWarfarinPostoperative deep venous thrombosisCase reportBayer Healthcare Italyissue-copyright-statement© The Author(s) 2016\n==== Body\nBackground\nAnticoagulant therapy is effective for the treatment of acute venous thromboembolism (VTE): deep vein thrombosis (DVT) and pulmonary embolism (PE) [1]. For more than half a century, standard anticoagulant therapy with heparin (mainly subcutaneous low molecular weight heparin; LMWH) overlapped and followed by oral vitamin K antagonists (VKAs), such as warfarin, represented the mainstay recommended by guidelines worldwide [2]. The combination of LMWH/VKAs given for ≥3 months is capable of significantly reducing morbidity and mortality, preventing recurrent thromboembolism (RTE) during the acute phase and avoiding long-term complications such as post-thrombotic syndrome (PTS) and secondary pulmonary hypertension (SPH) after PE [3]. However, one of the major limitations of oral VKAs is the need for laboratory monitoring by prothrombin time test expressed as the international normalized ratio (PT-INR). In fact, this parameter must be kept in a “therapeutic range” of 2 to 3 (target 2.5) throughout the entire course of therapy (that is, time in therapeutic range; TTR), and this goal is achieved by dose adjustments. Unfortunately, it is not always possible to obtain optimal values of PT-INR due to several variables that may interfere with VKAs, such as concomitant medications and some foods, making the anticoagulant effect unstable and therefore increasing the risk of failure.\n\nRecently, novel drugs termed “direct oral anticoagulants” (DOACs) have been introduced in clinical practice, including dabigatran, rivaroxaban, apixaban, and edoxaban, that were shown to be effective for the treatment of VTE [4–7], and represented an alternative to VKAs (defined as “indirect oral anticoagulants” [8]). DOACs have demonstrated the same efficacy and safety as standard therapy with combined LMWH/warfarin, but with the advantage of not requiring any laboratory monitoring with dose adjustments, due to a stable anticoagulant effect. In particular, in two clinical studies conducted in the setting of VTE (proximal DVT and PE) [5, 6], the efficacy of rivaroxaban was shown to be not inferior to that of conventional anticoagulant therapy. In a pooled analysis of the two studies, the drug also yielded a similar incidence of the main safety outcome but a significant reduction in the incidence of major bleeding: hazard ratio 0.54; 95 % confidence interval (CI) 0.37 to 0.79; p = 0.002 [9]. In randomized clinical trials, rivaroxaban was used for the initial treatment of an acute thrombotic event with a high dose (15 mg twice daily) administered for 3 weeks followed by a standard monodose (20 mg once daily) without the support of LMWH [5, 6]. Yet, in the real-life setting of DVT, no information is available on the switch to rivaroxaban after clinical failure with warfarin.\n\nCase presentation\nA 43-year-old white woman underwent saphenectomy (Table 1) of her right lower limb because of severe venous insufficiency caused by varicose syndrome (Fig. 1). An ultrasound examination of superficial and deep veins of her lower limbs carried out before surgery was judged normal. The surgical intervention of “stripping” was performed using traditional techniques, with no apparent perioperative complications. Her postoperative course appeared normal.Table 1 Intervention timeline\n\nIntervention\tTime point\t\nSaphenectomy\tDay 0\t\nEdema due to postoperative proximal DVT; start of anticoagulant therapy (enoxaparin and warfarin)\tDay 4\nUp to 3 months\t\nTherapy with rivaroxaban\tMonth 4 to 6\t\n\nDVT deep vein thrombosis\n\n\nFig. 1 Varicose syndrome of right lower limb\n\n\n\n\nPostoperative deep venous thrombosis\nDespite all precautions, including early mobilization, on the fourth postoperative day (Table 1) she experienced a significant edema of her right lower limb, which appeared warm and tense. Subjectively, an acute and persistent pain was referred. Laboratory tests showed a moderate increase in leukocytes (15.7 × 103/μl, reference values up to 10 × 103/μl) and elevated levels of fibrin D dimers (1800 ng/ml; reference values up to 250 ng/ml). An ultrasound examination (Philips HD7; 7.5 MHz linear array transducer) revealed the presence of thrombosis of her common femoral vein in her operated limb (Fig. 2). Diagnosis of postoperative proximal DVT was made (Table 1).Fig. 2 Ultrasound image of thrombosis of right common femoral vein\n\n\n\n\nAnticoagulant therapy\nAnticoagulant therapy with enoxaparin at a dosage of 100 IU/Kg subcutaneously every 12 hours was started overlapped with warfarin at adjusted dosage (Table 1). Heparin treatment was stopped when her PT-INR reached values between 2.0 and 2.5. She was discharged from our hospital with the indication to continue oral anticoagulants over a period of 3 months and to perform periodic laboratory monitoring (therapeutic range of PT-INR 2.0 to 3.0, target 2.5) initially every week (until optimal PT-INR) and every 3 weeks afterwards. An appropriate compression by elastic stockings was also prescribed [10].\n\nInstability of conventional anticoagulant therapy\nLaboratory tests were periodically performed in order to monitor the efficacy of oral anticoagulant therapy with warfarin. Despite frequent dose adjustments, values of PT-INR in the “therapeutic” range were reached only once (Fig. 3).Fig. 3 Instability of prothrombin time-international normalized ratio monitoring during the 3-month period of therapy with warfarin. Orange highlighted area shows instability range\n\n\n\n\nShe subjectively presented heaviness and aching of her right lower limb, which appeared objectively still hot and swollen with an increased circumference of 0.5 to 2.5 cm in comparison with her left leg (Fig. 4). Her values of fibrin D dimers were moderately high (780 ng/ml) and a residual vein thrombosis was shown by the echoDoppler (Fig. 5).Fig. 4 Swelling of the right leg compared with left leg after 3-month period of therapy with warfarin\n\n\nFig. 5 Residual thrombosis (circle) of right common femoral vein after 3-month period of therapy with warfarin\n\n\n\n\nSwitch to rivaroxaban\nBecause of the instability of conventional oral anticoagulants and the poor clinical outcome, warfarin was discontinued when her value of PT-INR was 1.43. Rivaroxaban was started at an intensive dosage of 15 mg every 12 hours for 3 weeks, followed by 20 mg/day for 3 months (Table 1).\n\nPatient outcome\nThree months after the induction of rivaroxaban, she showed a significant improvement in symptoms, with an objective evident reduction of edema of her right leg (Fig. 6), as well as a subjective pain relief with recovery of walking without interruption. Laboratory monitoring showed a return to a normal leukocyte count (8.7 × 103/μl) and fibrin D dimers values (210 ng/ml). An ultrasound examination confirmed the complete resolution of DVT (Fig. 7).Fig. 6 The right leg compared with the left leg after 3-month therapy with rivaroxaban\n\n\nFig. 7 Ultrasound image of the complete resolution of the right common femoral vein thrombosis after 3-month therapy with rivaroxaban\n\n\n\n\nDiscussion\nVTE including DVT and PE is a serious clinical condition that requires anticoagulants as first-line treatment [11]. Currently, conventional therapy consists of LMWH followed by VKAs. Although this approach is effective, it has some limitations, such as the need for frequent laboratory monitoring and, often, difficulty in reaching the therapeutic range of the PT-INR with consequent instable anticoagulant effect and poor clinical outcome. The inadequate management of VTE by standard VKAs may cause RTE and long-term serious sequelae including PTS and chronic SPH in case of PE, which represent a further burden for these patients [11].\n\nWhen used as monotherapy for VTE, rivaroxaban showed similar efficacy and safety compared to the current standard therapy, but without the need for routine laboratory monitoring [9, 11]. In our patient, the instability of conventional anticoagulation therapy with combined LMWH/warfarin as well as the persistence of objective and subjective symptoms after 3 months of treatment led us to switch from warfarin to rivaroxaban for a period of 3 more months. Oral rivaroxaban was able to induce complete resolution of her venous thrombosis, as shown by clinical, laboratory, and ultrasound imaging results. Neither bleedings nor renal venous thrombosis (RVT) was observed during her entire course of treatment. Conversely, the conventional adjusted therapy with LMWH/warfarin could not stabilize her PT-INR and did not improve her clinical outcome.\n\nOur patient was switched to rivaroxaban after discontinuation of warfarin, when her PT-INR value was 1.43, according to recent recommendations, although not evidence based [12]. In fact, to the best of our knowledge, this is the first example of switching to rivaroxaban in the treatment of DVT. In fact, this strategy has been investigated but only in healthy individuals and with regard to the pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban [13].\n\nConclusions\nGiven the positive outcome, our approach may be considered in similar clinical situations. In our experience, switching to rivaroxaban from conventional combined therapy with LMWH/warfarin was effective and easily manageable. Neither undesirable side effects nor complications such as RTE and bleeding occurred throughout the treatment period. Worth noting, the simple once-daily oral administration of rivaroxaban improved patient adherence to the extended period of anticoagulant therapy.\n\nAbbreviations\nCIConfidence interval\n\nDOACsDirect oral anticoagulants\n\nDVTDeep vein thrombosis\n\nLMWHLow molecular weight heparin\n\nPEPulmonary embolism\n\nPT-INRProthrombin time test expressed as the international normalized ratio\n\nPTSPost-thrombotic syndrome\n\nRTERecurrent thromboembolism\n\nRVTRenal venous thrombosis\n\nSPHSecondary pulmonary hypertension\n\nTTRTime in therapeutic range\n\nVKAsVitamin K antagonists\n\nVTEVenous thromboembolism\n\nAcknowledgements\nThe authors would like to thank Dr Colin Gerard Egan and Dr Clara Ricci (Primula Multimedia SRL, Pisa, Italy) who provided skillful editorial assistance. Financial support for editorial services was provided by Bayer HealthCare, Italy.\n\nFunding\nFinancial support for editorial services was provided by Bayer HealthCare, Italy. Bayer HealthCare was not involved in the study design, or in the collection, analysis, and interpretation of data.\n\nAvailability of data and materials\nNo relevant software, database, and raw data besides those reported in the main text are available.\n\nAuthors’ contributions\nBoth authors participated in the acquisition and interpretation of clinical data and writing of this case report. Both authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n==== Refs\nReferences\n1. Goldhaber SZ Bounameaux H Pulmonary embolism and deep vein thrombosis Lancet 2012 379 1835 46 10.1016/S0140-6736(11)61904-1 22494827 \n2. Kearon C Akl EA Comerota AJ Prandoni P Bounameaux H Goldhaber SZ Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines Chest 2012 141 e419S 94 10.1378/chest.11-2301 22315268 \n3. Cohen AT Agnelli G Anderson FA Arcelus JI Bergqvist D Brecht JG Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality Thromb Haemost 2007 98 756 64 17938798 \n4. Schulman S Kearon C Kakkar AK Mismetti P Schellong S Eriksson H Dabigatran versus warfarin in the treatment of acute venous thromboembolism N Engl J Med 2009 361 2342 52 10.1056/NEJMoa0906598 19966341 \n5. EINSTEIN Investigators Bauersachs R Berkowitz SD Brenner B Buller HR Decousus H Oral rivaroxaban for symptomatic venous thromboembolism N Engl J Med 2010 363 2499 510 10.1056/NEJMoa1007903 21128814 \n6. EINSTEIN–PE Investigators Büller HR Prins MH Lensin AWA Decousus H Jacobson BF Oral rivaroxaban for the treatment of symptomatic pulmonary embolism N Engl J Med 2012 366 1287 97 10.1056/NEJMoa1113572 22449293 \n7. Hokusai-VTE Investigators Büller HR Décousus H Grosso MA Mercuri M Middeldorp S Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism N Engl J Med 2013 369 1406 15 10.1056/NEJMoa1306638 23991658 \n8. Hillis CM Crowther MA Acute phase treatment of VTE: Anticoagulation, including non-vitamin K antagonist oral anticoagulants Thromb Haemost 2015 113 1193 202 10.1160/TH14-12-1036 25948149 \n9. Prins MH Lensing AW Bauersachs R van Bellen B Bounameaux H Brighton TA Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies Thromb J 2013 11 21 10.1186/1477-9560-11-21 24053656 \n10. Kahn SR Shapiro S Wells PS Rodger MA Kovacs MJ Anderson DR Compression stockings to prevent post-thrombotic syndrome: a randomised placebo-controlled trial Lancet 2014 383 880 8 10.1016/S0140-6736(13)61902-9 24315521 \n11. Simon McRae. Treatment options for venous thromboembolism: lessons learnt from clinical trials. Thromb J. 2014;12(1):27.\n12 Schulman S Crowther MA How I treat with anticoagulants in 2012: new and old anticoagulants, and when and how to switch Blood 2012 119 3016 23 10.1182/blood-2011-10-378950 22302737 \n13 Kubitza D Becka M Mück W Krätzschmar J Pharmacodynamics and pharmacokinetics during the transition from warfarin to rivaroxaban: a randomized study in healthy subjects Br J Clin Pharmacol 2014 78 353 63 10.1111/bcp.12349 24528331\n\n",
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"keywords": "Case report; Postoperative deep venous thrombosis; Rivaroxaban; Warfarin",
"medline_ta": "J Med Case Rep",
"mesh_terms": "D000328:Adult; D000925:Anticoagulants; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D035002:Lower Extremity; D011183:Postoperative Complications; D000069552:Rivaroxaban; D016896:Treatment Outcome; D020246:Venous Thrombosis; D014859:Warfarin",
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"primarysource": {
"literaturereference": "SCHIAVONI M, COLUCCIA A. SUCCESSFUL USE OF RIVAROXABAN IN POSTOPERATIVE DEEP VEIN THROMBOSIS OF THE LOWER LIMB FOLLOWING INSTABILITY WITH WARFARIN: A CASE REPORT. JOURNAL OF MEDICAL CASE REPORTS. 2016;10 (276):1 TO 5",
"literaturereference_normalized": "successful use of rivaroxaban in postoperative deep vein thrombosis of the lower limb following instability with warfarin a case report",
"qualification": "3",
"reportercountry": "IT"
},
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"transmissiondate": "20170207"
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{
"abstract": "Osteoporosis is a skeletal disorder characterized by reduced bone strength that increases the risk for fracture. Approximately 10 million men and women in the United States have osteoporosis, and more than 2 million osteoporosis-related fractures occur annually. In 2016, the American Association of Clinical Endocrinologists issued the \"Clinical Practice Guideline for the Diagnosis and Treatment of Postmenopausal Osteoporosis,\" and in 2017, the American College of Physicians issued the guideline \"Treatment of Low Bone Density or Osteoporosis to Prevent Fracture in Men and Women.\" Both guidelines agree that patients diagnosed with osteoporosis should be treated with an antiresorptive agent, such as alendronate, that has been shown to reduce hip and vertebral fractures. However, there is no consensus on how long patients with osteoporosis should be treated and whether bone density should be monitored during and after the treatment period. In this Beyond the Guidelines, 2 experts discuss management of osteoporosis in general and for a specific patient, the role of bone density monitoring during and after a 5-year course of alendronate, and treatment recommendations for a patient whose bone density decreases during or after a 5-year course of alendronate.",
"affiliations": "Beth Israel Deaconess Medical Center, Boston, Massachusetts (R.B.B., H.R., S.B., G.W.S.).;Beth Israel Deaconess Medical Center, Boston, Massachusetts (R.B.B., H.R., S.B., G.W.S.).;Beth Israel Deaconess Medical Center, Boston, Massachusetts (R.B.B., H.R., S.B., G.W.S.).;Beth Israel Deaconess Medical Center, Boston, Massachusetts (R.B.B., H.R., S.B., G.W.S.).",
"authors": "Burns|Risa B|RB|;Rosen|Harold|H|;Berry|Sarah|S|;Smetana|Gerald W|GW|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D019386:Alendronate",
"country": "United States",
"delete": false,
"doi": "10.7326/M18-0950",
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"issn_linking": "0003-4819",
"issue": "168(11)",
"journal": "Annals of internal medicine",
"keywords": null,
"medline_ta": "Ann Intern Med",
"mesh_terms": "D015502:Absorptiometry, Photon; D000368:Aged; D019386:Alendronate; D015519:Bone Density; D050071:Bone Density Conservation Agents; D000066491:Clinical Decision-Making; D004164:Diphosphonates; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D015663:Osteoporosis, Postmenopausal; D058866:Osteoporotic Fractures; D017410:Practice Guidelines as Topic",
"nlm_unique_id": "0372351",
"other_id": null,
"pages": "801-808",
"pmc": null,
"pmid": "29868815",
"pubdate": "2018-06-05",
"publication_types": "D016429:Clinical Conference",
"references": null,
"title": "How Would You Manage This Patient With Osteoporosis?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center.",
"title_normalized": "how would you manage this patient with osteoporosis grand rounds discussion from beth israel deaconess medical center"
} | [
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{
"abstract": "A 64-year-old man presented to the emergency department with sudden-onset upper abdominal pain and pain in the left chest area. His platelet count was 121.7×104/µl. Computed tomography (CT) showed bilateral adrenal swelling and inflammation of the adjacent tissue. Diffusion-weighted magnetic resonance imaging (MRI) showed hyperintensity in the bilateral adrenal glands. The patient was diagnosed with bilateral adrenal infarction. A bone marrow biopsy yielded a diagnosis of essential thrombocythemia, and a positive JAK2 V617F mutation was detected. He presented with recurrent adrenal infarction and developed aortic mural thrombosis and splenic infarction. We administered aspirin and performed cytoreductive therapy with hydroxyurea and anagrelide; however, the patient then went into heart failure resulting from coronary artery stenosis. We then added prasugrel to the list of medicines administered to manage his condition. Bilateral adrenal infarction is a very rare thrombotic event of essential thrombocythemia. CT and MRI were useful for making the diagnosis; however, we also had to rule out acute coronary syndrome or intestinal ischemia. Our patient presented with strong thrombotic diathesis, which prompted us to use dual antiplatelet therapy; however, further studies are needed to confirm the efficacy and safety of this treatment.",
"affiliations": "Department of Hematology, Kyoto City Hospital.;Department of Hematology, Kyoto City Hospital.;Department of Hematology, Kyoto City Hospital.;Department of Hematology, Kyoto City Hospital.;Department of Hematology, Kyoto City Hospital.;Department of Hematology, Kyoto City Hospital.;Department of Hematology, Kyoto City Hospital.;Department of Hematology, Kyoto City Hospital.",
"authors": "Iemura|Tomoki|T|;Mano|Chihiro|C|;Oba|Akifumi|A|;Kawabata|Norihiro|N|;Horisawa|Yoshihito|Y|;Matsui|Masashi|M|;Miyahara|Yasuko|Y|;Itoh|Mitsuru|M|",
"chemical_list": "D001241:Aspirin; D006918:Hydroxyurea",
"country": "Japan",
"delete": false,
"doi": "10.11406/rinketsu.60.106",
"fulltext": null,
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"issn_linking": "0485-1439",
"issue": "60(2)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Adrenal infarction; Dual antiplatelet therapy; Essential thrombocythemia",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000307:Adrenal Gland Diseases; D000311:Adrenal Glands; D000368:Aged; D001241:Aspirin; D006801:Humans; D006918:Hydroxyurea; D007238:Infarction; D008297:Male; D013920:Thrombocythemia, Essential; D013927:Thrombosis",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "106-111",
"pmc": null,
"pmid": "30842376",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Essential thrombocythemia accompanied by adrenal infarction.",
"title_normalized": "essential thrombocythemia accompanied by adrenal infarction"
} | [
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{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
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{
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],
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"literaturereference": "TOMOKI IEMURA, ET AL.. ESSENTIAL THROMBOCYTHEMIA ACCOMPANIED BY ADRENAL INFARCTION. THE JAPANESE JOURNAL OF CLINICAL HEMATOLOGY. 2019?60(2):106-111",
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] |
{
"abstract": "Allergic interstitial nephritis (AIN) is an underdiagnosed cause of acute kidney injury (AKI). Guidelines suggest that AIN should be suspected in a patient who presents with an elevated serum creatinine and a urinalysis that shows white cells, white cell casts, or eosinophiluria. Drug-induced AIN is suspected if AKI is temporally related to the initiation of a new drug. However, patients with bland sediment and normal urinalysis can also have AIN. Currently, a definitive diagnosis of AIN is made by renal biopsy which is invasive and fraught with risks such as bleeding, infection, and hematoma. Additionally, it is frequently unclear when a kidney biopsy should be undertaken. We describe a biopsy proven case of allergic interstitial nephritis which manifested on contrast enhanced Magnetic Resonance Imaging (MRI) as a striated nephrogram. Newer and more stable macrocyclic gadolinium contrast agents have a well-demonstrated safety profile. Additionally, in the presentation of AKI, gadolinium contrast agents are safe to administer in patients who demonstrate good urine output and a downtrending creatinine. We propose that the differential for a striated nephrogram may include AIN. In cases in which the suspicion for AIN is high, this diagnostic consideration may be further characterized by contrast enhanced MRI.",
"affiliations": "Division of Nephrology, University of Arizona Medical Center, Tucson, AZ 85724, USA.;Department of Pathology, University of Arizona Medical Center, Tucson, AZ 85724, USA.;Division of Nephrology, University of Arizona Medical Center, Tucson, AZ 85724, USA.;Division of Nephrology, University of Arizona Medical Center, Tucson, AZ 85724, USA.;Division of Nephrology, University of Arizona Medical Center, Tucson, AZ 85724, USA.;Department of Medical Imaging, University of Arizona Medical Center, Tucson, AZ 85724, USA.",
"authors": "Moinuddin|Irfan|I|;Bracamonte|Erika|E|;Thajudeen|Bijin|B|;Sussman|Amy|A|;Madhrira|Machaiah|M|;Costello|James|J|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2015/250530",
"fulltext": "\n==== Front\nCase Rep MedCase Rep MedCRIMCase Reports in Medicine1687-96271687-9635Hindawi Publishing Corporation 10.1155/2015/250530Case ReportAllergic Interstitial Nephritis Manifesting as a Striated Nephrogram Moinuddin Irfan \n1\n\n*\nBracamonte Erika \n2\nThajudeen Bijin \n1\nSussman Amy \n1\nMadhrira Machaiah \n1\nCostello James \n3\n1Division of Nephrology, University of Arizona Medical Center, Tucson, AZ 85724, USA2Department of Pathology, University of Arizona Medical Center, Tucson, AZ 85724, USA3Department of Medical Imaging, University of Arizona Medical Center, Tucson, AZ 85724, USA*Irfan Moinuddin: irfanmoinuddin@yahoo.comAcademic Editor: Masahiro Kohzuki\n\n2015 18 11 2015 2015 2505306 8 2015 10 11 2015 Copyright © 2015 Irfan Moinuddin et al.2015This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Allergic interstitial nephritis (AIN) is an underdiagnosed cause of acute kidney injury (AKI). Guidelines suggest that AIN should be suspected in a patient who presents with an elevated serum creatinine and a urinalysis that shows white cells, white cell casts, or eosinophiluria. Drug-induced AIN is suspected if AKI is temporally related to the initiation of a new drug. However, patients with bland sediment and normal urinalysis can also have AIN. Currently, a definitive diagnosis of AIN is made by renal biopsy which is invasive and fraught with risks such as bleeding, infection, and hematoma. Additionally, it is frequently unclear when a kidney biopsy should be undertaken. We describe a biopsy proven case of allergic interstitial nephritis which manifested on contrast enhanced Magnetic Resonance Imaging (MRI) as a striated nephrogram. Newer and more stable macrocyclic gadolinium contrast agents have a well-demonstrated safety profile. Additionally, in the presentation of AKI, gadolinium contrast agents are safe to administer in patients who demonstrate good urine output and a downtrending creatinine. We propose that the differential for a striated nephrogram may include AIN. In cases in which the suspicion for AIN is high, this diagnostic consideration may be further characterized by contrast enhanced MRI.\n==== Body\n1. Introduction\nMR angiography has a role in evaluating patients with suspected renovascular hypertension and renal vein thrombosis and MRI is useful in the evaluation of renal masses, including suspected or confirmed renal cell carcinoma. MRI is especially useful for distinguishing and characterizing complex solid and cystic masses [1, 2].\n\nThe MR nephrogram, defined as the imaging of opacified renal parenchyma following the administration of contrast material, can provide indispensable insight into the dynamic function of the kidney. Receiving approximately 25% of cardiac output, the kidneys improve avidly following contrast agent administration. The Computed Tomography (CT) and Magnetic Resonance Imaging (MRI) nephrograms are analogous imaging descriptions of the enhancement pattern of the renal cortex and medulla. Any process that elicits interstitial inflammation or edema can produce a variant of the CT or MR nephrogram, specifically called a striated nephrogram. Such processes as pyelonephritis, renal contusion, and tubular obstruction can produce a striated nephrogram, characterized by linear bands of alternating contrast enhancement oriented parallel to the axis of the tubules and the collecting ducts. There is currently no available noninvasive test to substantiate the diagnosis of AIN. If clinical suspicion of AIN is high, the observation of a CT or MR striated nephrogram can provide valuable information to help guide the clinicians towards a diagnosis.\n\nEarly renal enhancement on CT and MRI is termed the corticomedullary phase, an imaging stage when the peripheral renal cortex enhances more than the central renal medulla. The corticomedullary phase is followed by the nephrographic phase in which the renal cortex and medulla improve to roughly the same degree. Finally, in the excretory phase, a functioning kidney excretes the administered contrast material [3, 4].\n\nGlobal absence of the nephrogram highlights renal ischemia [5, 6]. Segmental absence may be due to renal space-occupying processes, hemodynamic changes in peripheral branches of the renal artery, or small vessel disease such as vasculitides [7, 8]. In the setting of renovascular compromise, the rim pattern represents preserved subcapsular perfusion by collateral flow [9, 10]. Temporal delay in the progression of the nephrogram may be attributed to a unilateral decrease in renal blood flow [11]. A persistent nephrogram may be due to systemic hypotension or acute tubular necrosis [12].\n\nA striated nephrogram is characterized by linear bands of contrast enhancement oriented parallel to the axis of the tubules and collecting ducts. Unilateral striated nephrograms have been associated with ureteric obstruction, acute pyelonephritis [13], renal contusion [14], and renal vein thrombosis. Bilateral striated nephrograms have been demonstrated in acute pyelonephritis [13], tubular obstruction [15], hypotension [12], and autosomal recessive polycystic kidney disease [16].\n\nOne of the most important imaging findings on MR is the direct identification of inflammation using T2 fat-saturated imaging. T2 fat-saturated sequences remove the contribution of the fat signal, leaving a description of contributing water signal. This technique details inflammation and is instrumental in the diagnosis of other inflammatory etiologies of the abdomen including acute cholecystitis, pancreatitis, and enteritis [17, 18].\n\nThere is a paucity of research concerning the clinical relevance of the striated nephrogram. Even reports of the appearance of the striated nephrogram in cases of pyelonephritis, renal contusion, and tubular obstruction are few and far between. This is the first report of acute allergic interstitial nephritis manifesting on gadolinium-enhanced MRI as a striated nephrogram.\n\n2. Materials/Methods and Results\nA 28-year-old male engineering graduate student with no significant past medical history presented with acute renal failure. He was in his usual state of good health when he went swimming in a pool and overexerted himself. Shortly after swimming, he developed a dull, bilateral, nonradiating flank pain. The emergency room physician attributed the pain to muscle spasm or muscle strain and advised him to take ibuprofen. Patient took 200 mg ibuprofen every 8 hours for 24 hours without relief, prompting a visit to his primary care physician, who advised him to stop taking the ibuprofen. Routine labs revealed a creatinine of 671 micromol/L, and the patient was admitted for further evaluation.\n\nIn the inpatient setting, the renal ultrasound was normal. CBC showed a white blood cell count of 7500/microliter with 2.1% eosinophils. Urinalysis revealed mild proteinuria and mild hematuria: specific gravity 1.004/pH 6.0/protein 100/RBC 2/WBC 4. The urine protein to creatinine ratio was 444 mg/g. With unexplained renal failure, the patient underwent a prompt renal biopsy. With a mildly elevated LDH of 4.34 microkat/L and concern for renal infarct, an MRI of the abdomen with and without gadolinium contrast was ordered to better characterize the renal cortex and medulla. Complements C3 and C4 were normal at 0.145 g/L (normal: 0.8–1.6 g/L) and 0.047 g/L (normal: 0.015–0.053 g/L), respectively. Cytoplasmic anti-neutrophil cytoplasmic antibodies (C-ANCA), perinuclear anti-neutrophil cytoplasmic antibodies (P-ANCA), and anti-nuclear antibodies (ANA) were all negative.\n\nThe kidney biopsy contained up to 23 viable glomeruli per level section with normal histologic appearance (no signs of inflammation, proliferation, segmental sclerosis, or other specific abnormalities). The interstitium was expanded by patchy edema and a mild to moderate chronic inflammatory infiltrate containing activated lymphocytes, histiocytes, and focal aggregates of eosinophils. There was no interstitial fibrosis or tubular atrophy. Muscular arteries and arterioles had no arteriosclerosis and showed no evidence of vasculitis. Immunofluorescence was performed; however, the sample was primarily renal medulla. Ultrastructural evaluation of the glomeruli was normal without evidence of immune deposits or podocyte abnormalities. The biopsy finding of active tubulointerstitial inflammation with eosinophils was most consistent with acute allergic interstitial nephritis (Figure 1).\n\nThe MRI of the abdomen demonstrated bilateral edematous kidneys with loss of the normal cortical medullary differentiation pattern. The unenhanced image does not provide dynamic information regarding the kidneys' uptake and excretion of contrast (Figure 2). Furthermore, the kidneys demonstrate a “striated nephrogram” appearance which is best visualized on contrast enhanced T1 fat-saturated imaging (Figure 3). This finding is best highlighted on 70-second portal venous phase imaging and 180 sec delayed phase imaging (Figure 4). The liver also demonstrated heterogeneous enhancement on T1 fat-saturated 20 sec arterial phase imaging. This finding is consistent with reactive inflammation of the liver (Figure 3). Axial T2-weighted fat-saturated images demonstrated increased inflammatory signal in the bilateral kidneys with the surrounding perinephric fluid (Figure 5).\n\nPatient was diagnosed with AIN attributable to unknown causes and treated with oral prednisone for a short course of two weeks with subsequent decrease in serum creatinine to 55.7 micromol/L.\n\n3. Discussion\nThe patient presented with a markedly elevated creatinine and acute renal failure. What were the possible contributing etiologies? Even sudden and complete loss of renal function would not raise the serum creatinine from normal to this level in only one day. It is far more likely that the renal injury causing AKI predated the creatinine measurement by at least 3 days or more. Thus, the AKI was not attributable to ibuprofen, particularly in a scenario of only three administered doses. Additionally, the patient reported no other outpatient medications. Within this context, the patient was diagnosed with AIN of unknown cause.\n\nAlthough some degree of peripheral eosinophilia may be present in AIN, peripheral eosinophilia is not an absolute criterion for the diagnosis of AIN. Urine eosinophils (EOS) demonstrate a prolonged turnaround time with poor sensitivity and specificity, and they are no longer recommended in the evaluation of AIN. In one study, urine EOS were found in a variety of kidney diseases besides AIN. At the commonly used 1% urine eos cutoff, the test does not shift pretest probability of AIN in any direction. Even at a 5% cutoff, urine eos performed poorly in distinguishing AIN from acute tubular necrosis or other kidney diseases [19].\n\nThe biopsy showed patchy edema and focal aggregates of eosinophils. This is consistent with AIN. Most cases of acute interstitial nephritis are characterized by focal infiltrates that are globally present [20]. A diffuse interstitial inflammatory process is not a prerequisite for the diagnosis of AIN. The biopsy also showed one or two partially denuded tubules, also consistent with AIN and tubular damage [21, 22].\n\nIn acute tubulointerstitial inflammation or edema, the cellular inflammatory infiltrate selectively increases parenchymal pressure within the affected medullary or cortical rays. Following the administration of an imaging contrast agent, these areas initially demonstrate decreased enhancement. With delayed imaging, the same areas may demonstrate enhancement that is increased relative to that of adjacent normal tissue. This nephrographic reversal is caused by tubular stasis in which contrast enters slowly and becomes hyperconcentrated in collecting ducts obstructed by inflammatory cells [23]. The end result is a striated nephrogram characterized by linear bands of alternating contrast enhancement oriented parallel to the axis of the tubules and the collecting ducts.\n\nIn the setting of acute kidney injury, questions may arise when ordering a gadolinium contrast enhanced MR exam. For patients with an acute drop in glomerular filtration rate (GFR), heightened attention must be heeded, but as long as the patient continues to produce urine and the GFR has demonstrated progressive interval improvement over an interval of a few days, a contrast enhanced MR exam can be pursued [24]. Moreover, recent data documents that the risk of nephrogenic systemic fibrosis is minimal with the newer and far more stable macrocyclic MR contrast agents. In the case of patients with good urine output and without documented stage 4 or stage 5 chronic kidney disease, the data indicates no increased risk for nephrogenic systemic fibrosis [25].\n\nThis report constitutes the first report of allergic interstitial nephritis manifesting on MRI as a striated nephrogram. The implications of this study are that allergic interstitial nephritis must be considered in the differential diagnosis of the striated nephrogram. Currently, there is no noninvasive means of substantiating a diagnosis of acute allergic interstitial nephritis. Our experience suggests that MR imaging evaluation of suspected cases of acute interstitial nephritis warrants further investigation.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 Renal cortex: the interstitium is expanded by edema and an inflammatory infiltrate containing lymphocytes, macrophages, and numerous eosinophils. H&E (200x magnification).\n\nFigure 2 Axial fat-saturated T1w precontrast image of the kidneys: the unenhanced image does not provide dynamic information regarding the kidneys' uptake and excretion of contrast.\n\nFigure 3 Axial fat-saturated T1w 20 second arterial phase contrast enhanced image: there is demonstration of heterogeneous enhancement of the renal cortex. Please note the “striated” appearance of the renal cortex (long arrows) which is also evident on 70-second venous phase and 180-second delayed venous phase imaging. Incidentally, the liver parenchyma also demonstrates heterogeneous enhancement (short arrow), consistent with inflammation.\n\nFigure 4 Axial fat-saturated T1w 180 second delayed venous phase contrast enhanced image: there is better conspicuity of the “striated” enhancement pattern (arrows) which is evident in both the renal cortex and the medulla. This finding contrasts with Figure 3 where the “striated” pattern is only evident with the renal cortex.\n\nFigure 5 Axial fat-saturated T2w image of the kidneys: the image demonstrates high signal (long arrows) within the renal cortex. Additionally, there is fluid signal and inflammation identified in the perinephric space (short arrows).\n==== Refs\n1 Prince M. R. Gadolinium-enhanced MR aortography Radiology 1994 191 1 155 164 10.1148/radiology.191.1.8134563 2-s2.0-0028351567 8134563 \n2 Pedrosa I. Sun M. R. Spencer M. MR imaging of renal masses: correlation with findings at surgery and pathologic analysis RadioGraphics 2008 28 4 985 1003 10.1148/rg.284065018 2-s2.0-53149118252 18635625 \n3 Pretorius E. S. Solomon J. A. Pretorius E. S. Solomon J. A. CT and MRI of the kidney Radiology Secrets Plus 2011 Philadelphia, Pa, USA Mosby 174 181 \n4 Saunders H. S. Dyer R. B. Shifrin R. Y. Scharling E. S. Bechtold R. E. Zagoria R. J. The CT nephrogram: implications for evaluation of urinary tract disease Radiographics 1995 15 5 1069 1085 10.1148/radiographics.15.5.7501851 2-s2.0-0029366960 7501851 \n5 Wong W. S. Moss A. A. Federle M. P. Cochran S. T. London S. S. Renal infarction: CT diagnosis and correlation between CT findings and etiologies Radiology 1984 150 1 201 205 10.1148/radiology.150.1.6689761 2-s2.0-0021364238 6689761 \n6 Glazer G. M. London S. S. CT appearance of global renal infarction Journal of Computer Assisted Tomography 1981 5 6 847 850 10.1097/00004728-198112000-00011 2-s2.0-0019833295 7320290 \n7 Haaga J. R. Morrison S. C. CT appearance of renal infarct Journal of Computer Assisted Tomography 1980 4 2 246 247 10.1097/00004728-198004000-00024 2-s2.0-0018879753 7365021 \n8 Harris R. D. Dorros S. Computed tomographic diagnosis of renal infarction Urology 1981 17 3 287 289 10.1016/0090-4295(81)90058-3 2-s2.0-0019514919 7210386 \n9 Frank P. H. Nuttall J. Brander W. L. Prosser D. The cortical rim sign of renal infarction British Journal of Radiology 1974 47 564 875 878 2-s2.0-0016173929 10.1259/0007-1285-47-564-875 4434058 \n10 Demos T. C. Gadwood K. Love L. Engel G. The rim nephrogram in renovascular compromise Urologic Radiology 1982 4 4 227 230 2-s2.0-0020424851 10.1007/BF02924052 7168103 \n11 Birnbaum B. A. Bosniak M. A. Megibow A. J. Asymmetry of the renal nephrograms on CT: significance of the unilateral prolonged cortical nephrogram Urologic Radiology 1991 12 4 173 177 2-s2.0-0025882145 2042266 \n12 Korobkin M. T. Kirkwood R. Minagi H. The nephrogram of hypotension. Radiology 1971 98 1 129 133 2-s2.0-0014981661 10.1148/98.1.129 5100044 \n13 Berliner L. Bosniak M. A. The striated nephrogram in acute pyelonephritis Urologic Radiology 1982 4 1 41 44 10.1007/bf02924024 2-s2.0-0020318109 7101603 \n14 Rubin B. E. Schliftman R. The striated nephrogram in renal contusion Urologic Radiology 1979 1 2 119 121 2-s2.0-0018625556 553371 \n15 Mangano F. A. Zaontz M. Pahira J. J. Computed tomography of acute renal failure secondary to rhabdomyolysis Journal of Computer Assisted Tomography 1985 9 4 777 779 2-s2.0-0022261378 10.1097/00004728-198507010-00021 4019835 \n16 Rabinowitz R. Segal A. J. Mohan Rao H. K. Pathak A. Computed tomography in diagnosis of infantile polycystic kidney disease Journal of Urology 1978 120 5 616 617 2-s2.0-0018117658 213619 \n17 Lauenstein T. C. Sharma P. Hughes T. Heberlein K. Tudorascu D. Martin D. R. Evaluation of optimized inversion-recovery fat-suppression techniques for T2-weighted abdominal MR imaging Journal of Magnetic Resonance Imaging 2008 27 6 1448 1454 10.1002/jmri.21350 2-s2.0-44449114205 18504735 \n18 Lubarsky M. Kalb B. Sharma P. Keim S. M. Martin D. R. MR imaging for acute nontraumatic abdominopelvic pain: rationale and practical considerations Radiographics 2013 33 2 313 337 10.1148/rg.332125116 2-s2.0-84875144917 23479698 \n19 Muriithi A. K. Nasr S. H. Leung N. Utility of urine eosinophils in the diagnosis of acute interstitial nephritis Clinical Journal of the American Society of Nephrology 2013 8 11 1857 1862 2-s2.0-84887291150 10.2215/CJN.01330213 24052222 \n20 Michel D. M. Kelly C. J. Acute interstitial nephritis Journal of the American Society of Nephrology 1998 9 3 506 515 2-s2.0-0031915036 9513915 \n21 Raghavan R. Eknoyan G. Acute interstitial nephritis—a reappraisal and update Clinical Nephrology 2014 82 3 149 162 10.5414/CN10838 2-s2.0-84905500504 25079860 \n22 Rossert J. Drug-induced acute interstitial nephritis Kidney International 2001 60 2 804 817 10.1046/j.1523-1755.2001.060002804.x 2-s2.0-0034911861 11473672 \n23 Bigongiari L. R. Patel S. K. Appelman H. Thornbury J. R. Medullary rays: visualization during excretory urography American Journal of Roentgenology 1975 125 4 795 803 10.2214/ajr.125.4.795 2-s2.0-0016805430 \n24 Martin D. R. Nephrogenic systemic fibrosis and gadolinium-enhanced magnetic resonance imaging: does a US food and drug administration alert influence practice patterns in CKD? American Journal of Kidney Diseases 2010 56 3 427 430 10.1053/j.ajkd.2010.07.001 2-s2.0-77956213418 20728788 \n25 Martin D. R. Krishnamoorthy S. K. Kalb B. Decreased incidence of NSF in patients on dialysis after changing gadolinium contrast-enhanced MRI protocols Journal of Magnetic Resonance Imaging 2010 31 2 440 446 10.1002/jmri.22024 2-s2.0-75749147050 20099361\n\n",
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"abstract": "Micturition Complaints in Men: One Symptom, Multiple Causes Abstract. Micturition complaints in male patients are a common problem in the general practice. The complaints are summarized as lower urinary tract symptoms (LUTS) and are often an expression of prostate enlargement and the resulting bladder outlet -obstruction. Differential diagnosis has to exclude prostate-related LUTS. Basic diagnostics are performed by means of detailed physical history, Combur test and ultrasound. The most common diagnoses can already be made at this point and therapy can be initiated. If -secondary changes of the urinary tract (dilated upper urinary tract, bladder diverticulum formation) already show, specialist -assessment and operative therapy are indicated.",
"affiliations": "1 Klinik für Urologie, Kantonsspital Aarau.;2 Uroviva Spezialklinik für Urologie, Bülach.",
"authors": "Cermak|Stefanie|S|;Putman|Scott|S|",
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"country": "Switzerland",
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"issue": "107(11)",
"journal": "Praxis",
"keywords": "Blasendivertikel; Blasenentleerungsstörung; LUTS; Miktionsbeschwerden; Prostataobstruktionssyndrom; bladder diverticulum; bladder dysfunction; micturition; prostate obstruction syndrome",
"medline_ta": "Praxis (Bern 1994)",
"mesh_terms": "D003558:Cystoscopy; D003937:Diagnosis, Differential; D019160:Endosonography; D006801:Humans; D059411:Lower Urinary Tract Symptoms; D008297:Male; D012307:Risk Factors; D014567:Urography",
"nlm_unique_id": "101468093",
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"pages": "593-598",
"pmc": null,
"pmid": "29788851",
"pubdate": "2018",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Micturition Complaints in Men: One Symptom, Multiple Causes.",
"title_normalized": "micturition complaints in men one symptom multiple causes"
} | [
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{
"abstract": "We report a 57-year-old male who was treated with high-dose danazol for hereditary angioedema for more than 30 years; he developed hepatocellular carcinoma in the absence of cirrhosis. Despite surgical resection, he had a recurrence and received sorafenib, but had a poor skin tolerance. Such tumors arising after danazol are infrequent, and this case is highly unique due to the minor lesions found on the liver.",
"affiliations": "Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France.;Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France.;Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France.;Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France.;Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France.;Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France.",
"authors": "Rahal|Soraya|S|;Gilabert|Marine|M|;Ries|Pauline|P|;Oziel-Taieb|Sandrine|S|;Dermeche|Slimane|S|;Raoul|Jean-Luc|JL|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000370106cro-0007-0825Published online: December, 2014Hepatocellular Carcinoma in a Noncirrhotic Liver after Long-Term Use of Danazol for Hereditary Angioedema Rahal Soraya Gilabert Marine Ries Pauline Oziel-Taieb Sandrine Dermeche Slimane Raoul Jean-Luc *Department of Medical Oncology, Paoli-Calmettes Institute, Marseille, France*Prof. Jean-Luc Raoul, Department of Medical Oncology, Paoli-Calmettes Institute, 232 Boulevard de Sainte Marguerite, FR-13273 Marseille (France), E-Mail raouljl@ipc.unicancer.frSep-Dec 2014 9 12 2014 9 12 2014 7 3 825 827 Copyright © 2014 by S. Karger AG, Basel2014This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.We report a 57-year-old male who was treated with high-dose danazol for hereditary angioedema for more than 30 years; he developed hepatocellular carcinoma in the absence of cirrhosis. Despite surgical resection, he had a recurrence and received sorafenib, but had a poor skin tolerance. Such tumors arising after danazol are infrequent, and this case is highly unique due to the minor lesions found on the liver.\n\nKey words\nHepatocellular carcinomaDanazolHealthy liverDrug-induced cancer\n==== Body\nIntroduction\nMen have a higher incidence of hepatocellular carcinoma (HCC) than women, suggesting a carcinogenic influence of androgens. Some cases of HCC associated with androgen uptake have been reported. Some are due to androgenic-anabolic steroids [1], but most are related to the treatment of diseases, such as Fanconi anemia [2]. Among these androgens, danazol, an inhibitor of gonadotropin with a weak androgenic effect, is frequently used to treat endometriosis, idiopathic thrombocytopenic purpura and hereditary angioedema (HAO) and has hepatic toxicities, including liver tumors, particularly hepatocellular adenoma [3], focal nodular hyperplasia [4] and surprisingly only a few cases of HCC [5]. We report a new case of HCC arising in a noncirrhotic liver in a patient receiving danazol for HAO.\n\nCase Presentation\nA 57-year-old male was diagnosed with HAO at the age of 24, and danazol (400 mg daily) was started some months after the diagnosis and showed a major improvement. In 2010, after 33 years of the same dose without interruption, his serum creatinine level increased, and an US of the kidneys was performed. On this US examination, an 11-cm liver tumor was found. Clinically, the patient was lean (54 kg, 1.68 m). There was a huge, painless, firm liver mass, without any sign of chronic liver disease. There was only a minor increase in alanine aminotransferase (1.6 upper limit of normal); his alpha fetoprotein was normal, and serology for B and C virus infections was negative. On CT scan and contrast-enhanced MRI, the 12-cm tumor was heterogeneous, with a clear washin and an imperfect washout; importantly, the fat content was noted on the MRI. The tumor seemed attached to segment VI, and surgical resection was performed without any difficulty; the liver seemed macroscopically normal. On pathological examination, the tumor was multinodular with necrosis and hemorrhagic areas. Microscopically, the surrounding liver had minor alterations, including minor fibrosis (F1) and some inflammation (A2). The tumor was a moderately differentiated HCC (Edmonson-Steiner grade 3), with a major vascular invasion and necrosis in more than 50% of the tumor area. The resection was complete, and follow-up was uneventful. Unfortunately, 3 years later, follow-up demonstrated a massive intrahepatic recurrence with more than 10 large nodules, and treatment with sorafenib was initiated at 800 mg/day. A few days later, the patient developed a severe hand-foot syndrome, and after a 2-week break, sorafenib was resumed at a dose of 400 mg/day. The severe hand-foot syndrome recurred within a few days, and after a new break, sorafenib was given at 200 mg/day and was well tolerated. The tumor remained stable for at least 4 months, and the patient tolerated 200 mg/day of sorafenib. Then, sorafenib was stopped after 6 months due to bone progression. Systemic chemotherapy was given, combining gemcitabine and oxaliplatin [6] (noncirrhotic liver), but that could not stabilize the disease. The patient died 13 months after the diagnosis of this recurrence.\n\nDiscussion\nHAO is caused by a deficiency of the C1-inhibitor, leading to spontaneous edema. New specific treatments are currently the first choice, but years ago, androgens were frequently used for prophylaxis and are still given to some patients. Our patient developed HCC in a noncirrhotic liver, without any other known cause of HCC, but he had taken a high dose of danazol for decades. In a recent international internet survey (66 physicians), 886 patients [7] received androgens, and only 1 developed HCC. None of the patients who were treated with another drug (>1,000 patients) had HCC. Only a few cases of danazol-induced HCC have been reported in HAO [7], without any data regarding the underlying liver pathology. However, considering the currently available new drugs and the risk of both benign liver tumors (adenoma or focal nodular hyperplasia) and HCC, particularly in patients who have taken danazol for more than 10 years at a dose of more than 100 mg [4], the use of danazol for extended periods of time or at high doses must be avoided. Additionally, these patients must be followed with regular US examinations. The association between sorafenib toxicity and HAO seemed to be incidental in our case.\n\nDisclosure Statement\nJ.-L.R. received lecture fees from Bayer SP.\n==== Refs\nReferences\n1 Farrel GC Joshua DE Uren RF Baird PJ Perkins KW Kronenberg H Androgen-induced hepatoma Lancet 1975 305 430 432 \n2 Velazquez I Alter BP Androgens and liver tumors: Fanconi's anemia and non-Fanconi's conditions Am J Hematol 2004 77 257 267 15495253 \n3 Bork K Pitton M Harten P Koch P Hepatocellular adenomas in patients taking danazol for hereditary angiooedema Lancet 1999 353 1066 1067 10199359 \n4 Helsing P Nielsen EW Hepatocellular focal nodular hyperplasia after danazol treatment for hereditary angio-oedema Acta Derm Venereol 2006 86 272 273 16710600 \n5 Confavreux C Seve P Broussolle C Renaudier P Ducerf C Danazol-induced hepatocellular carcinoma QJM 2003 96 317 318 12651980 \n6 Zaanan A Williet N Hebbar M Dabakuyo TS Fartoux L Mansourbakht T Gemcitabine plus oxaliplatin in advanced hepatocellular carcinoma: a large multicenter AGEO study J Hepatol 2013 58 81 88 22989572 \n7 Kalaria S Craig T Assessment of hereditary angioedema treatment risks Allergy Asthma Proc 2013 34 519 522 24169059\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-6575",
"issue": "7(3)",
"journal": "Case reports in oncology",
"keywords": "Danazol; Drug-induced cancer; Healthy liver; Hepatocellular carcinoma",
"medline_ta": "Case Rep Oncol",
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"nlm_unique_id": "101517601",
"other_id": null,
"pages": "825-7",
"pmc": null,
"pmid": "25606032",
"pubdate": "2014",
"publication_types": "D002363:Case Reports",
"references": "15495253;24169059;22989572;48615;10199359;16710600;12651980",
"title": "Hepatocellular carcinoma in a noncirrhotic liver after long-term use of danazol for hereditary angioedema.",
"title_normalized": "hepatocellular carcinoma in a noncirrhotic liver after long term use of danazol for hereditary angioedema"
} | [
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"abstract": "Ritonavir is a potent inhibitor of the cytochrome P450 enzyme CYP3A4 and is subject to multiple drug-drug interactions. This becomes especially important when the patient is also taking medications metabolized through CYP3A pathway as increased and potentially toxic drug levels may ensue. Herein we present one such interaction wherein a 57 year old gentleman with human immunodeficiency virus (HIV) infection on highly active antiretroviral therapy that included ritonavir, had addition of fluticasone inhaler to his medication repertoire for treatment of chronic obstructive pulmonary disease. This resulted in severe osteoporosis, iatrogenic Cushing syndrome and adrenal insufficiency due to the potentiated systemic glucocorticoid effect of inhaled fluticasone by ritonavir. This case emphasizes the need for pharmacovigilance when managing patients on complex drug regimens for physicians treating HIV infected patients.",
"affiliations": "Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI USA.;Center for Bone Disease, Marshfield Clinic, Marshfield, WI USA.",
"authors": "Epperla|Narendranath|N|;McKiernan|Fergus|F|",
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"fulltext": "\n==== Front\nSpringerplusSpringerplusSpringerPlus2193-1801Springer International Publishing Cham 121810.1186/s40064-015-1218-xCase StudyIatrogenic Cushing syndrome and adrenal insufficiency during concomitant therapy with ritonavir and fluticasone Epperla Narendranath nepperla@mcw.edu McKiernan Fergus mckiernan.fergus@marshfieldclinic.org Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI USA Center for Bone Disease, Marshfield Clinic, Marshfield, WI USA 27 8 2015 27 8 2015 2015 4 4554 3 2015 6 8 2015 © Epperla and McKiernan. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.Ritonavir is a potent inhibitor of the cytochrome P450 enzyme CYP3A4 and is subject to multiple drug–drug interactions. This becomes especially important when the patient is also taking medications metabolized through CYP3A pathway as increased and potentially toxic drug levels may ensue. Herein we present one such interaction wherein a 57 year old gentleman with human immunodeficiency virus (HIV) infection on highly active antiretroviral therapy that included ritonavir, had addition of fluticasone inhaler to his medication repertoire for treatment of chronic obstructive pulmonary disease. This resulted in severe osteoporosis, iatrogenic Cushing syndrome and adrenal insufficiency due to the potentiated systemic glucocorticoid effect of inhaled fluticasone by ritonavir. This case emphasizes the need for pharmacovigilance when managing patients on complex drug regimens for physicians treating HIV infected patients.\n\nKeywords\nRitonavirFluticasoneCytochrome P450Human immunodeficiency virusissue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nRitonavir is a potent inhibitor of the cytochrome P450 enzyme CYP3A4 that can lead to multiple drug–drug interactions. Systemic complications resulting from inhaled corticosteroids like fluticasone are rare but when used concomitantly with ritonavir can lead to iatrogenic Cushing syndrome and adrenal suppression. It is important to be aware of this interaction to avoid serious and potentially fatal complications. We report a case of iatrogenic Cushing syndrome, adrenal insufficiency and severe osteoporosis due to the potentiated systemic glucocorticoid effect of inhaled fluticasone by ritonavir in a patient with human immunodeficiency virus (HIV).\n\nCase presentation\nA 57 year old Caucasian male with HIV infection since 1986 was evaluated in 4/2010 for recurrent rib fractures following trivial stresses such as coughing. His highly active antiretroviral therapy (HAART) since 2006 consisted of lamivudine 150 mg twice daily, zidovudine 300 mg twice daily and lopinavir–ritonavir 400–100 mg twice daily. Fluticasone/salmeterol 250/50 mcg one puff twice daily was introduced in 9/2007 for severe COPD. Other medical conditions included coronary artery disease, dyslipidemia and GERD treated with aspirin, clopidogrel, omeprazole, pravastatin and niacin. Physical examination showed centripetal adiposity, multiple ecchymoses and pronounced pink abdominal and inguinal striae (Fig. 1). Weight had increased by 5 kg from baseline weight. There was palpable rib tenderness. The reminder of the physical examination was unremarkable. Of note his AIDS clinician mistook his phenotypic changes to be those of AIDS related lipodystrophy. These same changes eluded his PCP.Fig. 1 Centripetal adiposity, multiple ecchymoses and pronounced pink abdominal and inguinal striae\n\n\n\nChest radiographs confirmed numerous rib fractures (Fig. 2). Lumbar and proximal femur bone mineral density (BMD) T-scores were −5.2 and −3.4 respectively. Complete blood count, renal and hepatic function, electrolytes, calcium, phosphate, intact parathyroid hormone, 25-OH-VitD, prolactin, serum and urine protein electrophoresis and serum free light chains were normal. His random morning serum cortisol was 0.5 mcg/dl (normal 4–24 mcg/dL) and 1 h after 250 mcg intravenous cosyntropin stimulation was 7.1 mcg/dL (expected >20 mcg/dL) consistent with adrenal insufficiency. A 24 h urine free cortisol was <7.2 mcg, late night salivary cortisol was <10 ng/dL (<100 ng/dL) and dehydroepiandrosterone sulphate was <30 mcg/dL (40–310 mcg/dL). Serum ACTH was 32 pg/mL (normal 0–46 pg/mL). A 24 h urinary synthetic glucocorticoid screen was only positive for a fluticasone 17-β-carboxylic acid value of 243 pg/mL. Pituitary magnetic resonance imaging (MRI) was normal. Serum and 24-h urine N-telopeptides were 19.2 nmol BCE (5.4–24 nmol BCE) and 23 nmol/mmol BCE (21–66 nmol/mmol BCE) respectively. Total and bone specific alkaline phosphatase were 73 IU/L (20–71 IU/L) and 151 IU/L (40–125 IU/L) respectively.Fig. 2 Chest X-ray showing numerous rib fractures\n\n\n\nThe patient was diagnosed with iatrogenic Cushing syndrome and adrenal suppression secondary to the potentiated systemic glucocorticoid effect of inhaled fluticasone by ritonavir. Fluticasone was continued as the patient reported significant improvement in his COPD symptoms. Ritonavir boosted protease inhibitor therapy was discontinued and he was placed on Raltegravir which is not known to inhibit CYP3A4. His HIV viral load continues to be undetectable and 2 years after change in antiretroviral therapy his CD4 count is 624. He was placed on physiological doses of hydrocortisone at 20 mg per day and has gradually tapered to 5 mg/day of hydrocortisone 1 year from presentation. His severe osteoporosis was treated with subcutaneous teriparatide, appropriate calcium and vitamin D supplementation and a physical therapy.\n\nSerial basal and stimulated cortisol levels are reported in Table 1. His cushingoid features improved by 3 months (Fig. 3). One year after initiating osteoporosis treatment lumbar spine BMD improved from 0.530 to 0.932 gm/cm2 (+75.8 %) and total hip BMD from 0.681 to 0.761 gm/cm2 (+11.2 %). These BMD gains are significantly greater than those reported for lumbar spine (11 %) and total hip (5.2 %) in patients with glucocorticoid induced osteoporosis treated with teriparatide (Saag et al. 2009). Follow up BMD at the completion of teriparatide treatment is shown in Table 2 and Fig. 4. The patient has had no further fractures.Table 1 Basal and stimulated cortisol levels\n\n\tBasal cortisol (mcg/dL)\t1 h post ACTH cortisol level (mcg/dL)\t\nAt diagnosis\t0.5\t7.1\t\n2 months\t2.5\t–\t\n9 months\t3.3\t18\t\n12 months\t8.3\t23.6\t\n24 months\t7\t22.5\t\nFig. 3 Markedly improved abdominal and inguinal striae as well as the ecchymotic lesions\n\nTable 2 BMD improvement after withdrawal of ritonavir and treatment with teriparatide\n\n\tBMD in gm/cm2 (T-score)\t\nL-Spine\tTotal hip (mean)\tFemoral neck (mean)\t\nAt diagnosis\t0.530 (−5.7)\t0.681 (−2.9)\t0.589 (−3.7)\t\n12 months\t0.932 (−2.4)\t0.761 (−2.4)\t0.694 (−2.9)\t\n24 months\t1.065 (−1.3)\t0.825 (−1.9)\t0.734 (−2.6)\t\n36 months\t1.139 (−0.7)\t0.867 (−1.6)\t0.767 (−2.3)\t\nFig. 4 DXA trend after withdrawal of ritonavir and treatment with teriparatide along with depiction of improved trabecular bone scores\n\n\n\nDiscussion\nA search of published English language literature using the keywords ritonavir, protease inhibitors, fluticasone, inhaled corticosteroids, Cushing’s syndrome and adrenal suppression revealed a total of 11 pediatric and 26 adult cases of iatrogenic Cushing’s syndrome and adrenal suppression from concomitant fluticasone and ritonavir therapy. 3 of 24 adult cases were secondary to intranasal fluticasone preparations and rest was from inhaled fluticasone. Fluticasone dose ranged from 500 to 2000 mcg/day in adult patients and 200–1000 mcg/day in pediatric patients. Ritonavir in both low doses “boosted” and in high doses was associated with significant interaction (Table 3).Table 3 Review of literature and showing the cases of iatrogenic Cushing’s syndrome and adrenal suppression from concomitant fluticasone and ritonavir therapy\n\nAuthors\tAge\tRTV dose (mg/day)\tICS dose (mcg/day)\tDurationa\n\tIntervention\t\nMahlab-Guri and Asher (2011)\t\n Case 1\t12 F\t200\tFluticasone 200\t6 months\tFluticasone replaced by montelukast\t\n Case 2\t55 F\t200\tFluticasone 1000\t3 weeks\tFluticasone replaced by budesonide\t\n Case 3\t65 F\t200\tFluticasone 500\t6 months\tFluticasone discontinued\t\nKaviani et al. (2011)\t\n Case 1\t60 M\tNA\tFluticasone 1200\t2 years\tFluticasone discontinued\t\nKedem et al. (2010)\t\n Case 1\tF\tNA\tNA\tUNK\tFluticasone and budesonide discontinued\t\n\t\t\t\t\tRitonavir dose decreased\t\nSamaras et al. (2005)\t\n Case 1\t43 M\t200\tFluticasone 500\t2 years\tFluticasone discontinued\t\n Case 2\t43 M\t100\tFluticasone 1000\t18 months\tFluticasone discontinued\t\n Case 3\t53 M\t200\tFluticasone 1000\t2 years\tFluticasone discontinued\t\n Case 4\t49 M\t200\tFluticasone 1000\t6 weeks\tPI discontinued\t\n Case 5\t43 M\t200\tFluticasone 500\t4 months\tFluticasone discontinued\t\n Case 6\t50 M\t100\tFluticasone 1000\t2 months\tFluticasone discontinued\t\nNocent et al. (2004)\t\n Case 1\t38 M\tNA\tFluticasone 2000\t1.5 months\tFluticasone replaced with beclomethasone\t\nLeitman et al. (2009)\t\n Case 1\t49 M\tNA\tFluticasone 1000\tUNK\tFluticasone dose reduced\t\nValin et al. (2009)\t\n Case 1\t65 F\tNA\tFluticasone 500\t6 months\tFluticasone discontinued\t\n Case 2\t66 M\tNA\tFluticasone 500\t1 month\tFluticasone discontinued\t\n Case 3\t66 M\tNA\tFluticasone 500\t2 years\tFluticasone discontinued\t\n Case 4\t29 M\tNA\tFluticasone 2000\t1 month\tFluticasone discontinued PI replaced with nelfinavir\t\nJinno and Goshima (2008)\t\n Case 1\t60 M\tNA\tFluticasone NA\t18 months\tFluticasone discontinued\t\nGillett et al. (2005)\t\n Case 1\t27 F\t200\tFluticasone 1000\t10 weeks\tFluticasone discontinued\t\nSoldatos et al. (2005)\t\n Case 1\t66 M\t200\tFluticasone 1000\t4 months\tFluticasone dose decreased\t\n Case 2\t66 M\t200\tFluticasone 1000\t6 months\tFluticasone replaced with budesonide\t\nRouanet et al. (2003)\t\n Case 1\t44 M\t266.4\tFluticasone 2000\t2 months\tFluticasone discontinued\t\nGupta and Dubé (2002)\t\n Case 1\t45 M\t800\tFluticasone 880\t5 months\tFluticasone tapered\t\nClevenbergh et al. (2002)\t\n Case 1\t33 M\t200\tFluticasone 1000\t5 months\tFluticasone discontinued\t\nChen et al. (1999)\t\n Case 1\t32 M\t\tFluticasone 400\t5 months\tFluticasone discontinued\t\n Case 2\t39 M\t\tFluticasone 800\t18 months\tFluticasone discontinued\t\nHillebrand-Haverkort et al. (1999)\t\n Case 1\t30 M\t1200\tFluticasone 200\t5 months\tRTV replaced by NVP\t\nArrington-sanders et al. (2006)\t\n Case 1\t11.4 F\t133\tFluticasone 220\t\tFluticasone and PI discontinued\t\n Case 2\t20.9 M\t100\tFluticasone 200\t\tFluticasone discontinued\t\n Case 3\t16.8 M\t200\tFluticasone 250\t\tStopped all medications\t\n Case 4\t9.5 M\t133\tFluticasone 220\t\tFluticasone discontinued\t\n Case 5\t1.8 F\t60\tFluticasone 220\t\tFluticasone discontinued\t\nJohnson et al. (2006)\t\n Case 1\t12 F\t134\tFluticasone 500\t2 months\tRTV/LPV D/C\t\n Case 2\t15 F\t200\tFluticasone 1000\t13 weeks\tFluticasone dose decreased\t\nPessanha et al. (2007)\t\n Case 1\t16 F\tNA\tFluticasone 500\t3 months\tRTV replaced by EFV\t\nSt Germain et al. (2007)\t\n Case 1\t14 F\t100\tFluticasone 500\t2 weeks\tFluticasone discontinued\t\n\t\t\t\t\tRTV/ATV with held\t\nBhumbra et al. (2007)\t\n Case 1\t9 M\t108\tFluticasone 440\t2 months\tFluticasone discontinued\t\n\t\t\tMometasone 100\t11 months\tMometasone discontinued\t\nle Roux et al. (2001)\t\n Case 1\t47 M\t\tBudesonide 1600\t\tBudesonide discontinued\t\nSagir et al. (2002)\t\n Case 1\t48 M\t\tBudesonide 9000\t19 days\tBudesonide discontinued\t\n\nRTV ritonavir, LPV lopinavir, ICS inhaled corticosteroids, EFV efavirenz, PI protease inhibitors, ATV atazanavir, NA not available, UNK unknown, NVP nevirapine\n\n\naDuration until onset of first symptoms\n\n\n\nCombination anti-retroviral therapy, particularly the introduction of protease inhibitors has revolutionized HIV therapy and changed once a fatal disease to a chronic condition (Palella et al. 1998). Ritonavir is a potent inhibitor of cytochrome P450 (CYP) 3A4 isozymes and significantly increases the concentration of drugs primarily eliminated by CYP3A metabolism such as macrolides, azoles, protease inhibitors and corticosteroids (Hsu et al. 1998; Von Moltke et al. 1998). This property of ritonavir is used to therapeutic advantage in ritonavir boosted protease inhibitor regimens and has decreased the pill burden and treatment failures and improved compliance with therapy (Thompson et al. 2010).\n\nWith 30 % estimated prevalence of bronchial hyperactivity (Poirier et al. 2001), HIV infected men who smoke are frequently exposed to inhaled corticosteroid therapy. To reduce airway inflammation treatment guidelines for asthma and chronic obstructive airway disease (COPD) recommend the routine use of inhaled corticosteroid alone or in combination with long acting bronchodilators (National Asthma Education and Prevention Program 2002; Vestbo et al. 2013). Fluticasone is a potent glucocorticoid commonly used in reactive airway disease. Compared with other available inhaled steroids, it has high glucocorticoid receptor binding affinity, is highly lipophilic, a large volume of distribution (318 L) (Wuerthwein et al. 1992; Mackie et al. 1996) and a longer elimination half-life (t1/2 7–8 h). Less than 1 % of swallowed fluticasone is bioavailable due to its high first pass metabolism and rapid metabolism in liver by CYP3A4 enzyme system and conversion to inactive 17 B-carboxylic acid derivative (Harding 1990). Concomitant use of fluticasone with potent CYP3A4 inhibitors such as ritonavir can lead to systemic accumulation of fluticasone and suppression of hypothalamic pituitary adrenal (HPA) axis. Ritonavir increased the area under concentration–time curve (AUC) of serum fluticasone by 350-fold in healthy volunteers (Laboratories 2006). For this reason manufactures and the FDA recommend against routine use of combination of ritonavir and fluticasone unless benefits outweigh risks.\n\nFluticasone has been reported to cause greater dose related adrenal suppression when compared with budesonide, triamcinolone acetonide or beclomethasone dipropionate (Lipworth 1999) even in the absence of CYP3A4 inhibitors like ritonavir. In a recent meta-analysis of 732 subjects with asthma, fluticasone in small to medium doses (50–500 mcg/day) alone showed minimal effect on adrenal function (Masoli et al. 2006). In another prospective, non-randomized, open-label, cross sectional study, investigators found that patients taking high doses of fluticasone (>880 mcg per day) for longer duration had abnormal adrenal function (White et al. 2006).\n\nIatrogenic Cushing syndrome results from prolonged exposure to high doses of glucocorticoids. The vast majority of these cases result from administration of oral or parenteral glucocorticoids (Newell-Price et al. 2006). Typical features include weight gain, central obesity, dorsocervical hump, moon face, facial plethora, thin skin, easy bruising, abdominal striae, hirsutism, proximal myopathy, osteopenia, glucose intolerance, hypertension, nephrolithiasis and psychiatric manifestations such as depression and psychosis (Newell-Price et al. 2006). Osteoporosis is common and tends to involve trabecular bone resulting in an increased risk of fracture within 3 months of daily exposure (van Staa et al. 2000, 2002, 2005).\n\nPituitary production of corticotropin (ACTH) will be suppressed by exogenous steroids, which leads to atrophy of the adrenal cortex and adrenal insufficiency. Diagnosis is confirmed by low early morning serum cortisol levels and subnormal response to standard ACTH stimulation test. An early morning serum cortisol levels <3 mcg/dL (80 nmol/L) strongly suggests adrenal insufficiency, whereas levels >15 mcg/dL (415 nmol/L) predicts a normal response of serum cortisol to ACTH stimulation test (Hagg et al. 1987; Le Roux et al. 2002). Patients with low or equivocal serum cortisol levels in whom adrenal insufficiency is suspected should undergo standard or low dose synthetic ACTH (Cosyntropin) stimulation test. Suboptimal response to Cosyntropin stimulation test is diagnostic of adrenal insufficiency. Simultaneous measurement of plasma ACTH helps in differentiation of primary from secondary or tertiary adrenal insufficiency. ACTH levels tend to be higher than normal in primary adrenal insufficiency whereas low or low normal in patients with secondary and tertiary adrenal insufficiency. Corticotropin-releasing hormone (CRH) test further differentiate secondary from tertiary adrenal insufficiency (Schulte et al. 1984).\n\nHuman immunodeficiency virus associated lipodystrophy shares several morphological features and should be differentiated from Cushing Syndrome. Weight gain, central adiposity, dorsocervical hump, insulin resistance, osteopenia, dyslipidemia are common and are associated with ART therapy (Lichtenstein 2005; Dube et al. 2007; Carr and Cooper 1998). Presence of facial plethora, cutaneous striae, and proximal myopathy differentiates it from Cushing syndrome and should prompt physicians to evaluate for HPA axis suppression. Sudden withdrawal of from steroid therapy has a potential to develop catastrophic adrenal crisis. Replacement with physiological doses of prednisone 5–7.5 mg a day, hydrocortisone 15–20 mg a day or equivalent should be initiated. Measurement of morning cortisol levels every 4–6 weeks serves as screening test for recovery of adrenal function. Morning serum cortisol level less than 3 mcg/dL indicates the need for continued replacement therapy, whereas a value greater than 20 mcg/dL indicates recovered HPA axis. Patients with morning cortisol levels between 3 and 20 mcg/dL will need further studies like Cosyntropin stimulation test or overnight metyrapone test. It may take 9–12 months for the recovery of adrenal function (Hopkins and Leinung 2005).\n\nIn patients with iatrogenic Cushing syndrome and adrenal insufficiency secondary to the interaction between ritonavir and fluticasone available options include, replacing ritonavir with another antiretroviral agent, replacing fluticasone with another less potent steroid or leukotriene antagonists or long acting anticholinergic agent such as tiotropium. In the SPIRAL study, Raltegravir demonstrated the non-inferior efficacy and improved lipid profile when ritonavir boosted protease inhibitor therapy was replaced by Raltegravir (Martinez et al. 2010). The latter approach was taken in our patient with favourable outcome.\n\nConclusions\nDespite the recommendations against concomitant use of fluticasone and ritonavir several reports of Cushing syndrome and adrenal suppression are being reported. We believe physicians treating HIV infected patients must be aware of potential interaction of antiretroviral therapy and drugs used to treat associated co-morbidities. When iatrogenic Cushing syndrome is suspected, prompt evaluation and discontinuation of offending medication will prevent potentially fatal complications.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nHIVhuman immunodeficiency virus\n\nCYPcytochrome P450\n\nBMDbone mineral density\n\nHAARThighly active antiretroviral therapy\n\nAuthors’ contributions\nNE and FM conceived the study design. NE conducted the literature search and drafted the manuscript. FM assisted in the literature search and critical revisions of the manuscript for important intellectual content. All authors read and approved the final manuscript.\n\nAcknowledgments\nThe authors thank the Department of Radiology for providing the images.\n\nCompliance with ethical guidelines\nCompeting interests The authors declare that they have no competing interests.\n==== Refs\nReferences\nAbbott Laboratories (2006) Norvir (ritonavir) package insert. 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Ann Clin Biochem 2002 39 148 150 10.1258/0004563021901919 11930947 \nLeitman D Ross K Vertebral compression fractures in an HIV-positive patient with steroid-induced Cushing syndrome: a case report Cases J 2009 2 7034 10.4076/1757-1626-2-7034 19829900 \nLichtenstein KA Redefining lipodystrophy syndrome: risks and impact on clinical decision making J Acquir Immune Defic Syndr 2005 39 395 400 10.1097/01.qai.0000167478.28051.3a 16010159 \nLipworth BJ Systemic adverse effects of inhaled corticosteroid therapy: a systematic review and meta-analysis Arch Intern Med 1999 159 941 955 10.1001/archinte.159.9.941 10326936 \nMackie A Ventresca G Pharmacokinetics of intravenous fluticasone propionate in healthy subjects Br J Clin Pharmacol 1996 41 539 542 10.1046/j.1365-2125.1996.36110.x 8799519 \nMahlab-Guri K Asher I Inhaled fluticasone causes iatrogenic cushing’s syndrome in patients treated with Ritonavir J Asthma 2011 48 860 863 10.3109/02770903.2011.606580 21854345 \nMartinez E Larrousse M Substitution of raltegravir for ritonavir-boosted protease inhibitors in HIV-infected patients: the SPIRAL study AIDS 2010 24 1697 1707 10.1097/QAD.0b013e32833a608a 20467288 \nMasoli M Weatherall M Inhaled fluticasone propionate and adrenal effects in adult asthma: systematic review and meta-analysis Eur Respir J 2006 28 960 967 10.1183/09031936.06.00119305 16737984 \nNational Asthma Education and Prevention Program Expert panel report: guidelines for the diagnosis and management of asthma update on selected topics J Allergy Clin Immunol 2002 110 S141 S219 10.1016/S0091-6749(02)80002-1 12542074 \nNewell-Price J Bertagna X Cushing’s syndrome Lancet 2006 367 1605 1617 10.1016/S0140-6736(06)68699-6 16698415 \nNocent C Raherison C Unexpected effects of inhaled fluticasone in an HIV patient with asthma J Asthma 2004 41 793 795 10.1081/JAS-200038366 15641628 \nPalella FJ Delaney KM Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. HIV Outpatient Study Investigators N Engl J Med 1998 338 853 860 10.1056/NEJM199803263381301 9516219 \nPessanha TM Campos JM Iatrogenic Cushing’s syndrome in a adolescent with AIDSs on ritonavir and inhaled fluticasone. 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{
"abstract": "OBJECTIVE\nWe investigated the efficacy, safety and optimal schedule of nanoparticle albumin-bound paclitaxel monotherapy as second- or third-line treatment for non-small-cell lung cancer patients without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement.\n\n\nMETHODS\nPatients with pretreated advanced non-small-cell lung cancer without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement were included. The patients were administered 100 mg/m2 of nanoparticle albumin-bound paclitaxel on days 1, 8, 15 and 22 (level 0) or on days 1, 8 and 15 (level -1) every 4 weeks during phase I of the trial. The primary endpoint was objective response rate. The estimated objective response rate was 15% and the threshold was 5% with an α error of 0.05 and β error of 0.2 in phase II.\n\n\nRESULTS\nThe recommended schedule was determined as level -1 in phase I. The characteristics of the 55 patients enrolled in phase II were as follows: median age = 66 years, male/female = 40/15, second/third line = 34/21 and adenocarcinoma/squamous cell carcinoma/large cell carcinoma/others = 34/17/2/2. Objective response rate was 7.3% (95% confidence interval, 2.0-17.6%). Median progression-free survival was 3.4 months. Treatment-related grade 3 or 4 toxicities were neutropenia (36.4%), febrile neutropenia (5.5%) and pulmonary infection (3.6%). Three patients had grade 2 pneumonitis and one treatment-related death occurred due to adult respiratory distress syndrome.\n\n\nCONCLUSIONS\nThis study failed to meet predefined primary endpoints for pretreated patients with advanced non-small-cell lung cancer without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement.",
"affiliations": "Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan.;Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan.;Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan.;Department of Respiratory Medicine, Japanese Red Cross Okayama Hospital, Okayama, Japan.;Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.;Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.;Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.;Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, Japan.;Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, Japan.;Department of Respiratory Medicine, Kurashiki Central Hospital, Kurashiki, Japan.;Department of Respiratory Medicine, National Hospital Organization Iwakuni Medical Center, Yamaguchi, Japan.;Department of Respiratory Medicine, National Hospital Organization Iwakuni Medical Center, Yamaguchi, Japan.;Department of Respiratory Medicine, Chugoku Central Hospital, Fukuyama, Japan.;Department of General Internal Medicine 4, Kawasaki Medical School, Okayama, Japan.;Division of Molecular and Clinical Epidemiology, Aichi Cancer Center Research Institute, Nagoya, Japan.;Department of Respiratory Medicine, Okayama University Hospital, Okayama, Japan.",
"authors": "Harada|Daijiro|D|https://orcid.org/0000-0002-5314-2489;Kozuki|Toshiyuki|T|;Nogami|Naoyuki|N|;Bessho|Akihiro|A|;Hosokawa|Shinobu|S|;Fukamatsu|Nobuaki|N|;Hotta|Katsuyuki|K|;Ohashi|Kadoaki|K|;Kubo|Toshio|T|;Yoshioka|Hiroshige|H|;Yokoyama|Toshihide|T|;Sone|Naoyuki|N|;Kuyama|Shoichi|S|;Kudo|Kenichiro|K|;Yasugi|Masayuki|M|;Takigawa|Nagio|N|;Oze|Isao|I|;Kiura|Katsuyuki|K|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D000077548:Anaplastic Lymphoma Kinase; D066246:ErbB Receptors; D017239:Paclitaxel",
"country": "Australia",
"delete": false,
"doi": "10.1111/ajco.13147",
"fulltext": "\n==== Front\nAsia Pac J Clin OncolAsia Pac J Clin Oncol10.1111/(ISSN)1743-7563AJCOAsia-Pacific Journal of Clinical Oncology1743-75551743-7563John Wiley and Sons Inc. Hoboken 10.1111/ajco.13147AJCO13147Original ArticleOriginal ArticlesA phase I/II trial of weekly nab‐paclitaxel for pretreated non‐small‐cell lung cancer patients without epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement HARADA et al.Harada Daijiro https://orcid.org/0000-0002-5314-2489\n1\nh401068@yahoo.co.jp Kozuki Toshiyuki \n1\nNogami Naoyuki \n1\nBessho Akihiro \n2\nHosokawa Shinobu \n2\nFukamatsu Nobuaki \n2\nHotta Katsuyuki \n3\nOhashi Kadoaki \n3\nKubo Toshio \n3\nYoshioka Hiroshige \n4\nYokoyama Toshihide \n4\nSone Naoyuki \n4\nKuyama Shoichi \n5\nKudo Kenichiro \n5\nYasugi Masayuki \n6\nTakigawa Nagio \n7\nOze Isao \n8\nKiura Katsuyuki \n3\n\n1 \nDepartment of Thoracic Oncology\nNational Hospital Organization Shikoku Cancer Center\nMatsuyama\nJapan\n\n2 \nDepartment of Respiratory Medicine\nJapanese Red Cross Okayama Hospital\nOkayama\nJapan\n\n3 \nDepartment of Respiratory Medicine\nOkayama University Hospital\nOkayama\nJapan\n\n4 \nDepartment of Respiratory Medicine\nKurashiki Central Hospital\nKurashiki\nJapan\n\n5 \nDepartment of Respiratory Medicine\nNational Hospital Organization Iwakuni Medical Center\nYamaguchi\nJapan\n\n6 \nDepartment of Respiratory Medicine\nChugoku Central Hospital\nFukuyama\nJapan\n\n7 \nDepartment of General Internal Medicine 4\nKawasaki Medical School\nOkayama\nJapan\n\n8 \nDivision of Molecular and Clinical Epidemiology\nAichi Cancer Center Research Institute\nNagoya\nJapan\n* Correspondence\nDaijiro Harada, MD, PhD, Department of Thoracic Oncology, National Hospital Organization Shikoku Cancer Center, 160 Minami‐Umemoto‐cho, Matsuyama‐shi, Ehime 791‐0280, Japan.\nEmail: h401068@yahoo.co.jp\n01 4 2019 8 2019 15 4 10.1111/ajco.2019.15.issue-4250 256 22 12 2018 05 3 2019 © 2019 The Authors. Asia‐Pacific Journal of Clinical Oncology Published by John Wiley & Sons Australia, Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.Abstract\nAim\nWe investigated the efficacy, safety and optimal schedule of nanoparticle albumin‐bound paclitaxel monotherapy as second‐ or third‐line treatment for non‐small‐cell lung cancer patients without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement.\n\nMethods\nPatients with pretreated advanced non‐small‐cell lung cancer without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement were included. The patients were administered 100 mg/m2 of nanoparticle albumin‐bound paclitaxel on days 1, 8, 15 and 22 (level 0) or on days 1, 8 and 15 (level –1) every 4 weeks during phase I of the trial. The primary endpoint was objective response rate. The estimated objective response rate was 15% and the threshold was 5% with an α error of 0.05 and β error of 0.2 in phase II.\n\nResults\nThe recommended schedule was determined as level –1 in phase I. The characteristics of the 55 patients enrolled in phase II were as follows: median age = 66 years, male/female = 40/15, second/third line = 34/21 and adenocarcinoma/squamous cell carcinoma/large cell carcinoma/others = 34/17/2/2. Objective response rate was 7.3% (95% confidence interval, 2.0–17.6%). Median progression‐free survival was 3.4 months. Treatment‐related grade 3 or 4 toxicities were neutropenia (36.4%), febrile neutropenia (5.5%) and pulmonary infection (3.6%). Three patients had grade 2 pneumonitis and one treatment‐related death occurred due to adult respiratory distress syndrome.\n\nConclusion\nThis study failed to meet predefined primary endpoints for pretreated patients with advanced non‐small‐cell lung cancer without epidermal growth factor receptor mutation and anaplastic lymphoma kinase rearrangement.\n\ncytotoxic chemotherapynanoparticle albumin‐bound paclitaxelnon‐small cell lung cancerpretreated NSCLCwild‐type source-schema-version-number2.0cover-dateAugust 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.7.1 mode:remove_FC converted:12.11.2019\n\n\nHarada \nD \n, \nKozuki \nT \n, \nNogami \nN \n, et al. A phase I/II trial of weekly nab‐paclitaxel for pretreated non‐small‐cell lung cancer patients without epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement. \nAsia‐Pac J Clin Oncol . 2019 ;15 :250 –256 . 10.1111/ajco.13147 \n30938103\n==== Body\n1 INTRODUCTION\nNanoparticle albumin‐bound paclitaxel (nab‐PTX) showed a significantly higher overall response rate (ORR) than solvent‐based paclitaxel (sb‐PTX) in combination with carboplatin for patients with non‐small cell lung cancer (NSCLC) as first‐line treatment (33% vs 25%, P = 0.001). The frequency of some serious adverse events (AEs) in the nab‐PTX arm, such as peripheral neuropathy and neutropenia, was less than that in the sb‐PTX arm.1 A 4‐week cycle treatment (days 1, 8 and 15) of 125 mg/m2 of nab‐PTX for patients with naïve advanced NSCLC demonstrated efficacy and tolerability in phase I/II of the study; ORR and median time to progression were 30% and 5 months, respectively.2 In addition, a phase II study of weekly nab‐PTX in patients previously treated for advanced NSCLC demonstrated acceptable toxicity and promising activity; ORR and median progression‐free survival (mPFS) were 31.7% (95% confidence interval [CI] of 19.3–44.1%) and 4.9 months (95% CI, 2.4–7.4 months), respectively.3\n\n\n\nEpidermal growth factor receptor (EGFR) mutations may be predictive biomarkers for the effects of cytotoxic chemotherapy, according to some phase III randomized studies comparing the efficacy of EGFR‐tyrosine kinase inhibitors with cytotoxic chemotherapies in NSCLC patients. In the INTEREST study, the ORR of docetaxel (DOC) was 21.1% for the EGFR mutant, whereas it was 9.8% for wild‐type patients.4 In the V‐15‐32 study, the ORR of DOC was 46% for the EGFR mutant, whereas it was 13% for wild‐type patients.5 In the TRIBUTE trial, the progressive disease rate of carboplatin and paclitaxel chemotherapy was 21% for the EGFR mutant, whereas it was 37% for wild‐type patients.6 However, in the DELTA study, comparing erlotinib with DOC in previously treated NSCLC patients, the ORRs of DOC were similar: 17.9% for the EGFR‐unselected patients and 20.0% for wild‐type patients.7, 8\n\n\nAs the importance of individualized medicine increases, it is necessary to establish a treatment strategy that takes into consideration the presence or absence of driver mutations, such as EGFR or anaplastic lymphoma kinase (ALK). To date, no clinical trial prospectively examined the efficacy and safety of nab‐PTX for previously treated NSCLC patients without EGFR or ALK mutations. We believed that the development of a superior second‐line treatment was important for such cases.\n\nWith this background, we determined the recommended schedule of weekly nab‐PTX in phase I of the study. Subsequently, in phase II, we evaluated the efficacy and safety of nab‐PTX with the recommended schedule as second‐ or third‐line treatment for patients with advanced NSCLC without any driver mutation.\n\n2 PATIENTS AND METHODS\n2.1 Patients\nPatients aged ≥20 years were enrolled in the study. The inclusion criteria are as follows: histologically or cytologically confirmed advanced NSCLC; an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0–2; measurable lesions documented by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and adequate organ functions; and progressed after one or two chemotherapy regimens including platinum‐doublet chemotherapy. The driver mutation status for each patient was also confirmed; EGFR mutation was negative and ALK fusion status was negative or unknown. Patients who had a history of sb‐PTX or nab‐PTX and had symptomatic brain or meningeal metastasis were excluded.\n\nThis study protocol was developed according to the Declaration of Helsinki, and ethical guidelines for clinical research were approved by the ethics review boards of Shikoku Cancer Center, Matsuyama, Japan [H25‐71] and each participating institution. The unique ID issued by UMIN was UMIN000012404. Written informed consent was obtained from each patient before enrollment. All patients provided written informed consent before enrollment.\n\n2.2 Treatment and assessment in phase I\nThis study was an open‐label, multicenter, single‐arm prospective study.\n\nIn phase I, a 4‐week cycle (dose level 0: days 1, 8, 15 and 22 or dose level –1: days 1, 8 and 15) of 100 mg/m2 nab‐PTX was administered until disease progression or unacceptable AEs were observed. The study treatment was started at dose level 0 and six patients were initially enrolled. If the predefined dose‐limiting toxicity (DLT) was observed in zero or one patient, we determined the recommended schedule to be dose level 0, and subsequently proceeded to phase II. If DLT was observed in two patients, six additional patients were enrolled and evaluated at dose level 0. If DLT was observed in ≥3 out of six patients, we determined the recommended schedule to be dose level –1. If DLT was observed in ≤5 out of 12 patients, we determined the recommended schedule to be dose level 0. If DLT was observed in ≥6 out of 12 patients, we determined the recommended schedule to be dose level –1. The definition of DLTs is defined as follows; nab‐PTX was not administered on days 8, 15 and 22 in the first cycle because of neutrophil count of < 1000/#x000B5;L, platelet count of <50 000/#x000B5;L, infection, peripheral neuropathy, aspartate aminotransferase (AST) increased, alanine aminotransferase (ALT) increased, blood bilirubin increased, creatinine increased, mucositis or diarrhea of ≥grade 2 or the other nonhematological toxicity of ≥ grade 3, the administration of nab‐PTX on day 1 in the second cycle was late for 8 or more days because of neutrophil count of <1500/#x000B5;L, platelet count of <100 000/#x000B5;L, hemoglobin of <8.0 g/dL, blood bilirubin of ≥ 1.5 mg/dL or creatinine of >1.5 mg/dL, peripheral neuropathy or infection of ≥grade 2, pneumonitis of any grade, the other nonhematological toxicities of ≥grade 3 or ECOG PS 3 or more.\n\nThe primary endpoints of phase I were feasibility and determination of the recommended nab‐PTX schedule.\n\n2.3 Treatment and assessment in phase II\nIn phase II, nab‐PTX was administered according to the recommended schedule determined in phase I until disease progression and unacceptable AEs were observed. The primary endpoint of phase II was ORR and the secondary endpoints were overall survival (OS), PFS and safety. Tumor response was assessed according to the RECIST v1.1. AEs were graded in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI‐CTCAE), version 4.0.\n\n2.4 Statistical analysis\nThe sample size was calculated according to Simon's optimal and minimax two‐stage sequential design. The expected ORR and threshold ORR for this study were assumed to be 15% and 5%, respectively.9 Given this assumption, calculation of the required number of subjects with α = 0.05 (one‐sided) and β = 0.2 yielded 52 patients; considering that some patients may be ineligible, the planned enrollment number for phase II was set at 55 patients. These 55 patients included patients enrolled in phase I with the recommended schedule. We considered weekly nab‐PTX to be an effective treatment regimen, if complete response (CR) or partial response (PR) was confirmed in ≥9 patients from the total of 55.\n\n3 RESULTS\n3.1 Phase I\nA total of five patients were enrolled in phase I. The patient characteristics in phase I are presented in Table 1. The recommended schedule of weekly nab‐PTX was determined as level –1, because DLT was observed in four of five patients. The contents of DLTs were grade 3/4 neutropenia in three patients (60%) and grade 2 pneumonitis in one patient (20%).\n\nTable 1 Characteristics of patients in the study (n = 60)\n\n\tPhase I (n = 5)\tPhase II (n = 55)\t\nCharacteristics\t\nn\n\t%\t\nn\n\t%\t\nAge (years)\t\nMedian (range)\t67 (61–71)\t66 (41–90)\t\nSex\t\nMale\t5\t100.0\t40\t72.7\t\nFemale\t0\t0.0\t15\t27.3\t\nSmoking status\t\nNonsmoker\t2\t40.0\t12\t21.8\t\nEx‐smoker\t1\t20.0\t39\t70.9\t\nCurrent smoker\t2\t40.0\t4\t7.3\t\nECOG performance status\t\n0\t1\t20.0\t12\t21.8\t\n1\t4\t80.0\t39\t70.9\t\n2\t0\t0.0\t4\t7.3\t\nHistology\t\nAdenocarcinoma\t4\t80.0\t34\t61.8\t\nSquamous cell carcinoma\t1\t20.0\t17\t30.9\t\nLarge cell carcinoma\t0\t0.0\t2\t3.6\t\nOthers\t0\t0.0\t2\t3.6\t\nDisease stage\t\nIIIB\t1\t20.0\t6\t10.9\t\nIV\t4\t80.0\t37\t67.3\t\nPostoperative recurrence\t0\t0.0\t12\t21.8\t\nTreatment line\t\nSecond line\t5\t100.0\t34\t61.8\t\nThird line\t0\t0.0\t21\t38.2\t\nPrevious treatment with docetaxel\t1\t20.0\t20\t36.4\t\nAbbreviation: ECOG, Eastern Cooperative Oncology Group.\n\nJohn Wiley & Sons, Ltd.3.2 Phase II\nA total of 55 patients were enrolled in phase II between April 2014 and July 2016. The patient characteristics in phase II are presented in Table 1. The median age was 66 years (range, 41–90 years). The proportion of male patients was 72.7% and the PS 0/1/2 was 12/39/4, respectively. Thirty‐four (61.8%) patients were administered second‐line therapy. Twenty patients (36.3%) previously received DOC treatment. In 21 patients, (38.2%) who previously received both first‐ and second‐line treatments, DOC was most frequently administered as the second‐line treatment (52.4%). The proportion of patients with adenocarcinoma and squamous cell carcinoma (Sq) was 34 (61.8%) and 17 (30.9%) patients, respectively.\n\n3.3 Efficacy\nTreatment efficacy is summarized in Table 2. All 55 patients were eligible for efficacy analysis. Based on the investigator's assessment, four patients had a PR, and none demonstrated CR, yielding an ORR of 7.3% (95% CI, 2.0–17.6%). Twenty‐six patients had stable disease (SD), yielding a disease control rate (DCR: CR + PR + SD) of 54.5% (95% CI, 40.6–68.0%). In addition, subanalysis of clinical concerned factors predicting ORR and DCR was conducted (Table 3). The patients with non‐Sq histology tended to have better ORR and DCR. At the median follow‐up time of 9.6 months (range, 2.1–34.8 months) for all patients, mPFS was 3.4 months (95% CI, 1.9–4.0 months) and median survival time was 10.6 months (95% CI, 6.9–17.8 months) (Figure 1). The median number of treatment cycles was three. Among all treated patients, nine (16.4%) reduced the dose of nab‐PTX. The median dose intensity (DI) was 62.5 mg/m2 per week and the median relative DI (RDI) was 83.3%.\n\nTable 2 Objective response\n\nBest response\t\nn\n\t%\t\nCR\t0\t0\t\nPR\t4\t7.3\t\nSD\t26\t47.3\t\nPD\t24\t43.6\t\nNE\t1\t1.8\t\nResponse rate\t%\t[95% CI]\t\nORR\t7.3\t[2.0–17.6]\t\nDCR\t54.5\t[40.6–68.0]\t\nAbbreviations: CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NE, not evaluated; ORR, overall response rate; DCR, disease control rate; CI, confidence interval.\n\nJohn Wiley & Sons, Ltd.Table 3 Subanalysis of ORR and DCR\n\n\tNo. of pts (n = 55)\tORR\t［95% CI］\tDCR\t［95% CI］\t\nPrevious docetaxel treatment\t\nYes\t20\t5.0\t［0.1–24.8］\t45.0\t［23.1–68.4］\t\nNo\t35\t8.5\t［1.8–23.1］\t60.0\t［42.1–76.1］\t\nTreatment line\t\nSecond line\t34\t8.8\t［1.9–23.7］\t61.8\t［43.6–77.8］\t\nThird line\t21\t4.7\t［0.1–23.8］\t42.9\t［21.8–66.0］\t\nHistology\t\nNonsquamous\t38\t10.5\t［2.9–24.8］\t63.2\t［46.0–78.2］\t\nSquamous\t17\t0\t［0–19.5］\t35.3\t［14.2–61.7］\t\nAbbreviations: ORR, overall response rate; DCR, disease control rate; CI, confidence interval.\n\nJohn Wiley & Sons, Ltd.Figure 1 Progression‐free survival and overall survival\n\nProgression‐free survival curve (A) and overall survival curve (B)\n\nAbbreviations: PFS, progression‐free survival; CI, confidence interval; OS, overall survival; MST, median survival time\n\n3.4 Safety\nAll 55 patients enrolled in the study treatment were eligible for safety analysis. The major treatment‐related toxicities are presented in Tables 4 and 5. The major nonhematologic toxicities (total/grade 3 or more) were peripheral sensory neuropathy (49.1%/1.8%), fatigue (27.3%/0%) and anorexia (27.3%/1.8%). The most frequent treatment‐related grade 3 or 4 toxicities were neutropenia (36%), febrile neutropenia (5.5%) and pulmonary infection (3.6%). Five patients (9.1%) and one patient received granulocyte‐colony‐stimulating factor support and erythrocyte transfusion, respectively. Seven patients (13%) discontinued the study treatment because of grade 2 pneumonitis (n = 3), grade 3 AST/ALT elevation (n = 1), grade 4 sepsis (n = 1), grade 3 anorexia (n = 1) and grade 5 adult respiratory distress syndrome (ARDS) (n = 1).\n\nTable 4 Treatment‐related adverse events in phase II of the trial\n\nAdverse event\tTotal (%)\tGrade 3 or above (%)\t\nGeneral\t\nPeripheral sensory neuropathy\t49.1\t1.8\t\nFatigue\t27.3\t0.0\t\nAnorexia\t27.3\t1.8\t\nNausea\t12.7\t0.0\t\nMyalgia\t12.7\t0.0\t\nPeripheral motor neuropathy\t9.1\t1.8\t\nArthralgia\t7.3\t0.0\t\nVomiting\t5.5\t1.8\t\nPneumonitis\t5.5\t0.0\t\nFebrile neutropenia\t5.5\t5.5\t\nPulmonary infection\t3.6\t3.6\t\nDiarrhea\t3.6\t1.8\t\nSepsis\t1.8\t1.8\t\nARDS\t1.8\t1.8\t\nAbbreviation: ARDS, adult respiratory distress syndrome.\n\nJohn Wiley & Sons, Ltd.Table 5 Treatment‐related adverse events in phase II of the trial\n\nAdverse event\tGrade 3 or above (%)\t\nHematologic\t\nNeutropenia\t36.4\t\nAnemia\t1.8\t\nThrombocytopenia\t0.0\t\nBiochemical\t\nBlood bilirubin increased\t1.8\t\nAST/ALT elevation\t1.8\t\nHyponatremia\t1.8\t\nHypokalemia\t1.8\t\nAbbreviations: ALT, alanine amino transferase; AST, aspartate amino transferase.\n\nJohn Wiley & Sons, Ltd.Two deaths (3.6%) were observed during the protocol study. One patient developed grade 5 ARDS on day 26 of the second cycle. Considering that the patient had increasing bilateral pleural effusion and exacerbation of dyspnea on day 1 of the second cycle and home oxygen therapy was introduced, his cancer may have progressed after the first cycle. Nevertheless, the patient received 2 mg oral dexamethasone to treat dyspnea, which was an inhibited agent in this protocol and the second treatment cycle was started. This case was considered to deviate from the study protocol. This deviation may have caused the patient's death. Thus, we considered this patient's demise to be probably a nab‐PTX treatment‐related death. The other patient died on day 10 of the fourth cycle, two days after day 8 of nab‐PTX administration. Loss of consciousness occurred as the patient was going to the toilet at his home on day 9. He vomited, and subsequently experienced a cardiac arrest. In this case, AEs of nausea, vomiting and loss of appetite had not yet been reported. Despite emergency cardiopulmonary resuscitation, the patient died the next day. Computed tomography imaging of the head revealed no evidence of cerebral bleeding or infarction. Although grade 4 vomiting in this case was considered to be possibly related to nab‐PTX treatment, the causal relationship between death and the treatment protocol is unknown.\n\n3.5 Poststudy chemotherapy\nOverall, 70.9% (39/55) patients received subsequent systemic chemotherapy after poststudy treatment. The median number of poststudy treatment lines was one (range: 0–5). Drugs administered to the patients were as follows: nivolumab (30.9%), DOC (18.2%), S1 (12.7%), pemetrexed (10.9%) and vinorelbine (10.9%).\n\n4 DISCUSSION\nWe performed a prospective, multicenter phase I/II study of weekly nab‐PTX therapy in patients with advanced NSCLC without EGFR mutations or ALK rearrangement who were previously treated with platinum‐doublet chemotherapy. Although the level –1 schedule was not investigated in phase I, the proportion of AEs as the cause of discontinuation of therapy and dose reduction in phase II was 9/55 (16.4%) and 7/55 (13%) patients, respectively. The incidence of nonhematologic toxicities of grade ≥3 with the level –1 schedule was < 5%, except for febrile neutropenia (5.5%). Hematological toxicity was mild, with an incidence of 36.4% for grade ≥3 neutropenia. In contrast, the incidence of grade ≥3 neutropenia was 90.1% and that of febrile neutropenia was 19.1% in the DOC arm of phase III studies in previously treated Japanese patients with advanced NSCLC.10 Considering these factors, the level –1 schedule was feasible and appropriate in this setting.\n\nAlthough patients with histology of non‐Sq tended to have better ORR in subanalysis, the experimental regimen yielded an ORR of 7.3% (95% CI, 2.0–17.6%) in total, which did not meet the primary endpoint of the study. In other clinical trials involving EGFR‐mutated NSCLC patients, ORR was 14.5–31.7%, indicating good efficacy.3, 11, 12 In the KTOSG trial 1301, indicating the proportion of cases with EGFR mutations, 56.1% patients had wild‐type EGFR mutations, but the effectiveness analysis with or without EGFR mutation has not yet been investigated.3 Although this may not be the only reason for the low ORR obtained in this study, targeting only wild‐type EGFR patients may have resulted in this outcome.\n\nIn this study, the median DI was 62.5 mg/m2/week. This value was 89.1 mg/m2/week in the KTOSG trial 1301. The low DI may be one of the reasons for low ORR in our study. Although the prescribed DI was 75 mg/m2/week, skipping treatment or dose reduction of nab‐PTX may have resulted in the reduction of the RDI to 83.3%. The proportion of patients who skipped nab‐PTX treatment on day 15 was 62/194 cycles (31.9%), which may be the main reason for the reduced RDI.\n\nHowever, DCR, PFS and OS were not lower than those in other trials, where patients with EGFR mutation were included (Table 6).3, 11, 12 The argument whether ORR is appropriate to determine the efficiency criteria in second‐ or third‐line treatment is ongoing. Because PFS and OS of patients ≥70 years administered nab‐PTX in the CA031 trial tended to be superior to those administered sb‐PTX, a phase III trial (ABOUND .70+ trial) was conducted to investigate the efficacy and safety of weekly nab‐PTX either continuously or with a 1‐week interval, both in combination with carboplatin for patients aged ≥70 years.13 The study showed that the 1‐week break between treatment cycles significantly improved PFS (mPFS was 3.6 and 7.0 months [Hazard Ratio 0.48, P < 0.0019]) and ORR (23.9% and 40.3%; P = 0.0376). These findings support the safety and efficacy of first‐line nab‐paclitaxel/carboplatin in elderly patients with advanced NSCLC.\n\nTable 6 The treatment response and survival benefit\n\n\t\tAge, median\t\tORR\tDCR\tmPFS\tMST\t\nAuthor\t\nn\n\t(range)\tDose\t(%)\t(%)\t[95% CI]\t[95% CI]\t\nSakata et al.3\n\t41\t68\t100 mg/m2\n\t31.7\t65.9\t4.9\t11\t\n\t\t(43–77)\tQ3w, days 1, 8 and 15\t\t\t[2.4–7.4]\t\t\nHu et al.12\n\t56\t59.6\t100 mg/m2\n\t16.1\t51.7\t3.5\t6.8\t\n\t\t(32–83)\tQ4w, days 1, 8 and 15\t\t\t[1.9–5.8]\t[4.7–9.3]\t\nLiu et al.11\n\t55\t52.5\t150 mg/m2\n\t14.5\t65.5\t4.9\t11\t\n\t\t(29–74)\tQ3w, days 1 and 8\t\t\t[2.4–7.4]\t\t\nPresent study\t55\t66\t100 mg/m2\n\t7.3\t54.5\t3.4\t10.6\t\n\t\t(41–90)\tQ4w, days 1, 8 and 15\t\t\t[1.9–4.0]\t[6.9–17.8]\t\nAbbreviations: ORR, objective response rate; DCR, disease control rate; MST, median survival time; mPFS, median progression‐free survival; CI, confidence interval.\n\nJohn Wiley & Sons, Ltd.In preclinical data, it was shown that combination therapy with PTX/nab‐PTX and angiogenesis inhibitor bevacizumab increased the antitumor effect as compared with PTX/nab‐PTX monotherapy.14 Actually, in advanced gastric cancer, angiogenesis inhibitor ramucirumab + PTX has been statistically significantly prolonged OS compared with PTX alone as a secondary treatment in patients who progressed after platinum‐containing chemotherapy, and it is regarded as standard treatment.15 In the future, it might be necessary to verify the effectiveness and safety of combination therapy of nab‐PTX and angiogenesis inhibitor as a second‐line chemotherapy in NSCLC.\n\nThis study failed to meet predefined primary endpoints for patients with advanced NSCLC, although the PFS and OS were comparable with those in previous reports and toxicity was acceptable. The weekly nab‐PTX was not a promising treatment for NSCLC patients without EGFR or ALK mutations as a second‐ or third‐line treatment setting.\n\nACKNOWLEDGMENTS\nFor the study, there are no financial grants and other funding. We disclose the conflict of interests as follows; Daijiro Harada has been paid lecture fees to participate in a speakers’ bureau by Ono Pharmaceutical Co., Ltd., Bristol‐Myers Squibb Company, Yakult Honsha Co., Ltd., Kyowa Hakko Kirin Co., Ltd., AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd. and Eli Lilly Japan. Toshiyuki Kozuki has received honoraria outside the current work from Chugai Pharmaceutical, AstraZeneca, Eli Lilly Japan, Boehringer–Ingelheim, Ono Pharmaceutical, Bristol‐Myers Squibb Company, Taiho Pharmaceutical, MSD K.K., Pfizer Inc. Japan and Kyowa Hakko Kirin. Naoyuki Nogami has received honoraria from Astellas Pharma, AstraZeneca, Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Boehringer Ingelheim and Pfizer. Akihiro Bessho has received a speaker's fee from Taiho Pharmaceutical, Ono Pharmaceutical, Eli Lilly Japan, Bristol‐Myers Squibb and MSD K.K. Katsuyuki Hotta has received grants and personal fees from AstraZeneca, Ono Pharmaceutical, Boehringer‐Ingelheim, Chugai Pharmaceutical, Novartis, BMS, Eli Lilly Japan and MSD, personal fees from Nihon Kayaku and Taiho Pharmaceutical. Hiroshige Yoshioka has received honoraria outside the current work from Boehringer–Ingelheim, AstraZeneca, Eli Lilly Japan, Chugai Pharmaceutical, Bristol‐Myers Squibb Company, Ono Pharmaceutical, Taiho Pharmaceutical and Takeda Pharmaceutical Co. Ltd. Toshihide Yokoyama has been paid lecture fees to participate in a speakers’ bureau by Ono Pharmaceutical Co., Ltd., AstraZeneca K.K., Nippon Boehringer Ingelheim Co., Ltd., Chugai Pharmaceutical, MSD, Taiho Pharmaceutical and Eli Lilly Japan. Nagio Takigawa has received honoraria outside the current work from Eli Lilly Japan, AstraZeneca, Daiichi–Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Pfizer Inc. Japan, Boehringer–Ingelheim and Ono Pharmaceutical. Katsuyuki Kiura has received honoraria from Eli Lilly Japan, Nihon Kayaku, AstraZeneca, Daiichi‐Sankyo Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical and Sanofi‐Aventis. The remaining authors declare that they have no competing interests.\n\nWe would like to thank the patients and their family members, all participating physicians and medical assistants from cooperating hospitals and the independent review committee members for their involvement in the study, and Editage (http://www.editage.jp) for English language editing.\n==== Refs\nREFERENCES\n1 \n\nSocinski \nMA \n, \nBondarenko \nI \n, \nKaraseva \nNA \n, et al. Weekly nab‐paclitaxel in combination with carboplatin versus solvent‐based paclitaxel plus carboplatin as first‐line therapy in patients with advanced non‐small‐cell lung cancer: final results of a phase III trial . J Clin Oncol . 2012 ;30 (17 ):2055 ‐2062 .22547591 \n2 \n\nRizvi \nNA \n, \nRiely \nGJ \n, \nAzzoli \nCG \n, et al. Phase I/II trial of weekly intravenous 130‐nm albumin‐bound paclitaxel as initial chemotherapy in patients with stage IV non‐small‐cell lung cancer . 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Clin Cancer Res . 2006 ;12 (14 Pt 2 ):4451s ‐4457s .16857827 \n7 \n\nKawaguchi \nT \n, \nAndo \nM \n, \nAsami \nK \n, et al. Randomized phase III trial of erlotinib versus docetaxel as second‐ or third‐line therapy in patients with advanced non‐small‐cell lung cancer: Docetaxel and Erlotinib Lung Cancer Trial (DELTA) . J Clin Oncol . 2014 ;32 (18 ):1902 ‐1908 .24841974 \n8 \n\nYuan \nY \n, \nLi \nXF \n, \nChen \nJQ \n, \nDong \nCX \n, \nWeng \nSS \n, \nHuang \nJJ \n. Critical appraisal of the role of gefitinib in the management of locally advanced or metastatic non‐small cell lung cancer . Onco Targets Ther . 2014 ;7 :841 ‐852 .24920926 \n9 \n\nShepherd \nFA \n, \nDancey \nJ \n, \nRamlau \nR \n, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non‐small‐cell lung cancer previously treated with platinum‐based chemotherapy . J Clin Oncol . 2000 ;18 (10 ):2095 ‐2103 .10811675 \n10 \n\nYoh \nK \n, \nHosomi \nY \n, \nKasahara \nK \n, et al. A randomized, double‐blind, phase II study of ramucirumab plus docetaxel vs placebo plus docetaxel in Japanese patients with stage IV non‐small cell lung cancer after disease progression on platinum‐based therapy . Lung Cancer . 2016 ;99 :186 ‐193 .27565938 \n11 \n\nLiu \nZ \n, \nWei \nZ \n, \nHu \nY \n, et al. A phase II open‐label clinical study of comparing nab‐paclitaxel with pemetrexed as second‐line chemotherapy for patients with stage IIIB/IV non‐small‐cell lung cancer . Med Oncol . 2015 ;32 (8 ):216 .26168982 \n12 \n\nHu \nW \n, \nZhang \nZ \n. A phase II clinical study of using nab‐paclitaxel as second‐line chemotherapy for Chinese patients with advanced non‐small cell lung cancer . Med Oncol . 2015 ;32 (6 ):498 .25944796 \n13 \n\nLanger \nCJ \n, \nKim \nES \n, \nAnderson \nEC \n, et al. nab‐paclitaxel‐based therapy in underserved patient populations: the ABOUND.70+ study in elderly patients with advanced NSCLC . Front Oncol . 2018 ;8 :262 .30087851 \n14 \n\nTonissi \nF \n, \nLattanzio \nL \n, \nMerlano \nMC \n, \nInfante \nL \n, \nLo Nigro \nC \n, \nGarrone \nO \n. The effect of paclitaxel and nab‐paclitaxel in combination with anti‐angiogenic therapy in breast cancer cell lines . Invest New Drugs . 2015 ;33 (4 ):801 ‐809 .25947567 \n15 \n\nWilke \nH \n, \nMuro \nK \n, \nVan Cutsem \nE \n, et al. Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro‐oesophageal junction adenocarcinoma (RAINBOW): a double‐blind, randomised phase 3 trial . Lancet Oncol . 2014 ;15 (11 ):1224 ‐1235 .25240821\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1743-7555",
"issue": "15(4)",
"journal": "Asia-Pacific journal of clinical oncology",
"keywords": "cytotoxic chemotherapy; nanoparticle albumin-bound paclitaxel; non-small cell lung cancer; pretreated NSCLC; wild-type",
"medline_ta": "Asia Pac J Clin Oncol",
"mesh_terms": "D000368:Aged; D000418:Albumins; D000077548:Anaplastic Lymphoma Kinase; D002289:Carcinoma, Non-Small-Cell Lung; D066246:ErbB Receptors; D005260:Female; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009154:Mutation; D017239:Paclitaxel",
"nlm_unique_id": "101241430",
"other_id": null,
"pages": "250-256",
"pmc": null,
"pmid": "30938103",
"pubdate": "2019-08",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "25944796;26168982;20038723;27565912;30938103;25947567;18779611;30087851;25240821;24841974;16857827;27565938;24920926;18235124;10811675;22547591",
"title": "A phase I/II trial of weekly nab-paclitaxel for pretreated non-small-cell lung cancer patients without epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement.",
"title_normalized": "a phase i ii trial of weekly nab paclitaxel for pretreated non small cell lung cancer patients without epidermal growth factor receptor mutations and anaplastic lymphoma kinase rearrangement"
} | [
{
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{
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{
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}
],
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}
},
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"qualification": "3",
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},
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] |
{
"abstract": "Infantile haemangiomas, benign vascular tumours seen in 4-10% of infants are characterised by their spontaneous remission following a 3-9 month period of dynamic growth. Propranolol has been reported to be used as a successful treatment of severe symptomatic infantile haemangiomas. Hyperkalaemia has not been recognised as a serious effect of propranolol since recently. Here, we would like to portray a 2-year-old male patient with intestinal haemangiomatosis who presented with severe hyperkalaemia and was successfully managed with hydration, loop diuretics, potassium binding granules, inhaler β-2 agonists and insulin. To date, this is the first case of intestinal haemangiomatosis complicated with severe hyperkalaemia. Our case suggested the idea of close monitorisation of potassium levels as well as haemodynamic status at the initialisation of the propranolol treatment.",
"affiliations": "Department of Pediatric Hematology and Oncology, Gaziantep Childrens' Hospital, Gaziantep, Turkey.;Department of Pediatric Oncology, Gazi University School of Medicine, Ankara, Turkey.;Department of Pediatric Oncology, Gazi University School of Medicine, Ankara, Turkey.;Department of Pediatric Gastroenterology, Gazi University School of Medicine, Ankara, Turkey.",
"authors": "Belen|Burcu|B|;Oguz|Aynur|A|;Okur|Arzu|A|;Dalgic|Buket|B|",
"chemical_list": "D005665:Furosemide; D011433:Propranolol; D000420:Albuterol",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2014()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000420:Albuterol; D000792:Angiography; D001707:Biopsy, Needle; D004359:Drug Therapy, Combination; D005440:Fluid Therapy; D005500:Follow-Up Studies; D005665:Furosemide; D006471:Gastrointestinal Hemorrhage; D018324:Hemangioma, Capillary; D006801:Humans; D006947:Hyperkalemia; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D008551:Melena; D008991:Monitoring, Physiologic; D011433:Propranolol; D018570:Risk Assessment; D012720:Severity of Illness Index; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "24842358",
"pubdate": "2014-05-19",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "11559219;3528616;17872454;20674045;18550886;9789259;21115582;7911127;21774911;22962431;23438019;18940356;19840322;10788502;20456345;9094988;6101508;22516868;21434528;22303875;10541160;20015661",
"title": "A complication to be aware of: hyperkalaemia following propranolol therapy for an infant with intestinal haemangiomatozis.",
"title_normalized": "a complication to be aware of hyperkalaemia following propranolol therapy for an infant with intestinal haemangiomatozis"
} | [
{
"companynumb": "TR-AMNEAL PHARMACEUTICALS-2020-AMRX-01128",
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"occurcountry": "TR",
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{
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"activesubstance": {
"activesubstancename": "PROPRANOLOL HYDROCHLORIDE"
},
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{
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{
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},
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},
{
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},
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"drugdosagetext": "2 MILLIGRAM/KILOGRAM, INCREASED DOSE",
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"drugintervaldosagedefinition": "804",
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}
],
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"reaction": [
{
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"reactionmeddraversionpt": "23.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BELEN B, OGUZ A, OKUR A, DALGIC B. A COMPLICATION TO BE AWARE OF: HYPERKALAEMIA FOLLOWING PROPRANOLOL THERAPY FOR AN INFANT WITH INTESTINAL HAEMANGIOMATOZIS. BMJ CASE REP. 2014",
"literaturereference_normalized": "a complication to be aware of hyperkalaemia following propranolol therapy for an infant with intestinal haemangiomatozis",
"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20200413",
"receivedate": "20200413",
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},
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"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200713"
},
{
"companynumb": "TR-ROXANE LABORATORIES, INC.-2014-RO-00981RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PROPRANOLOL\\PROPRANOLOL HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
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"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "INTRA-ABDOMINAL HAEMANGIOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"medicinalproduct": "PROPRANOLOL"
}
],
"patientagegroup": "2",
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"patientweight": null,
"reaction": [
{
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"reactionmeddraversionpt": "17.1",
"reactionoutcome": "1"
}
],
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] |
{
"abstract": "Adjuvant chemotherapy with docetaxel/cyclophosphamide (TC) is adopted worldwide as a valuable option for elderly patients with high-risk early breast cancer. Some studies suggest that paclitaxel may have a better therapeutic ratio than docetaxel. Therefore we have implemented an adjuvant chemotherapy in which docetaxel was replaced by paclitaxel. We report here the retrospective analysis of that cohort and make a safety comparison with an earlier TC cohort in the same target population. This retrospective analysis demonstrates the feasibility of paclitaxel/cyclophosphamide as an alternative, better tolerated adjuvant regimen for elderly patients. Further evaluation and assessment of noninferiority to TC is warranted.",
"affiliations": "Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Jette, Belgium.;Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Jette, Belgium.;Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Jette, Belgium.;Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Jette, Belgium.;Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Jette, Belgium.;Department of Medical Oncology, Oncologisch Centrum, UZ Brussel, Jette, Belgium.",
"authors": "Joris|Sofie|S|0000-0003-4785-8891;Fontaine|Christel|C|;Decoster|Lore|L|0000-0001-7563-0179;Vanacker|Leen|L|;Schallier|Denis|D|;De Grève|Jacques|J|",
"chemical_list": "D000077143:Docetaxel; D003520:Cyclophosphamide; D017239:Paclitaxel",
"country": "United States",
"delete": false,
"doi": "10.1111/tbj.13306",
"fulltext": null,
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"issn_linking": "1075-122X",
"issue": "25(4)",
"journal": "The breast journal",
"keywords": "breast cancer; chemotherapy; elderly",
"medline_ta": "Breast J",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide; D000077143:Docetaxel; D005260:Female; D006801:Humans; D017239:Paclitaxel; D012189:Retrospective Studies",
"nlm_unique_id": "9505539",
"other_id": null,
"pages": "663-666",
"pmc": null,
"pmid": "31074007",
"pubdate": "2019-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Retrospective comparison of two consecutive cohorts of adjuvant chemotherapy regimens of cyclophosphamide with either docetaxel or paclitaxel in older patients with early breast cancer.",
"title_normalized": "retrospective comparison of two consecutive cohorts of adjuvant chemotherapy regimens of cyclophosphamide with either docetaxel or paclitaxel in older patients with early breast cancer"
} | [
{
"companynumb": "BE-MYLANLABS-2019M1072542",
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"medicinalproduct": "PACLITAXEL."
},
{
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}
],
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"reactionoutcome": "6"
}
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},
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"literaturereference": "JORIS S, FONTAINE C, DECOSTER L, VANACKER L, SCHALLIER D, DE GREVE J. RETROSPECTIVE COMPARISON OF TWO CONSECUTIVE COHORTS OF ADJUVANT CHEMOTHERAPY REGIMENS OF CYCLOPHOSPHAMIDE WITH EITHER DOCETAXEL OR PACLITAXEL IN OLDER PATIENTS WITH EARLY BREAST CANCER. BREAST-J 2019?25(4):663-666.",
"literaturereference_normalized": "retrospective comparison of two consecutive cohorts of adjuvant chemotherapy regimens of cyclophosphamide with either docetaxel or paclitaxel in older patients with early breast cancer",
"qualification": "3",
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},
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"seriousnessother": 1,
"transmissiondate": "20191004"
}
] |
{
"abstract": "A 35-year-old man with generalized insults was admitted to the intensive care unit because of third-line treatment of persistent epileptic insults with antiepileptic drug therapy. Topiramate was added on top of his outpatient regimen in combination with intravenous antiepileptic drugs. Miscommunication and inappropriate topiramate dosing (2,500 mg twice) resulted in an acute topiramate intoxication. Toxicokinetic assessment showed toxic serum topiramate concentration of 55 mg/L and a dose-dependent shift of peak time tmax. According to our modulations, tmax follows Y = 0.0009X + 2.65, where X is the topiramate dose. Our results have important implications for effectiveness of gut decontamination modalities.",
"affiliations": null,
"authors": "Hoebregts|Vera M G|VMG|;Foudraine|Norbert|N|;Janssen|Paddy K C|PKC|;le Noble|Jos L M L|JLML|",
"chemical_list": "D000927:Anticonvulsants; D000077236:Topiramate; D005632:Fructose",
"country": "Germany",
"delete": false,
"doi": "10.5414/CP204067",
"fulltext": "\n==== Front\nInt J Clin Pharmacol Ther\nInt J Clin Pharmacol Ther\nDustri\nInternational Journal of Clinical Pharmacology and Therapeutics\n0946-1965\nDustri-Verlag Dr. Karl Feistle\n\n34622772\n10.5414/CP204067\nCase Report\nPharmacology\nIatrogenic topiramate poisoning in an ICU patient: Focus on topiramate peak time prolongation\nHoebregts Vera M.G. 1\nFoudraine Norbert 2\nJanssen Paddy K.C. 34\nle Noble Jos L.M.L. 25\n1 Department of Clinical Pharmacy, Pharmacology and Toxicology, Zuyderland Medical Center, Sittard-Geleen,\n2 Department of Intensive Care,\n3 Department of Hospital Pharmacy, VieCuri Medical Center Venlo,\n4 Department of Clinical Pharmacy and Toxicology, Maastricht University Medical Center, and\n5 Department of Pharmacology and Toxicology, Maastricht, The Netherlands\nCorrespondence to Jos L.M.L. le Noble, MD, PhD Department of Intensive Care, VieCuri Medical Center Venlo, 5900 BX Venlo, The Netherlands jlenoble@viecuri.nl\n12 2021\n8 10 2021\n59 12 784786\n12 5 2021\n2 6 2021\n© Dustri-Verlag Dr. K. Feistle\n2021\nhttps://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nA 35-year-old man with generalized insults was admitted to the intensive care unit because of third-line treatment of persistent epileptic insults with antiepileptic drug therapy. Topiramate was added on top of his outpatient regimen in combination with intravenous antiepileptic drugs. Miscommunication and inappropriate topiramate dosing (2,500 mg twice) resulted in an acute topiramate intoxication. Toxicokinetic assessment showed toxic serum topiramate concentration of 55 mg/L and a dose-dependent shift of peak time tmax. According to our modulations, tmax follows Y = 0.0009X + 2.65, where X is the topiramate dose. Our results have important implications for effectiveness of gut decontamination modalities.\n\ntoxicokinetics\ntopiramate\npoisoning\nICU\ntherapeutic drug monitoring\n==== Body\npmc What is known about this subject\n\nTopiramate intoxications can lead to coma, confusion, somnolence, and seizures. Gut decontamination should be applied immediately before tmax is reached because increasing time between topiramate intake and decontamination will decrease efficacy to decontaminate. However, limited data exist on pharmacokinetics during topiramate overdose, and current consensus guidelines of gut decontamination do not include shifts of tmax during topiramate intoxication.\n\nWhat this study adds\n\nOur case is the first case to describe the following:\n\ntmax in topiramate intoxication may considerably increase in a dose-dependent manner following the equation Y = 0.0009X + 2.65 (in which Y is tmax (h), where X is the topiramate dose (mg)).\n\nExtended tmax can cause symptoms later than expected.\n\nFor clinicians, it is important to note that present guidelines for gut decontamination for acute poisoning during topiramate overdose do not include shifts with an increase in tmax. Beneficial effects of gastrointestinal decontamination persist longer in patients with topiramate intoxication due to lengthened tmax.\n\nIntroduction\n\nTopiramate is a broad-spectrum anticonvulsant drug (AED). Acute poisoning with topiramate primarily involves the central nervous system [1]. Antidotes are lacking in case of poisoning [1, 2]. General measures include support of vital functions [1, 2]. Charcoal gastrointestinal decontamination can yield treatment benefits [3], but its effectiveness beyond the generally accepted time window of 1 – 3 hours remains to be elucidated.\n\nWe report a case of an intensive care unit (ICU) patient with topiramate toxicity from an unintended overdose due to prescribing errors. We assessed the effectiveness of gastrointestinal decontamination related to topiramate peak time based on data from our patient and those previously published.\n\nCase report\n\nA 35-year-old Caucasian male weighing 124 kg (body mass index: 34 kg/m2) with a history of epilepsy was admitted to the ICU with generalized seizures. On arrival, the patient was unresponsive, and his body temperature was 35.9 °C. His blood pressure was 194/119 mmHg, pulse rate was 100/minute, and respiratory rate was 18/minute. The clinical assessment of disease severity according to the APACHE IV score was 92. Renal and liver tests were normal. Endotracheal intubation was performed. Lacosamide and levetiracetam were administered intravenously twice daily (50 mg and 1,500 mg, respectively). On day 4, due to increased antiepileptic activity, 250 mg topiramate twice daily was prescribed.\n\nDue to miscommunication, a dose of 2,500 mg topiramate was administered by a nasogastric tube. The next day, the prescription error was discovered but a toxicity syndrome was already suspected. Prompt gastrointestinal decontamination, including active charcoal, was initiated within 12 hours from administration. A laxative (sodium thiosulphate) was administered every 4 hours to prevent drug absorption. No seizures were recorded on the EEG. The patient recovered fully and was discharged on day 6.\n\nTopiramate plasma concentrations and toxicokinetics\n\nThe data set of our patient consisted of five serial pharmacokinetic concentration time profiles of topiramate representing the elimination phase. Topiramate plasma concentrations were determined in left over samples. The peak plasma concentration of topiramate was 55 µg/mL. Table 1 shows the pharmacokinetic parameters of topiramate of our patient, the population average, and a case reported by Brandt et al. [2]. After the tmax, first-order kinetics could be used to fit topiramate clearance. Similar simulations were done for standard oral dosing of 100 mg topiramate. Finally, we used 10 serial pharmacokinetic concentration time profiles representing the elimination phase (first-order kinetics) from a patient with a topiramate intoxication published by Brandt et al. [2].\n\nFigure 1 presents the topiramate peak time and ranges plotted against the topiramate dosage based on the data set from Table 1. The best-fit linear regression line showed a linear relationship between ingested dose and topiramate peak time, represented graphically with the ingested dose on the X-axis and the peak time on the Y-axis (Y = 0.0009X + 2.65).\n\nThe oral topiramate doses used for the simulations were 250 mg as standard dose, 2,500 mg for the present patient, and 8,000 mg for the dose obtained from available data published by Brandt et al. [2]. tmax (h) is presented as mean values with ranges.\n\nDiscussion\n\nThe topiramate dose administered in our patient was 10 times the prescribed dose, causing acute toxicity. Our pharmacokinetic modeling demonstrated a prolongation of tmax during topiramate toxicity, which occurred linearly in a dose-dependent manner (Figure 1) for up to 10 hours. Delayed gastric emptying as a result of narcotic administration or diminished splanchnic blood flow may have contributed to the delay in tmax that we found.\n\nIn case of absence of a topiramate toxicity syndrome in the first hours of ingestion, it could be falsely interpreted as favorable and may lead to delayed supportive treatment. Our case aligns with experimental data showing that peak times following a single dose appear earlier when the patient is receiving repeated consistent doses over time, but that it is longer when the patient receives a single new dose [4]. Furthermore, topiramate elimination is capacity-limited [2]. Other agents may have changed the absorption rate in the gastrointestinal tract [5], and obesity in our patient might have affected liver function and topiramate kinetics [2].\n\nConclusion\n\nWith our newly developed equation (Y = 0.0009X + 2.65), clinicians can easily determine the expected peak time of topiramate. Moreover, we have shown that patients may still benefit from gastrointestinal decontamination up to 10 hours following ingestion of toxic doses.\n\nAcknowledgment\n\nWe would like to thank Hai Holthuysen, a laboratory technician at the VieCuri Medical Center for the determination of topiramate.\n\nFunding\n\nThe authors declare that no external funding was received for the conduct of this study and/or the preparation of this manuscript.\n\nConflict of interest\n\nAuthors declare no conflict of interest. Authors declare that they have no commercial or proprietary interest in any drug, device, or equipment mentioned in the article.\n\nTable 1. Pharmacokinetic modeling using MWPharm 3.58 of three different oral doses of topiramate: 100, 2,500, and 8,000 mg.\n\n\tGeneral population\tPresent case report\tPatient by Brandt et al. [2]\t\nIngested dose (mg)\t100\t2,500\t800\t\ntmax (h), ranges\t2.5 (2 – 3)\t5.28 (3.6 – 7.8)\t9.84 (8.7 – 10.9)\t\nT1/2 (h)\t± 21\t16.48\t23.26\t\nVd (L/kg)\t0.55 – 0.80\t0.69\t0.46\t\nTotal body clearance (L/h)\t1.7 – 1.8\t2.39\t1.04\t\nThe pharmacokinetic parameters were assessed in: 1. an adult healthy subject using published clinical PK data from the Summary of Product Characteristics of Topamax (Janssen-Cilag B.V., Breda, The Netherlands) [6]; 2. the present patient using experimental data of 5 measurements; 3. a patient with a topiramate intoxication described by Brandt et al. [2] using experimental data of 10 measurements. tmax (h) values are presented as mean and ranges. Drug dosing and calculation of the volume of distribution (L/kg) were based on lean body mass.\n\nFigure 1 The best-fit linear regression line showing a linear relationship between ingested dose and topiramate peak time, represented graphically with the ingested dose on the X-axis and the peak time on the Y-axis (Y = 0.0009X + 2.65). The dotted line represents the maximum ranges to either side. The left, middle, and right data points represent patients 1, 2, and 3, respectively, presented in Table 1. Data points represent means of experimental data.\n==== Refs\nReferences\n\n1 Lynch MJ Pizon AF Siam MG Krasowski MD Clinical effects and toxicokinetic evaluation following massive topiramate ingestion. J Med Toxicol. 2010; 6 : 135–138. 20376593\n2 Brandt C Elsner H Füratsch N Hoppe M Nieder E Rambeck B Ebner A May TW Topiramate overdose: a case report of a patient with extremely high topiramate serum concentrations and nonconvulsive status epilepticus. Epilepsia. 2010; 51 : 1090–1093. 19889015\n3 Thanacoody R Caravati EM Troutman B Höjer J Benson B Hoppu K Erdman A Bedry R Mégarbane B Position paper update: whole bowel irrigation for gastrointestinal decontamination of overdose patients. Clin Toxicol (Phila). 2015; 53 : 5–12. 25511637\n4 Greenberg HE England MJ Hellriegel ET Bjornsson TD Time of peak drug concentration after a single dose and a dose at steady state. J Clin Pharmacol. 1997; 37 : 480–485. 9208354\n5 Yamaguchi J Kinoshita K Noda A Furukawa M Sakurai A Delayed increase in serum acetaminophen concentration after ingestion of a combination medications: a case report. J Int Med Res. 2018; 46 : 3435–3439. 29882461\n6 Janssen-Cilag BV Summary of Product Characteristics. Topamax 25, 50, 100, 200 mg. 2010. URL: https://www.geneesmiddeleninformatiebank.nl/smpc/h24167_smpc.pdf.Date of access: May 22, 2021.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0946-1965",
"issue": "59(12)",
"journal": "International journal of clinical pharmacology and therapeutics",
"keywords": null,
"medline_ta": "Int J Clin Pharmacol Ther",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D005632:Fructose; D006801:Humans; D007049:Iatrogenic Disease; D007362:Intensive Care Units; D008297:Male; D000077236:Topiramate",
"nlm_unique_id": "9423309",
"other_id": null,
"pages": "784-786",
"pmc": null,
"pmid": "34622772",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "25511637;19889015;29882461;20376593;9208354",
"title": "Iatrogenic topiramate poisoning in an ICU patient: Focus on topiramate peak time prolongation.",
"title_normalized": "iatrogenic topiramate poisoning in an icu patient focus on topiramate peak time prolongation"
} | [
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{
"abstract": "BACKGROUND\nImmune reconstitution syndrome (IRS) is a relatively common complication in HIV-infected adults starting combination antiretroviral therapy (cART). Data on IRS in HIV-infected children remain limited and are largely restricted to resource-limited settings. This study investigated the incidence, spectrum and outcome of IRS in a pediatric cohort in the United Kingdom.\n\n\nMETHODS\nRetrospective analysis of clinical events during the first 12 months after initiation of cART in 135 treatment-naïve, HIV-infected children in the United Kingdom over a 5-year period. Demographic and laboratory data were provided by the Collaborative HIV Paediatric Study.\n\n\nRESULTS\nThe median age at cART initiation was 6.6 years (interquartile range: 2.3-10.2). The median CD4 lymphocyte percentage (CD4%) at baseline was 15% (median CD4 lymphocyte count: 390 cells/μL). Eight patients (5.9%) developed IRS (incidence: 5.7/100 person years). The IRS events comprised: Bacillus Calmette-Guerin-related complications (local ulceration/lymphadenitis; n = 4), pulmonary tuberculosis (n = 1), Mycobacterium avium intracellulare infection (n = 1), combined tuberculosis/Mycobacterium avium intracellulare infection (n = 1) and cutaneous herpes simplex (n = 1). The mortality was significantly higher in children with IRS than in those without (P < 0.0001). The only statistically significant risk factor for IRS identified was increment in CD4 count at 12 months after starting cART (P = 0.03).\n\n\nCONCLUSIONS\nThe incidence of IRS was significantly lower than previously reported from resource-limited settings, likely reflecting less profound immunodeficiency at cART initiation and fewer coexisting opportunistic infections in our cohort. However, IRS events were associated with considerable morbidity and mortality. Therefore, preventive strategies that can reduce the risk of IRS in children need to be identified.",
"affiliations": "From the *Paediatric Infectious Diseases Unit, St. George's Hospital; † Paediatric Infectious Diseases Unit, Imperial College Healthcare NHS Trust, London, United Kingdom; ‡Department of Paediatrics, The University of Melbourne, Parkville, Australia; §Academic Unit of Clinical and Experimental Sciences, Faculty of Medicine; ¶Institute for Life Sciences, University of Southampton, Southampton; ‖Faculty of Medicine, Imperial College; and **Department of Paediatrics, St. George's Medical School, London, United Kingdom.",
"authors": "Gkentzi|Despoina|D|;Tebruegge|Marc|M|;Tudor-Williams|Gareth|G|;Walters|Sam|S|;Lyall|Hermione|H|;Sharland|Mike|M|;Doerholt|Katja|K|",
"chemical_list": "D044966:Anti-Retroviral Agents; D001500:BCG Vaccine",
"country": "United States",
"delete": false,
"doi": "10.1097/INF.0000000000000331",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0891-3668",
"issue": "33(9)",
"journal": "The Pediatric infectious disease journal",
"keywords": null,
"medline_ta": "Pediatr Infect Dis J",
"mesh_terms": "D044966:Anti-Retroviral Agents; D001500:BCG Vaccine; D018791:CD4 Lymphocyte Count; D002648:Child; D002675:Child, Preschool; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections; D006561:Herpes Simplex; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D015994:Incidence; D007223:Infant; D008199:Lymphadenitis; D008297:Male; D015270:Mycobacterium avium-intracellulare Infection; D012189:Retrospective Studies; D017193:Skin Diseases, Viral; D014397:Tuberculosis, Pulmonary",
"nlm_unique_id": "8701858",
"other_id": null,
"pages": "953-8",
"pmc": null,
"pmid": "24618936",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Incidence, spectrum and outcome of immune reconstitution syndrome in HIV-infected children after initiation of antiretroviral therapy.",
"title_normalized": "incidence spectrum and outcome of immune reconstitution syndrome in hiv infected children after initiation of antiretroviral therapy"
} | [
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},
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"drugindication": "HIV INFECTION",
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"drugindication": "HIV INFECTION",
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},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMIVUDINE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "020564",
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"drugindication": "HIV INFECTION",
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"medicinalproduct": "LAMIVUDINE."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZIDOVUDINE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
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"drugindication": "HIV INFECTION",
"drugintervaldosagedefinition": null,
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"drugrecurrence": null,
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"drugstartdate": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ZIDOVUDINE."
}
],
"patientagegroup": null,
"patientonsetage": "14",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Abdominal pain",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Abdominal lymphadenopathy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pyrexia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hepatomegaly",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Lung infiltration",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Respiratory disorder",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Immune reconstitution inflammatory syndrome",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Mycobacterium avium complex infection",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Granuloma",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pleural effusion",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "GKENTZI D, TEBRUEGGE M, TUDOR-WILLIAMS G, WALTERS S, LYALL H, SHARLAND M ET AL. INCIDENCE, SPECTRUM AND OUTCOME OF IMMUNE RECONSTITUTION SYNDROME IN HIV-INFECTED CHILDREN AFTER INITIATION OF ANTIRETROVIRAL THERAPY. THE PEDIATRIC INFECTIOUS DISEASE JOURNAL. 2014;33:9",
"literaturereference_normalized": "incidence spectrum and outcome of immune reconstitution syndrome in hiv infected children after initiation of antiretroviral therapy",
"qualification": "1",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20150501",
"receivedate": "20150501",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 11082121,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "♦\n\n\n\nDaily gentamicin cream exit-site prophylaxis reduces peritoneal dialysis (PD)-related gram-negative infections. However, there is a concern about the potential for increasing gentamicin resistance with the long-term use of prophylactic gentamicin. This study evaluated the incidence of gentamicin-resistant PD-related infections over more than 2 decades. ♦\n\n\n\nStudy data on prevalent PD patients were retrieved from a prospectively maintained institutional review board (IRB)-approved PD registry at a single center from January 1, 1991, to December 31, 2000, and January 1, 2004, to December 31, 2013. The rates of gram-negative infections, fungal infections and those infections with organisms resistant to gentamicin were examined for the 2 periods. Period 1 from 1991 to 2000 when S. aureus prophylaxis consisted initially of oral rifampin to treat nasal carriage with S. aureus, and was then daily exit-site mupirocin ointment for all PD patients, was compared to the period from 2004 to 2013 when daily exit-site gentamicin cream was prescribed as prophylaxis (Period 2). ♦\n\n\n\nThe study included a total of 444 PD patients (265 and 179 in Period 1 and Period 2, respectively). No significant difference was noted in demographics between the 2 periods except race. The gram-negative exit-site infection rates for Period 1 and Period 2 were 0.109 versus 0.027 (p < 0.0001). Gram-negative peritonitis rates were similar. There were 3 episodes of gentamicin-resistant infections in each period. Fungal infections remained consistently low. ♦\n\n\n\nDespite a decade of exit-site gentamicin prophylaxis, gentamicin-resistant PD-related infections and fungal infections remained very low and similar to the prior period.",
"affiliations": "Nephrology Division, Department of Medicine at the University of New Mexico School of Medicine, Albuquerque, NM, USA SSChen@salud.unm.edu.;Renal-Electrolyte Division, Department of Medicine at the University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.;Renal-Electrolyte Division, Department of Medicine at the University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.;Renal-Electrolyte Division, Department of Medicine at the University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.",
"authors": "Chen|Shan Shan|SS|;Sheth|Heena|H|;Piraino|Beth|B|;Bender|Filitsa|F|",
"chemical_list": "D000900:Anti-Bacterial Agents; D005839:Gentamicins",
"country": "United States",
"delete": false,
"doi": "10.3747/pdi.2015.00162",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0896-8608",
"issue": "36(4)",
"journal": "Peritoneal dialysis international : journal of the International Society for Peritoneal Dialysis",
"keywords": "Exit-site infection; gentamicin cream; gentamicin-resistant; peritoneal dialysis; peritonitis; prophylaxis",
"medline_ta": "Perit Dial Int",
"mesh_terms": "D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D055499:Catheter-Related Infections; D002408:Catheters, Indwelling; D015331:Cohort Studies; D024881:Drug Resistance, Bacterial; D005260:Female; D005839:Gentamicins; D016905:Gram-Negative Bacterial Infections; D006801:Humans; D007676:Kidney Failure, Chronic; D008297:Male; D008875:Middle Aged; D010530:Peritoneal Dialysis; D010538:Peritonitis",
"nlm_unique_id": "8904033",
"other_id": null,
"pages": "387-9",
"pmc": null,
"pmid": "26634567",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": "22641737;24584620;21880990;15625071;20628102;22302770;3812473;14604197",
"title": "Long-Term Exit-Site Gentamicin Prophylaxis and Gentamicin Resistance in a Peritoneal Dialysis Program.",
"title_normalized": "long term exit site gentamicin prophylaxis and gentamicin resistance in a peritoneal dialysis program"
} | [
{
"companynumb": "US-BAUSCH-BL-2016-018090",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "64048",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "CREAM",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROPHYLAXIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": "2005",
"drugstartdateformat": "602",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "GENTAMICIN."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CHEN S, SHETH H, PIRAINO B, BENDER F. LONG-TERM EXIT-SITE GENTAMICIN PROPHYLAXIS AND GENTAMICIN RESISTANCE IN A PERITONEAL DIALYSIS PROGRAM. PERITONEAL DIALYSIS INTERNATIONAL. 2016;36:387-389.",
"literaturereference_normalized": "long term exit site gentamicin prophylaxis and gentamicin resistance in a peritoneal dialysis program",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20160728",
"receivedate": "20160728",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 12604702,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20161109"
},
{
"companynumb": "US-BAUSCH-BL-2016-017445",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "GENTAMICIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "64048",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "CREAM",
"drugdosagetext": "BETWEEN 2005 TO 2013",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PROPHYLAXIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "GENTAMICIN."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2005"
}
},
"primarysource": {
"literaturereference": "CHEN S, SHETH H, PIRAINO B, BENDER F. LONG-TERM EXIT-SITE GENTAMICIN PROPHYLAXIS AND GENTAMICIN RESISTANCE IN A PERITONEAL DIALYSIS PROGRAM. PERITONEAL DIALYSIS INTERNATIONAL. 2016;36:387-389.",
"literaturereference_normalized": "long term exit site gentamicin prophylaxis and gentamicin resistance in a peritoneal dialysis program",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20160728",
"receivedate": "20160728",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 12604701,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20161109"
}
] |
{
"abstract": "OBJECTIVE\nReport a novel case of new-onset type 1 diabetes in a pediatric patient presenting with DKA and concurrent Streptococcus intermedius brain abscess.\n\n\nMETHODS\nThe following case report is that of a previously healthy 12 year-old girl presenting with new-onset type 1 diabetes with mild diabetic ketoacidosis and subsequently found to have a brain abscess. Over the course of her hospital stay, she developed seizures and was found to have a 1.3 × 1.0 × 1.2 cm right frontal parasagittal mass culture-positive for S. intermedius. Neurologic symptoms were unmasked once insulin treatment was initiated and ketosis improved, supporting the relationship between therapeutic ketosis and the management of medication-refractory epilepsy.\n\n\nCONCLUSIONS\nThis case both supports the relationship between therapeutic ketosis and the management of medication-refractory epilepsy and highlights the need to carefully consider comorbid conditions in patients with DKA and new onset neurological symptoms.",
"affiliations": "East Tennessee State University James H Quillen College of Medicine, Johnson City, Tennessee, USA.;East Tennessee State University James H Quillen College of Medicine, Johnson City, Tennessee, USA.;Le Bonheur Children's Hospital, Memphis, Tennessee, USA.;Pediatric Endocrinology, East Tennessee State University James H Quillen College of Medicine, Johnson City, Tennessee, USA.",
"authors": "Mintz|Judy L|JL|;Jameson|Morghan B|MB|;Akinseye|Leah|L|;Los|Evan A|EA|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1515/jpem-2020-0711",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0334-018X",
"issue": "34(6)",
"journal": "Journal of pediatric endocrinology & metabolism : JPEM",
"keywords": "DKA; Streptococcus intermedius; brain abscess",
"medline_ta": "J Pediatr Endocrinol Metab",
"mesh_terms": "D001922:Brain Abscess; D002648:Child; D003922:Diabetes Mellitus, Type 1; D016883:Diabetic Ketoacidosis; D005260:Female; D006801:Humans; D011379:Prognosis; D013290:Streptococcal Infections; D034367:Streptococcus intermedius",
"nlm_unique_id": "9508900",
"other_id": null,
"pages": "817-820",
"pmc": null,
"pmid": "33851524",
"pubdate": "2021-06-25",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Pediatric diabetic ketoacidosis presenting with Streptococcus intermedius brain abscess.",
"title_normalized": "pediatric diabetic ketoacidosis presenting with streptococcus intermedius brain abscess"
} | [
{
"companynumb": "US-MYLANLABS-2022M1014117",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN GLARGINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "210605",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "13 INTERNATIONAL UNIT (13 UNITS NIGHTLY)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Type 1 diabetes mellitus",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstructuredosagenumb": "13",
"drugstructuredosageunit": "025",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "INSULIN GLARGINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN GLARGINE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "210605",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Diabetic ketoacidosis",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "INSULIN GLARGINE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN LISPRO"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1 INTERNATIONAL UNIT (1 UNIT/12 G OF CARBOHYDRATE)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Type 1 diabetes mellitus",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1",
"drugstructuredosageunit": "025",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "INSULIN LISPRO"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INSULIN LISPRO"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Diabetic ketoacidosis",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "INSULIN LISPRO"
}
],
"patientagegroup": null,
"patientonsetage": "12",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Unmasking of previously unidentified disease",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Neurological symptom",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Streptococcal infection",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Brain abscess",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Mintz JL, Jameson MB, Akinseye L, Los EA. Pediatric diabetic ketoacidosis presenting with Streptococcus intermedius brain abscess. J-Pediatr-Endocrinol-Metab 2021;34(6):817-820.",
"literaturereference_normalized": "pediatric diabetic ketoacidosis presenting with streptococcus intermedius brain abscess",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20220222",
"receivedate": "20220222",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 20500504,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 2,
"seriousnessother": 2,
"transmissiondate": "20220423"
}
] |
{
"abstract": "BACKGROUND\nHere we present a case of acute ovarian cyst haemorrhage in a young female during induction therapy for acute myelomonocytic leukaemia (AMML).\n\n\nMETHODS\nA patient undergoing chemotherapy on the AML19 trial for AMML developed severe abdominal pain and haemodynamic compromise during cycle 2 of fludarabine, cytarabine and idarubicin. The patient was found to have a large ruptured haemorrhagic ovarian cyst on computed tomography. She was managed conservatively due to relative haematological contraindications to surgery and haemodynamic stability following transfer to the high dependency unit. The patient had recently discontinued anticoagulation for pulmonary emboli due to thrombocytopenia.\n\n\nCONCLUSIONS\nThis highlights the importance of recognising coexistent pathology in patients undergoing high intensity chemotherapy.",
"affiliations": "North Hampshire and Basingstoke Hospital, Basingstoke, UK amy.irwin@hhft.nhs.uk.;North Hampshire and Basingstoke Hospital, Basingstoke, UK.;North Hampshire and Basingstoke Hospital, Basingstoke, UK.",
"authors": "Irwin|Amy L|AL|;Smith|Katherine|K|;Sargant|Nigel|N|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "England",
"delete": false,
"doi": "10.7861/clinmed.2019-0355",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2118",
"issue": "19(6)",
"journal": "Clinical medicine (London, England)",
"keywords": "AMML; anticoagulation; chemotherapy; ovarian cyst haemorrhage; thrombocytopenia",
"medline_ta": "Clin Med (Lond)",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Ovarian cyst haemorrhage as a complication of acute myelomonocytic leukaemia induction therapy.",
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] |
{
"abstract": "Drug analysis in hair is useful when seeking to establish drug intake over a period of months to years. Segmental hair analysis can also document whether psychiatric patients are receiving a stable intake of antipsychotics. This study describes segmental analysis of the antipsychotic drug quetiapine in post-mortem hair samples from long-term quetiapine users by ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) analysis. The aim was to obtain more knowledge on quetiapine concentrations in hair and to relate the concentration in hair to the administered dose and the post-mortem concentration in femoral blood. We analyzed hair samples from 22 deceased quetiapine-treated individuals, who were divided into two groups: natural hair colour and dyed/bleached hair. Two to six 1cm long segments were analyzed per individual, depending on the length of the hair, with 6cm corresponding to the last six months before death. The average daily quetiapine dose and average concentration in hair for the last six months prior to death were examined for potential correlation. Estimated doses ranged from 45 to 1040mg quetiapine daily over the period, and the average concentration in hair ranged from 0.18 to 13ng/mg. A significant positive correlation was observed between estimated daily dosage of quetiapine and average concentration in hair for individuals with natural hair colour (p=0.00005), but statistical significance was not reached for individuals with dyed/bleached hair (p=0.31). The individual coefficient of variation (CV) of the quetiapine concentrations between segments ranged from 3 to 34% for individuals with natural hair colour and 22-62% for individuals with dyed/bleached hair. Dose-adjusted concentrations in hair were significantly lower in females with dyed/bleached hair than in individuals with natural hair colour. The quetiapine concentrations in post-mortem femoral blood and in the proximal hair segment, segment 1 (S1), representing the last month before death were also investigated for correlation. A significant positive correlation was observed between quetiapine concentrations in blood at the time of death and concentrations in S1 for individuals with natural hair colour (p=0.003) but not for individuals with dyed/bleached hair (p=0.31). The blood concentrations of quetiapine ranged from 0.006 to 1.9mg/kg, and the quetiapine concentrations in S1 ranged from 0.22 to 24ng/mg. The results of this study suggest a positive correlation of quetiapine between both concentrations in hair and doses, and between proximal hair (S1) and blood concentrations, when conditions such as hair treatments are taken into consideration.",
"affiliations": "Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's vej 11, DK-2100, Denmark. Electronic address: kamilla.nyborg.nielsen@sund.ku.dk.;Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's vej 11, DK-2100, Denmark.;Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's vej 11, DK-2100, Denmark.;Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's vej 11, DK-2100, Denmark.;Section of Forensic Pathology, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's vej 11, DK-2100, Denmark.;Section of Forensic Chemistry, Department of Forensic Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Frederik V's vej 11, DK-2100, Denmark.",
"authors": "Günther|Kamilla Nyborg|KN|;Johansen|Sys Stybe|SS|;Nielsen|Marie Katrine Klose|MKK|;Wicktor|Petra|P|;Banner|Jytte|J|;Linnet|Kristian|K|",
"chemical_list": "D014150:Antipsychotic Agents; D006202:Hair Dyes; D000069348:Quetiapine Fumarate",
"country": "Ireland",
"delete": false,
"doi": "10.1016/j.forsciint.2018.01.020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0379-0738",
"issue": "285()",
"journal": "Forensic science international",
"keywords": "Antipsychotics; Post-mortem toxicology; Quetiapine; Segmental hair analysis; UHPLC–MS/MS",
"medline_ta": "Forensic Sci Int",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014150:Antipsychotic Agents; D002851:Chromatography, High Pressure Liquid; D005260:Female; D006197:Hair; D006200:Hair Color; D006202:Hair Dyes; D006801:Humans; D008297:Male; D001523:Mental Disorders; D008875:Middle Aged; D000069348:Quetiapine Fumarate; D053719:Tandem Mass Spectrometry; D055815:Young Adult",
"nlm_unique_id": "7902034",
"other_id": null,
"pages": "58-64",
"pmc": null,
"pmid": "29453005",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Post-mortem quetiapine concentrations in hair segments of psychiatric patients - Correlation between hair concentration, dose and concentration in blood.",
"title_normalized": "post mortem quetiapine concentrations in hair segments of psychiatric patients correlation between hair concentration dose and concentration in blood"
} | [
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{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
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"drugauthorizationnumb": "201504",
"drugbatchnumb": "UNKNOWN",
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"medicinalproduct": "QUETIAPINE FUMARATE."
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}
],
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},
"primarysource": {
"literaturereference": "GUNTHER KN, JOHANSEN SS, NIELSEN MKK, WICKTOR P AND ET. AL.. POST-MORTEM QUETIAPINE CONCENTRATIONS IN HAIR SEGMENTS OF PSYCHIATRIC PATIENTS - CORRELATION BETWEEN HAIR CONCENTRATION, DOSE AND CONCENTRATION IN BLOOD. FORENSIC SCIENCE INTERNATIONAL. 2018?285:58?64",
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"qualification": "3",
"reportercountry": "DK"
},
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"receiptdate": "20180419",
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20180711"
},
{
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"patient": {
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{
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"activesubstance": {
"activesubstancename": "QUETIAPINE FUMARATE"
},
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"drugcharacterization": "1",
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"drugdosageform": "TABLET",
"drugdosagetext": "800-1040 MG/KG PER DAY",
"drugenddate": null,
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"drugindication": "MENTAL DISORDER",
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"medicinalproduct": "QUETIAPINE FUMARATE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cardiovascular disorder",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
}
],
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},
{
"companynumb": "DK-ALEMBIC PHARMACUETICALS LIMITED-2018SCAL000202",
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{
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"activesubstancename": "QUETIAPINE FUMARATE"
},
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"medicinalproduct": "QUETIAPINE FUMARATE."
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"reaction": [
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],
"summary": null
},
"primarysource": {
"literaturereference": "GUNTHER K N, JOHANSEN S S, NIELSEN M K K, WICKTOR P, BANNER J, LINNET K. POST-MORTEM QUETIAPINE CONCENTRATIONS IN HAIR SEGMENTS OF PSYCHIATRIC PATIENTS-CORRELATION BETWEEN HAIR CONCENTRATION, DOSE AND CONCENTRATION IN BLOOD. FORENSIC SCIENCE INTERNATIONAL. 2018?285:58-64",
"literaturereference_normalized": "post mortem quetiapine concentrations in hair segments of psychiatric patients correlation between hair concentration dose and concentration in blood",
"qualification": "3",
"reportercountry": "DK"
},
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},
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] |
{
"abstract": "BACKGROUND\nBone metastases and skeletal-related events (SREs) are a frequent cause of morbidity in patients with metastatic non-small cell lung cancer (mNSCLC). Data are limited on bone metastases and SREs in patients with mNSCLC treated using immune checkpoint inhibitors (ICIs), and on the efficacy of bone-modifying agents (BMAs) in this setting. Here we report the incidence, impact on survival, risk factors for bone metastases and SREs, and impact of BMAs in patients with mNSCLC treated with ICIs in a multi-institutional cohort.\n\n\nMETHODS\nWe conducted a retrospective study of patients with mNSCLC treated with ICIs at 2 tertiary care centers from 2014 through 2017. Overall survival (OS) was compared between patients with and without baseline bone metastases using a log-rank test. A Cox regression model was used to evaluate the association between OS and the presence of bone metastases at ICI initiation, controlling for other confounding factors.\n\n\nRESULTS\nWe identified a cohort of 330 patients who had received ICIs for metastatic disease. Median patient age was 63 years, most patients were treated in the second line or beyond (n=259; 78%), and nivolumab was the most common ICI (n=211; 64%). Median OS was 10 months (95% CI, 8.4-12.0). In our cohort, 124 patients (38%) had baseline bone metastases, and 43 (13%) developed SREs during or after ICI treatment. Patients with bone metastases had a higher hazard of death after controlling for performance status, histology, line of therapy, and disease burden (hazard ratio, 1.57; 95% CI, 1.19-2.08; P=.001). Use of BMAs was not associated with OS or a decreased risk of SREs.\n\n\nCONCLUSIONS\nPresence of bone metastases at baseline was associated with a worse prognosis for patients with mNSCLC treated with ICI after controlling for multiple clinical characteristics. Use of BMAs was not associated with reduced SREs or a difference in survival.",
"affiliations": "1Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.;2Center for Biostatistics.;3Division of Medical Oncology, and.;2Center for Biostatistics.;4Department of Internal Medicine, The Ohio State University, Columbus, Ohio.;4Department of Internal Medicine, The Ohio State University, Columbus, Ohio.;3Division of Medical Oncology, and.;3Division of Medical Oncology, and.;3Division of Medical Oncology, and.;3Division of Medical Oncology, and.;1Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.;1Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.;1Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.;1Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.;1Division of Hematology and Oncology, University of Michigan, Ann Arbor, Michigan.;7Department of Neurosurgery.;8Department of Medical Education, and.;8Department of Medical Education, and.;8Department of Medical Education, and.;2Center for Biostatistics.;3Division of Medical Oncology, and.;3Division of Medical Oncology, and.;3Division of Medical Oncology, and.;9Department of Radiation Oncology, University of Michigan, Ann Arbor, Michigan.;3Division of Medical Oncology, and.",
"authors": "Qin|Angel|A|;Zhao|Songzhu|S|;Miah|Abdul|A|;Wei|Lai|L|http://orcid.org/0000-0002-7248-3828;Patel|Sandipkumar|S|;Johns|Andrew|A|http://orcid.org/0000-0001-9821-8662;Grogan|Madison|M|;Bertino|Erin M|EM|;He|Kai|K|;Shields|Peter G|PG|http://orcid.org/0000-0002-7404-217X;Kalemkerian|Gregory P|GP|;Gadgeel|Shirish M|SM|;Ramnath|Nithya|N|;Schneider|Bryan J|BJ|;Hassan|Khaled A|KA|;Szerlip|Nicholas|N|;Chopra|Zoey|Z|http://orcid.org/0000-0002-6349-2431;Journey|Sara|S|;Waninger|Jessica|J|;Spakowicz|Daniel|D|http://orcid.org/0000-0003-2314-6435;Carbone|David P|DP|;Presley|Carolyn J|CJ|;Otterson|Gregory A|GA|;Green|Michael D|MD|;Owen|Dwight H|DH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1540-1405",
"issue": "19(8)",
"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
"keywords": null,
"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": null,
"nlm_unique_id": "101162515",
"other_id": null,
"pages": "915-921",
"pmc": null,
"pmid": "33878726",
"pubdate": "2021-04-20",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Bone Metastases, Skeletal-Related Events, and Survival in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors.",
"title_normalized": "bone metastases skeletal related events and survival in patients with metastatic non small cell lung cancer treated with immune checkpoint inhibitors"
} | [
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}
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"reaction": [
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Musculoskeletal disorder",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Qin A.; Zhao S.; Miah A. et al.. Bone Metastases, Skeletal- Related Events, and Survival in Patients With Metastatic Non-Small Cell Lung Cancer Treated With Immune Checkpoint Inhibitors. Journal of the National Comprehensive Cancer Network. 2021;19 (8):915-921",
"literaturereference_normalized": "bone metastases skeletal related events and survival in patients with metastatic non small cell lung cancer treated with immune checkpoint inhibitors",
"qualification": "1",
"reportercountry": "US"
},
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"receiptdate": "20220302",
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 1,
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"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220423"
}
] |
{
"abstract": "BACKGROUND\nCytomegalovirus (CMV) retinitis is an opportunistic infection that primarily affects immunocompromised individuals. Intravitreal ganciclovir injection monotherapy or in combination with systemic anti-CMV therapy are effective treatments for CMV retinitis. Crystallization of ganciclovir after intravitreal injection is extremely rare. Only two cases had been reported in literature. Crystallization in only one eye after bilateral injections had not been reported before. We hereby report a case of intraocular ganciclovir crystallization in one eye after bilateral intravitreal injections, and repeated crystallization in the same eye after repeated injections.\n\n\nMETHODS\nA 79-year-old patient had bilateral cytomegalovirus retinitis and received bilateral intravitreal ganciclovir injections of 2.5 mg in 0.05 ml sterile water. Fundus examination after injection showed formation of needle-shaped, golden-yellow crystals in the vitreous of right eye but not in left eye. The crystals dissolved spontaneously. Repeated bilateral intravitreal ganciclovir injections 4 days later resulted in repeated crystallization of ganciclovir in right eye but not in left eye. The crystals dissolved spontaneously and completely after 5 minutes. Visual acuity remained unchanged and intraocular pressure was normal.\n\n\nCONCLUSIONS\nIntraocular ganciclovir crystallization could occur after intravitreal injections. It is important to perform fundus examination after injection. The crystals may dissolve rapidly and vitrectomy may not be necessary. Our case suggested intraocular ganciclovir crystallization is an idiosyncratic phenomenon, subjects to distinctive intraocular environment which could be different between two eyes of the same patient. The susceptible intraocular environment could be persistent leading to repeated crystallization.",
"affiliations": "Department of Ophthalmology, The University of Hong Kong, Grantham Hospital, 125 Wong Chuk Hang Road, Aberdeen, Hong Kong, Hong Kong. lawipl@hku.hk.;Department of Ophthalmology, The University of Hong Kong, Grantham Hospital, 125 Wong Chuk Hang Road, Aberdeen, Hong Kong, Hong Kong.;Department of Ophthalmology, The University of Hong Kong, Grantham Hospital, 125 Wong Chuk Hang Road, Aberdeen, Hong Kong, Hong Kong.;Department of Ophthalmology, The University of Hong Kong, Grantham Hospital, 125 Wong Chuk Hang Road, Aberdeen, Hong Kong, Hong Kong.",
"authors": "Iu|Lawrence P L|LPL|;Fan|Michelle C Y|MCY|;Lam|Wai-Ching|WC|;Wong|Ian Y H|IYH|",
"chemical_list": "D000998:Antiviral Agents; D015774:Ganciclovir",
"country": "England",
"delete": false,
"doi": "10.1186/s12886-018-0703-8",
"fulltext": "\n==== Front\nBMC OphthalmolBMC OphthalmolBMC Ophthalmology1471-2415BioMed Central London 70310.1186/s12886-018-0703-8Case ReportRepeated intraocular crystallization of ganciclovir in one eye after bilateral intravitreal injections: a case report Iu Lawrence P. L. (852) 2518-2144lawipl@hku.hk Fan Michelle C. Y. fanmichelle@gmail.com Lam Wai-Ching waichlam@hku.hk Wong Ian Y. H. ianyhwong@gmail.com 0000000121742757grid.194645.bDepartment of Ophthalmology, The University of Hong Kong, Grantham Hospital, 125 Wong Chuk Hang Road, Aberdeen, Hong Kong, Hong Kong 9 2 2018 9 2 2018 2018 18 364 4 2017 1 2 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nCytomegalovirus (CMV) retinitis is an opportunistic infection that primarily affects immunocompromised individuals. Intravitreal ganciclovir injection monotherapy or in combination with systemic anti-CMV therapy are effective treatments for CMV retinitis. Crystallization of ganciclovir after intravitreal injection is extremely rare. Only two cases had been reported in literature. Crystallization in only one eye after bilateral injections had not been reported before. We hereby report a case of intraocular ganciclovir crystallization in one eye after bilateral intravitreal injections, and repeated crystallization in the same eye after repeated injections.\n\nCase presentation\nA 79-year-old patient had bilateral cytomegalovirus retinitis and received bilateral intravitreal ganciclovir injections of 2.5 mg in 0.05 ml sterile water. Fundus examination after injection showed formation of needle-shaped, golden-yellow crystals in the vitreous of right eye but not in left eye. The crystals dissolved spontaneously. Repeated bilateral intravitreal ganciclovir injections 4 days later resulted in repeated crystallization of ganciclovir in right eye but not in left eye. The crystals dissolved spontaneously and completely after 5 minutes. Visual acuity remained unchanged and intraocular pressure was normal.\n\nConclusions\nIntraocular ganciclovir crystallization could occur after intravitreal injections. It is important to perform fundus examination after injection. The crystals may dissolve rapidly and vitrectomy may not be necessary. Our case suggested intraocular ganciclovir crystallization is an idiosyncratic phenomenon, subjects to distinctive intraocular environment which could be different between two eyes of the same patient. The susceptible intraocular environment could be persistent leading to repeated crystallization.\n\nKeywords\nGanciclovirCrystallizationCytomegalovirus retinitisCMVIntraocularIntravitrealPrecipitationissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nCytomegalovirus (CMV) retinitis is an opportunistic infection that primarily affects immunocompromised individuals. Intravitreal ganciclovir injection monotherapy or in combination with systemic anti-CMV therapy are effective treatments for CMV retinitis [1–3]. Crystallization of ganciclovir after intravitreal injection is extremely rare. Only two cases had been reported in literature [4, 5]. Crystallization in only one eye after bilateral injections had not been reported before. We hereby report a case of intraocular ganciclovir crystallization in one eye after bilateral intravitreal injections, and repeated crystallization in the same eye after repeated injections.\n\nCase presentation\nA 79-year-old male was referred to our institution for bilateral blurring of vision. He had multiple medical problems including diabetes mellitus, bronchiectasis, ischemic heart disease, bullous pemphigoid, carcinoma of prostate with bone metastases and end-stage renal failure. He was on long term oral steroid for the disease of bullous pemphigoid. His systemic medication included allopurinol 100 mg daily, calcium carbonate 1000 mg daily, aspirin 100 mg with glycine 45 mg daily, ferrous sulphate 300 mg daily, flutamide 250 mg three times daily, frusemide 80 mg twice daily, insulin 32 units in the morning and 10 units in the afternoon, pantoprazole 20 mg daily, potassium chloride 600 mg daily, senna 15 mg daily, simvastatin 10 mg daily and prednisolone 10 mg daily. On presentation, his visual acuity (VA) was 20/60 OD and 20/100 OS. Intraocular pressure (IOP) was 11 mmHg OD and 10 mmHg OS. Slit-lamp examination showed mild anterior chamber cells and moderate cataract bilaterally. Fundus examination showed retinal infiltrates in right inferonasal and left superotemporal peripheral retinae (Fig. 1). There was bilateral mild vitreous haze and vessels detail was still visible (binocular indirect ophthalmoscopy score of 1). Diagnostic aqueous tap was performed for both eyes, which showed presence of CMV DNA in both eyes by polymerase chain reaction. Varicella-zoster virus and herpes simplex virus DNA were absent. A diagnosis of bilateral CMV retinitis was made. His white blood cell count was elevated at 12.8 × 109/L (normal range 3.8–9.9 × 109/L). He was anemic with blood hemoglobin count at 3.5 g/dL (normal range 4.4–5.7 g/dL). Liver and renal functions were deranged.Fig. 1 Fundus photography showing bilateral cytomegalovirus retinitis with retinal infiltrates in (a) right inferonasal and (b) left superotemporal peripheral retinae\n\n\n\nIn view of the problem of CMV retinitis, oral valganciclovir was initiated at 450 mg on alternate days. Intravitreal ganciclovir treatment of 2.5 mg in 0.05 ml sterile water was given to both eyes. The ganciclovir solution was prepared by our institution’s pharmacy in two separate syringes for separate eye injections. Fundus examination after injections showed formation of needle-shaped, golden-yellow crystals in vitreous of right eye but not in left eye. He did not report any ocular pain or visual change. The crystals dissolved spontaneously.\n\nThe patient was reviewed 4 days later, his VA was 20/600 OD and 20/100 OS. There were no signs of retinal vascular occlusion or optic neuropathy. Intravitreal ganciclovir injections of 2.5 mg in 0.05 ml sterile water were repeated. The ganciclovir solution was prepared by our institution’s pharmacy and had been checked to ensure it did not contain any crystals before injections. Crystallization of ganciclovir was noted again in right eye (Fig. 2a) but not in left eye after injections. He did not report any visual change. VA remained unchanged and IOP was normal. The crystals dissolved spontaneously after 5 minutes (Fig. 2b). There were no signs of retinal vascular occlusion. No further intravitreal ganciclovir treatment was given because his general condition deteriorated with sepsis, pneumonia and peritonitis. He passed away 1 month later.Fig. 2 Fundus photography of right eye. a After intravitreal ganciclovir injection, needle-shaped, golden-yellow crystals were formed in the vitreous (arrowheads). Inset showing magnified view of the crystals. b The crystals dissolved spontaneously after 5 minutes\n\n\n\nDiscussion\nGanciclovir is a synthetic analogue of guanine which, after phosphorylation by CMV-encoded enzymes in infected cells, inhibits viral DNA synthesis and viral replication [6]. Ganciclovir is commercially available as lyophilized powder of ganciclovir sodium in strength of 500 mg per vial [6]. It is normally reconstituted with 10 ml of sterile water for injection to yield a solution with concentration of 50 mg/ml and an alkaline pH of 11 [6]. Ganciclovir sodium has an aqueous solubility of greater than 50 mg/ml at room temperature of 25 °C, and a much lower aqueous solubility of 6 mg/ml at physiological pH under body temperature of 37 °C [6]. The reconstituted solution is stable at room temperature for 12 h [6]. Crystallization of ganciclovir could occur if the reconstituted solution is exposed to temperature other than room temperature. In a previous report, crystals were observed in syringes after the reconstituted solution had been stored for 24 h in refrigerator at 4 °C, and the crystals dissolved within 4 h at room temperature [7]. It is also known that precipitation would occur if bacteriostatic water containing the preservatives parabens is used for reconstitution instead of sterile water [6].\n\nIn our case, the ganciclovir solution for intravitreal injection was prepared by institution pharmacy to avoid preparation errors. Sterile water was used for reconstitution and it did not contain any preservatives parabens. The solution was prepared within 4 h prior to intravitreal injection without being refrigerated or being exposed to change of temperature and therefore the solution should remain stable. This case suggests there are other mechanisms which give rise to intraocular crystallization of ganciclovir.\n\nIntraocular crystallization of ganciclovir after intravitreal injection had been reported in only two cases in literature. In first report [4], crystallization occurred because the ganciclovir was prepared inadvertently at a high dose of 40 mg in 0.1 ml solution and resulted in retinal ischemia and necrosis. In a normal vitreous of around 4 ml volume and physiological pH, such a highly-concentrated ganciclovir solution would precipitate out and crystallize. Vitrectomy was performed to remove the crystals in that case [4]. In second report [5], crystallization occurred after intravitreal injection of ganciclovir at a dose of 4 mg in 0.04 ml solution which resulted in central retinal artery occlusion and optic neuropathy. Vitrectomy was performed to remove the crystals [5]. The authors postulated that sudden change of osmolarity or pH in the globe after injection played a role in crystallization [5]. In both cases, patients had immediate drop of vision and acute rise of IOP after injections [4, 5].\n\nThe needle-shaped, golden-yellow ganciclovir crystals in our case resembled those reported in literature [4, 5]. Our patient, however, had spontaneous rapid dissolution of crystals and did not have any signs of vascular occlusion or acute rise of IOP. The exact mechanism of crystallization is unknown. Our case concurred with previous authors’ postulation that sudden change of osmolarity or pH in the globe after injection might contribute [5]. Interestingly, our case also suggested intraocular ganciclovir crystallization is an idiosyncratic phenomenon, subjects to distinctive intraocular environment which could be different between two eyes of the same patient. The susceptible intraocular environment could persist and result in repeated crystallization with repeated injections. We also speculated that the volume of vitreous cavity and amount of vitreous syneresis were attributable factors because they could influence the distribution and dispersion of ganciclovir in vitreous. Uneven distribution in vitreous cavity could result in more concentrated ganciclovir in some parts of vitreous that exceeds aqueous solubility.\n\nFoscarnet is another anti-CMV drug which is often used intravenously and intravitreally for CMV retinitis. In a previous case report [8], foscarnet crystals appeared in the vitreous after 11 intravitreal injections of foscarnet (2.4 mg in 0.1 ml) were given within 2 months. Similar to our case of ganciclovir crystallization, there was no evidence of retinal or optic nerve damage [8]. The authors postulated that foscarnet crystallization was caused by sudden change of vitreous pH after injections [8].\n\nThe major limitation of this case report is that it consists of a single case only, therefore causal-effect relationship was difficult to interpret and the clinical features might not be representative. In addition, due to the poor general condition of patient, the number of intravitreal treatments was limited. Investigations such as fluorescein angiography and optical coherence tomography were also not performed. Despite these limitations, this case report added a new observation of intraocular ganciclovir crystallization which occurred repeatedly in the same eye after bilateral injections.\n\nConclusions\nIn conclusion, intraocular ganciclovir crystallization could occur after intravitreal injections and could be related to distinctive intraocular environment. It is important to perform fundus examination after injection. The crystals may dissolve rapidly and vitrectomy may not be necessary. Further studies are warranted to investigate the mechanism for intraocular ganciclovir crystallization.\n\nAbbreviations\nCMVCytomegalovirus\n\nIOPIntraocular pressure\n\nVAVisual acuity\n\nAcknowledgements\nNone.\n\nFunding\nNo funding was obtained.\n\nAvailability of data and materials\nThe authors confirm that all relevant data are included in the article.\n\nAuthors’ contributions\nLPLI, WCL and IYHW analyzed and interpreted the patient data. LPLI and MCYF were major contributors in writing the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nEthics approval has been obtained from the Institutional Review Board of the University of Hong Kong.\n\nConsent for publication\nWritten informed consent has been obtained from patient’s next of kin as patient is deceased.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Agarwal A Kumari N Trehan A Khadwal A Dogra MR Gupta V Sharma A Gupta A Singh R Outcome of cytomegalovirus retinitis in immunocompromised patients without human immunodeficiency virus treated with intravitreal ganciclovir injection Graefes Arch Clin Exp Ophthalmol 2014 252 9 1393 1401 10.1007/s00417-014-2587-5 24557658 \n2. Jeon S Lee WK Cytomegalovirus retinitis in a human immunodeficiency virus-negative cohort: long-term management and complications Ocul Immunol Inflamm 2015 23 5 392 399 10.3109/09273948.2014.985385 25760914 \n3. Iu LP Fan MC Lau JK Chan TS Kwong YL Wong IY Long-term follow-up of cytomegalovirus retinitis in non-HIV Immunocompromised patients: clinical features and visual prognosis Am J Ophthalmol 2016 165 145 153 10.1016/j.ajo.2016.03.015 27005706 \n4. Saran BR Maguire AM Retinal toxicity of high dose intravitreal ganciclovir Retina 1994 14 3 248 252 10.1097/00006982-199414030-00010 7973120 \n5. Choopong P Tesavibul N Rodanant N Crystallization after intravitreal ganciclovir injection Clin Ophthalmol 2010 4 709 711 10.2147/OPTH.S10949 20689786 \n6. Cymevene® Ganciclovir. May 2008. Available at: https://www.old.health.gov.il/units/pharmacy/trufot/alonim/Cymevene_dr_1361088488473.pdf. Accessed 5 Feb 2018.\n7. Fiscella RG Goldstein D Labib S Sarris H The formation of crystals in ganciclovir used for intraocular injection Arch Ophthalmol 1997 115 7 945 946 10.1001/archopht.1997.01100160115034 9230850 \n8. Martinez-Castillo S Marin-Lambies C Gallego-Pinazo R Arévalo JF Díaz-Llopis M Crystallization after intravitreous foscarnet injections Arch Ophthalmol 2012 130 5 658 659 10.1001/archophthalmol.2011.1836 22652858\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2415",
"issue": "18(1)",
"journal": "BMC ophthalmology",
"keywords": "CMV; Crystallization; Cytomegalovirus retinitis; Ganciclovir; Intraocular; Intravitreal; Precipitation",
"medline_ta": "BMC Ophthalmol",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D011232:Chemical Precipitation; D003460:Crystallization; D017726:Cytomegalovirus Retinitis; D017809:Fatal Outcome; D015774:Ganciclovir; D006801:Humans; D058449:Intravitreal Injections; D008297:Male; D014822:Vitreous Body",
"nlm_unique_id": "100967802",
"other_id": null,
"pages": "36",
"pmc": null,
"pmid": "29426296",
"pubdate": "2018-02-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "24557658;7973120;20689786;22652858;27005706;25760914;9230850",
"title": "Repeated intraocular crystallization of ganciclovir in one eye after bilateral intravitreal injections: a case report.",
"title_normalized": "repeated intraocular crystallization of ganciclovir in one eye after bilateral intravitreal injections a case report"
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"abstract": "In a patient with a medical history of cancer, the most probable diagnosis of an 18FDG-avid pulmonary mass combined with intracranial abnormalities on brain imaging is metastasized cancer. However, sometimes a differential diagnosis with an infectious cause such as aspergillosis can be very challenging as both cancer and infection are sometimes difficult to distinguish. Pulmonary aspergillosis can present as an infectious pseudotumour with clinical and imaging characteristics mimicking lung cancer. Even in the presence of cerebral lesions, radiological appearance of abscesses can look like brain metastasis. These similarities can cause significant diagnostic difficulties with a subsequent therapeutic delay and a potential adverse outcome. Awareness of this infectious disease that can mimic lung cancer, even in an immunocompetent patient, is important. We report a case of a 65-year-old woman with pulmonary aspergillosis disseminated to the brain mimicking metastatic lung cancer.",
"affiliations": "Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium.;Department of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, Netherlands.;Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium.;Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium.;Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre (MUMC +), Maastricht, Netherlands.;Department of Medical Microbiology, Section Infectious Diseases, Maastricht University Medical Centre (MUMC +), Maastricht, Netherlands.;Department of Respiratory Medicine, Laurentius Hospital Roermond, Roermond, Netherlands.;Department of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, Netherlands.",
"authors": "Vanfleteren|Michiel J E G W|MJEGW|;Dingemans|Anne-Marie C|AC|;Surmont|Veerle F|VF|;Vermaelen|Karim Y|KY|;Postma|Alida A|AA|;Oude Lashof|Astrid M L|AML|;Pitz|Cordula C M|CCM|;Hendriks|Lizza E L|LEL|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2018.00188",
"fulltext": "\n==== Front\nFront OncolFront OncolFront. Oncol.Frontiers in Oncology2234-943XFrontiers Media S.A. 10.3389/fonc.2018.00188OncologyCase ReportInvasive Aspergillosis Mimicking Metastatic Lung Cancer Vanfleteren Michiel J. E. G. W. 123*Dingemans Anne-Marie C. 2Surmont Veerle F. 1Vermaelen Karim Y. 1Postma Alida A. 4Oude Lashof Astrid M. L. 5Pitz Cordula C. M. 6Hendriks Lizza E. L. 21Department of Respiratory Medicine, University Hospital Ghent, Ghent, Belgium2Department of Respiratory Medicine, Maastricht University Medical Centre (MUMC+), Maastricht, Netherlands3Department of Respiratory Medicine, Sint-Jozefskliniek Izegem, Izegem, Belgium4Department of Radiology and Nuclear Medicine, Maastricht University Medical Centre (MUMC +), Maastricht, Netherlands5Department of Medical Microbiology, Section Infectious Diseases, Maastricht University Medical Centre (MUMC +), Maastricht, Netherlands6Department of Respiratory Medicine, Laurentius Hospital Roermond, Roermond, NetherlandsEdited by: Marco Lucchi, Università degli Studi di Pisa, Italy\n\nReviewed by: Christopher William Seder, Rush University Medical Center, United States; Janaki Deepak, University of Maryland, Baltimore, United States\n\n*Correspondence: Michiel J. E. G. W. Vanfleteren, michielvanfleteren@msn.comSpecialty section: This article was submitted to Thoracic Oncology, a section of the journal Frontiers in Oncology\n\n05 6 2018 2018 8 18818 2 2018 11 5 2018 Copyright © 2018 Vanfleteren, Dingemans, Surmont, Vermaelen, Postma, Oude Lashof, Pitz and Hendriks.2018Vanfleteren, Dingemans, Surmont, Vermaelen, Postma, Oude Lashof, Pitz and HendriksThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.In a patient with a medical history of cancer, the most probable diagnosis of an 18FDG-avid pulmonary mass combined with intracranial abnormalities on brain imaging is metastasized cancer. However, sometimes a differential diagnosis with an infectious cause such as aspergillosis can be very challenging as both cancer and infection are sometimes difficult to distinguish. Pulmonary aspergillosis can present as an infectious pseudotumour with clinical and imaging characteristics mimicking lung cancer. Even in the presence of cerebral lesions, radiological appearance of abscesses can look like brain metastasis. These similarities can cause significant diagnostic difficulties with a subsequent therapeutic delay and a potential adverse outcome. Awareness of this infectious disease that can mimic lung cancer, even in an immunocompetent patient, is important. We report a case of a 65-year-old woman with pulmonary aspergillosis disseminated to the brain mimicking metastatic lung cancer.\n\nlung cancerlung neoplasmsbrain metastasisbrain neoplasmsbrain abscessaspergillosisdifferential diagnosis\n==== Body\nCase Description\nA 65-year-old woman, never-smoker, was referred for a second opinion in January 2014 because of an abnormal computed tomography (CT) of the chest with a mass in the right lower lobe. Extensive evaluation in the referring hospital had not revealed a diagnosis. A clear overview of the medical disease history is demonstrated in a timeline (Figure 1). Her medical history consisted of a right-sided mastectomy for breast cancer in 2006, with no adjuvant treatment indicated. On the staging 18-fluordeoxyglucose positron emission tomography-computed tomography (18FDG-PET-CT) for the breast cancer in 2006 an asymptomatic, 30-mm diameter, lobulated 18FDG-negative solitary mass was seen in the right lower lobe. Bronchoscopic sampling for cytology and microbiological cultures showed neither proof of malignancy nor infection, and follow-up was chosen. Serial follow-up chest CTs up to December 2011 (total follow-up of 5 years) showed no change and follow-up was ended.\n\nFigure 1 Timeline. Abbreviations: 18FDG, 18-fluordeoxyglucose; CT, computed tomography; VATS, video assisted thoracic surgery; 18FDG-PET-CT, 18-fluordeoxyglucose positron emission tomography-computed tomography; EBUS-TBNA, endobronchial ultrasound with transbronchial needle aspiration; MRI, magnetic resonance imaging.\n\nIn August 2013, she was seen in the referring hospital because of a productive cough, dyspnea on exertion, tiredness, and weight loss since the last 3 months. There was no fever nor night sweats. 18FDG-PET-CT revealed an intense 18FDG-avid mass in the right lower lobe, just next to the old pulmonary lesion, with intense hilar lymphadenopathy (Figure 2). Differential diagnosis consisted of malignancy (metastatic breast cancer or primary lung cancer) or infection. Bronchoscopic sampling, CT-guided biopsy, and endobronchial ultrasound with transbronchial needle aspiration (EBUS-TBNA) revealed no malignancy and cultures were negative (Table 1). Transthoracic biopsy of the mass showed fibrosis and a chronic inflammation with histiocytic reaction. A video-assisted thoracoscopy with partial wedge resection of the pulmonary nodule was performed to obtain a definitive diagnosis and to rule out or confirm malignancy. Pathologic analysis of the resection specimen showed fibrosis with bronchiectasis, focal inflammation, and bronchiolisation of the alveoli, but no malignancy or microorganisms (Table 1). With a diagnosis suggestive of cryptogenic organizing pneumonia, prednisone 0.5 mg/kg/day was initiated, although, due to steroid side-effects, limited in dose and duration (prednisone 0.5 mg/kg/day for 3 weeks followed by gradual tapering of the dose, total duration of prednisone treatment was 2 months). Despite the steroids, her complaints worsened and the patient was referred to our tertiary center in January 2014. A new 18FDG-PET-CT showed progression of the 18FDG-avid lesion with extension into the mediastinum and lymph node station 4R, with also mass effect on the right pulmonary artery and invasion of the left superior pulmonary vein (Figure 2). There was no evidence of extrathoracic lesions. Because of the invasive growth, malignancy was again in the differential diagnosis. In our hospital, renewed analysis was performed with bronchoscopy and mediastinoscopy, both without evidence of malignancy or infection (Table 1). Cytology of the bronchial aspirate showed sporadic hyphae (most probable Aspergillus), but without growth on culture and these were considered contamination or colonization. In March 2014, a multidisciplinary decision was made for a treatment with a higher dose of prednisone 1 mg/kg/day in combination with macrolide antibiotic treatment for 3 months (with slow tapering of the steroids) under suspicion of cryptogenic organizing pneumonia, but without clinical or radiologic response. Additional diagnostics were considered for the growing part of the lesion, but a CT-guided biopsy and surgical sampling were both not possible because of the risk of a massive bleeding. A follow-up 18FDG-PET-CT was scheduled to evaluate whether in the follow-up lesions would become better accessible for further diagnostic work-up. During the pulmonary work-up, in March 2014, the patient developed new complaints of progressive muscle weakness and sensibility loss of the right upper arm. She was hospitalized in the referring hospital. Additional brain imaging with magnetic resonance imaging (MRI) revealed multiple brain lesions in the cortex and watershed region, in the left corpus callosum, the left thalamus and partially in the right semioval center, which were considered brain metastases by the referring hospital (Figure 3). The MRI was revised by an experienced neuro-radiologist in our hospital who withheld a differential diagnosis of ischemia and metastasis. The brain lesions were not accessible for a biopsy because of the location and small size. Because of a poor clinical condition combined with a differential diagnosis of ischemia, no brain radiation was initiated. Patient was discharged after 1½-week hospitalization in the referring hospital. The neuro-oncology multidisciplinary team advised follow-up MRI 3 months later. On this MRI (May 2014), two lesions had enlarged significantly with marked perilesional edema but other lesions showed shrinkage (Figure 4). The radiologic appearance with restrictive diffusion of these lesions on diffusion-weighted images was suggestive for (atypical) cerebral abscesses rather than metastases. The 18FDG-PET-CT showed further growth of the mass in the right lower lobe but without distant lesions. At the same time, the patient developed multiple ill-defined skin lesions. Because of her worse clinical condition, she was hospitalized in our tertiary hospital and cerebral and skin biopsies were performed: both showed marked inflammation and fungal hyphae with dichotomous branching, suggestive for Aspergillus, there was no evidence for malignancy (Table 1; Figures 5 and 6). Cultures of the wound fluid after skin biopsy also revealed Aspergillus (Table 1). The definitive diagnosis of proven invasive aspergillosis with pulmonary, mediastinal, cerebral, and skin involvement was made. Treatment with voriconazole was initiated with monitoring of serum and cerebral spinal fluid (CSF) voriconazole levels. Because of progressive somnolence caused by hydrocephalus, repeated CSF drainage was necessary. Eventually, five neurosurgical procedures were needed for effective control of the infection and adequate drainage of the CSF, with in the end placement of an internal ventriculo-peritoneal drain. During treatment with voriconazole, there was a slow clinical recovery. Additional immunological analysis did not reveal an immunity disorder; there were normal titers of total IgG, IgM, IgG, and IgA, there were no complement abnormalities, screening for antinuclear antibodies and antineutrophil cytoplasmic antibodies was negative. Only the use of prednisone could be identified as immunosuppressant factor which aided the further dissemination of this opportunistic infection. MRI of the brain performed after 6 months of treatment showed marked improvement without evidence of hydrocephalus, the chest CT also improved. Patient was discharged in December 2014, 7 months after admission. She rehabilitated and made a near complete recovery.\n\nFigure 2 Evolution of thoracic lesions. Top: Follow-up chest computed tomography (CT) in 2011 showing a right-sided lobulated pulmonary mass at the right lower lobe (3.0-cm diameter). Middle: CT (left) and fusion 18-fluordeoxyglucose positron emission tomography-computed tomography (18FDG-PET-CT) (right) in August 2013 shows an increase at the medial side of the mass and right hilar lymphadenopathy, with intense 18-fluordeoxyglucose (18FDG) uptake. Bottom: CT (left) and fusion 18FDG-PET-CT (right) in January 2014 showing further growth of the 18FDG-avid mass in the right lower lobe with hilar invasion and a mild 18FDG-avid subcarinal lymph node.\n\nTable 1 Diagnostic test results.\n\nDate\tSpecimen\tMicrobiological test results\tPathological test results\t\n2006\tBronchial washing right lower lobe\tCulture negative for bacteria and fungi\nAuramine-rhodamine stain negative\tNo arguments for malignancy\t\n\t\nAugust 15, 2013\tBronchial (brushing and) washing right lower lobe\tCulture negative for bacteria and fungi\nAuramine-rhodamine stain negative\tActive inflammation\nNo arguments for malignancy\t\n\t\nSeptember 03, 2013\tComputed tomography-guided biopsy right lower lobe\tNA\tFibrosis with anthracosis and chronic inflammation\nNo arguments for malignancy\t\n\t\nSeptember 23, 2013\tEBUS 10R\tNA\tRepresentative specimen of reactive lymph node without arguments for malignancy\t\n\t\nOctober 29, 2013\tWedge resection apical segment right lower lobe\tCulture negative for bacteria\tFibrotic node with extensive chronic inflammation and bronchialization of the alveoli\nNo arguments for malignancy\nNo arguments for actinomyces infection\t\n\t\nOctober 29, 2013\tUrine\tCulture negative for bacteria and fungi\tNA\t\n\t\nNovember 04, 2013\tBlood\tCulture negative for bacteria and fungi\tNA\t\n\t\nNovember 07, 2013\tUrine\tCulture negative for bacteria and fungi\tNA\t\n\t\nNovember 07, 2013\tWound fluid chest drain entrance\tSporadic S. aureus\tNA\t\n\t\nJanuary 20, 2014\tBronchial washing right lower lobe\tBacterial culture with commensal throat flora\nCulture negative for fungi\nCulture negative for actinomyces\nCulture negative for nocardia\nAuramine-rhodamine stain negative\nCulture negative for mycobacteria\tActive inflammation, sparse fungal hyphae and bacteria\nNo arguments for malignancy\t\n\t\nJanuary 30, 2014\tMediastinoscopy 4L and 7\tNA\tLymph node tissue without evidence of malignancy\nExtensive sinushistiocytosis at lymph node station 7\t\n\t\nMarch 31, 2014\tCerebrospinal tap\tNA\tNo arguments for malignancy or infection\t\n\t\nMay 02, 2014\tSkin biopsy\tBacterial culture with coagulase-negative staphylococci\nFungal culture with Verticillium species and Aspergillus fumigatus\tExtensive active inflammation with a lobular panniculitis and localization of fungal hyphae\nNo arguments for malignancy\t\n\t\nMay 02, 2014\tWound fluid skin biopsy\tFungal culture with A. fumigatus\tNA\t\n\t\nMay 13, 2014\tSerum\tGalactomannan negative\nHIV 1 and HIV 2 antigen and immunoglobulin negative\nToxoplasma gondii IgG positive, IgM negative\nTreponema pallidum immunoglobulin negative\tNA\t\n\t\nMay 13, 2014\tBlood (×2)\tCulture negative for bacteria and fungi\tNA\t\n\t\nMay 13, 2014\tUrine\tCulture negative for bacteria and fungi\tNA\t\n\t\nMay 19, 2014\tSerum\tCryptococcus neoformans antigen negative\tNA\t\n\t\nMay 26, 2014\tSerum\tInterferon-gamma release assay negative\tNA\t\n\t\nJune 02, 2014\tCerebral biopsy\tAspergillus fumigatus\tCerebral material with lytic cell remnants, active inflammation and presence of fungi (preference for Aspergillus)\t\nNA, not available.\n\nFigure 3 Brain magnestic resonance imaging in March 2014. T1-weighted image after gadolinium of the brain shows a small right frontal enhancing cerebral lesion.\n\nFigure 4 Brain magnetic resonance imaging in May 2014. There is an increase in size of the right frontal lesion with surrounding perilesional edema. T2-weighted image (left) demonstrates a hypo-intense rim with ring-enhancement after gadolinium (contrast-enhanced T1-weighted middle). At diffusion imaging (right panels) there is restricted diffusion in a part of the central area.\n\nFigure 5 Skin biopsy with presence of fungal hyphae. Periodic Acid Schiff stain on skin biopsy with fungal hyphae stained purple. Two fungal hyphae with dichotomous branching (diagnostic of Aspergillus) are depicted (arrows).\n\nFigure 6 Cerebral biopsy with presence of fungal hyphae. Hematoxylin and eosin stain on cerebral biopsy showing nectrotic tissue with moderate numbers of septate fungal hyphae with parallel walls. Two fungal hyphae with dichotomous branching (diagnostic of Aspergillus) are depicted (arrows).\n\nDiscussion\nWe report our experience of the diagnostic dilemma in this patient with disseminated aspergillosis mimicking metastatic cancer. The 18FDG-avid pulmonary lesions were highly suspicious for malignancy, especially in a patient with a history of breast cancer. Even in the presence of brain lesions, this suspicion remained high, as these brain lesions were first thought to be of metastatic origin. Eventually skin and cerebral biopsies and wound cultures did reveal the definitive diagnosis of disseminated invasive aspergillosis.\n\nAs a tertiary center, patients are frequently referred to our center with presumed lung cancer. In a retrospective analysis of a tertiary US hospital, the majority of such patients were proven to have a neoplastic process, only 1.3% had an infection (1). Pulmonary aspergillosis mimicking lung malignancy remains rare and only sporadic case reports are available in literature (1–7). In addition, symptoms (such as malaise, weight loss, cough, and hemoptysis) are non-specific and are overlapping those of a pulmonary neoplasm. Moreover, pulmonary aspergillosis can present as an infectious pseudotumour with radiological appearance and features similar and indistinguishable from lung cancer. When clinical and radiological features are suspected for malignancy, it is of utmost importance to strive for a definitive histopathological diagnosis. Many minimal invasive techniques such as bronchoscopy, CT-guided biopsy or EBUS-TBNA are available today to obtain this histopathological diagnosis. If not amenable or feasible or histopathological diagnosis cannot be obtained, a surgical approach might be necessary. The differential diagnosis can be very challenging and perseverance for diagnostic accuracy can be a hard and exhaustive exercise, which is demonstrated in our case. Despite several attempts with noninvasive and invasive procedures to obtain a histopathological diagnosis, there was no clear evidence for malignancy or infection. Maybe in retrospect, the hyphae in the bronchial aspirate could have raised the suspicion for invasive aspergillosis, although this is very rare in an immunocompetent host such as our patient. In retrospective studies with immunocompromised patients with a diagnosis of invasive aspergillosis, cytological examination of bronchial washings had a sensitivity of 64.0%, specificity of 99.1%, and positive predictive value of 88.9% (8), However, predictive values depend upon the prevalence of disease in the population tested and our patient did not have an impaired immunity. Moreover, various species of Aspergillus spp. can colonize the airways, especially in patients with a chronic pulmonary disease, without any pathogenic consequences (as was thought to be the case in our patient), but they are also capable of causing several and severe types of disease as has been described in patients with bronchiectasis (9). Pathological features in the surgical specimen suggestive for cryptogenic organizing pneumonia made this case more complex. Furthermore, the suspicion of malignancy remained high, with further growth of her thoracic disease and development of brain lesions, suspicious for brain metastasis. Indeed, cerebral abscesses caused by Aspergillus spp. can also mimic cerebral metastasis. Contrast-enhanced CT and MRI are the modalities of choice for imaging of the brain when brain metastasis is suspected, with MRI more appropriate in characterizing lesions (10–13). Although many MR features have been described, the differentiation between abscesses and necrotic brain tumors cannot be made in many cases with conventional MR imaging since its signal appearance can be similar to that of a cystic or necrotic tumor on conventional series (14, 15). A combination with diffusion-weighted MRI has been shown to be useful in the diagnosis of acute cerebral ischemia, malignancy, abscesses, cysts, and various forms of white matter disorders (16). In our case, the dissociated response, the hypo-intense rim at T2-weighted imaging and the diffusion-weighted MRI aided toward an infectious diagnosis. Previous reports in literature of a cerebral Aspergillus abscess mimicking a solid tumor are sparse; we could only identify two case resports (15, 17).\n\nCoexistence of infectious pseudotumours and solid tumors at initial diagnosis have previously been reported (18), but are rather rare, especially in an immunocompetent patient. However, an endobronchial aspergilloma is thought to be able to infect endobronchial cancer lesions (19, 20). In general, most cases of coexisting infectious pseudotumours and lung cancer are rather a consequence of treatments with corticosteroids and/or chemotherapy.\n\nConclusion\nPulmonary aspergillosis, even in the presence of cerebral abscesses, can present as an infectious pseudotumour with clinical and imaging characteristics resembling lung malignancy. These clinical and radiological similarities can cause significant diagnostic difficulties, with a subsequent therapeutic delay and a potential adverse outcome. A definitive histopathological diagnosis should always be strived for when malignancy is suspected, but awareness that this infectious disease can mimic lung cancer even in immunocompetent patients is of great diagnostic and prognostic importance.\n\nEthics Statement\nPatient gave written informed consent in accordance with the Declaration of Helsinki.\n\nAuthor Contributions\nConception and design and drafting of the manuscript: MV, AD, and LH. Drafting the manuscript for important intellectual content: all authors. All co-authors critically revised the article and gave final approval of this version to be published.\n\nConflict of Interest Statement\nMV has nothing to disclose. AD: none related to current manuscript. Outside of the submitted work: advisory boards: Roche, Pfizer, Eli Lilly Boehringer Ingelheim, MSD, Astra Zeneca, BMS; fees for lectures: BMS, Roche, Ely Lilly. VS: none related to current manuscript. KV: none related to current manuscript. AP: none related to current manuscript. Outside of the submitted work: fees for lectures: Bayer. AL: none related to current manuscript. CP has nothing to disclose. LH: none related to current manuscript. Outside of the submitted work: advisory boards: Boehringer Ingelheim and BMS; fees for lectures: MSD, Astra Zeneca, Roche, research grant: Roche.\n\nThe authors wish to thank C. J. Kootstra, department of Pathology, Maastricht University Medical Centre (MUMC+), Maastricht, The Netherlands, for the selection and preparation of artwork.\n==== Refs\nReferences\n1 Rolston KV Rodriguez S Dholakia N Whimbey E Raad I . Pulmonary infections mimicking cancer: a retrospective, three-year review . Support Care Cancer (1997 ) 5 (2 ):90 –3 .10.1007/BF01262563 9069606 \n2 Baxter CG Bishop P Low SE Baiden-Amissah K Denning DW . Pulmonary aspergillosis: an alternative diagnosis to lung cancer after positive [18F]FDG positron emission tomography . Thorax (2011 ) 66 (7 ):638 –40 .10.1136/thx.2010.155515 21460371 \n3 Sanchez-Alarcos JM Martínez-Cruz R Ortega L Calle M Rodríguez-Hermosa JL Alvarez-Sala JL \nABPA mimicking bronchogenic cancer . Allergy (2001 ) 56 (1 ):80 –1 .10.1034/j.1398-9995.2001.00840.x 11167358 \n4 Schweigert M Dubecz A Beron M Ofner D Stein HJ . Pulmonary infections imitating lung cancer: clinical presentation and therapeutical approach . Ir J Med Sci (2013 ) 182 (1 ):73 –80 .10.1007/s11845-012-0831-8 22592566 \n5 Stern JB Wyplosz B Validire P Angoulvant A Fregeville A Caliandro R \nBulky mediastinal aspergillosis mimicking cancer in an immunocompetent patient . Ann Thorac Surg (2014 ) 98 (4 ):1472 –5 .10.1016/j.athoracsur.2013.11.055 25282220 \n6 Takeuchi Y Shirai T Sakurai S Mikamo M Fujii M Suda T . Allergic bronchopulmonary aspergillosis presenting with a pulmonary mass mimicking lung cancer . Respirol Case Rep (2013 ) 1 (1 ):5 –7 .10.1002/rcr2.4 25473526 \n7 Yasuda M Nagashima A Haro A Saitoh G . Aspergilloma mimicking a lung cancer . Int J Surg Case Rep (2013 ) 4 (8 ):690 –2 .10.1016/j.ijscr.2013.02.028 23792483 \n8 Levy H Horak DA Tegtmeier BR Yokota SB Forman SJ . The value of bronchoalveolar lavage and bronchial washings in the diagnosis of invasive pulmonary aspergillosis . Respir Med (1992 ) 86 (3 ):243 –8 .10.1016/S0954-6111(06)80062-4 1620912 \n9 Maiz L Nieto R Cantón R Gómez de la Pedrosa GE Martinez-García MÁ . Fungi in bronchiectasis: a concise review . Int J Mol Sci (2018 ) 19 (1 ):E142 .10.3390/ijms19010142 29300314 \n10 Yokoi K Kamiya N Matsuguma H Machida S Hirose T Mori K \nDetection of brain metastasis in potentially operable non-small cell lung cancer: a comparison of CT and MRI . Chest (1999 ) 115 (3 ):714 –9 .10.1378/chest.115.3.714 10084481 \n11 Suzuki K Yamamoto M Hasegawa Y Ando M Shima K Sako C \nMagnetic resonance imaging and computed tomography in the diagnoses of brain metastases of lung cancer . Lung Cancer (2004 ) 46 (3 ):357 –60 .10.1016/j.lungcan.2004.05.011 15541821 \n12 Seute T Leffers P ten Velde GP Twijnstra A . Detection of brain metastases from small cell lung cancer: consequences of changing imaging techniques (CT versus MRI) . Cancer (2008 ) 112 (8 ):1827 –34 .10.1002/cncr.23361 18311784 \n13 Hendriks LE Bootsma GP de Ruysscher DK Scheppers NA Hofman PA Brans BT \nScreening for brain metastases in patients with stage III non-small cell lung cancer: Is there additive value of magnetic resonance imaging above a contrast-enhanced computed tomography of the brain? \nLung Cancer (2013 ) 80 (3 ):293 –7 .10.1016/j.lungcan.2013.02.006 23518381 \n14 Yikilmaz A Durak AC Mavili E Donmez H Kurtsoy A Kontas O . The role of diffusion-weighted magnetic resonance imaging in intracranial cystic lesions . Neuroradiol J (2009 ) 21 (6 ):781 –90 .10.1177/197140090802100605 24257045 \n15 Patiroglu T Unal E Yikilmaz A Koker MY Ozturk MK . Atypical presentation of chronic granulomatous disease in an adolescent boy with frontal lobe located aspergillus abscess mimicking intracranial tumor . Childs Nerv Syst (2010 ) 26 (2 ):149 –54 .10.1007/s00381-009-1003-7 19859718 \n16 Baehring JM Fulbright RK . Diffusion-weighted MRI in neuro-oncology . CNS Oncol (2012 ) 1 (2 ):155 –67 .10.2217/cns.12.28 25057865 \n17 Sidani C Freiser ME Saigal G Sklar E . Unusual case of cerebral aspergillosis with clinical and imaging findings mimicking lymphoma . Neuroradiol J (2013 ) 26 (3 ):290 –6 .10.1177/197140091302600306 23859284 \n18 Nilsson JR Restrepo CS Jagirdar J . Two cases of endobronchial carcinoid masked by superimposed aspergillosis: a review of the literature of primary lung cancers associated with aspergillus . Ann Diagn Pathol (2013 ) 17 (1 ):131 –6 .10.1016/j.anndiagpath.2011.06.005 22079170 \n19 Hirano T Yamada M Igusa R Tanno A Numakura T Sakamoto K \nTwo cases of endobronchial aspergilloma complicated with primary and metastatic lung cancer: a case report and literature review . Respir Investig (2016 ) 54 (3 ):211 –5 .10.1016/j.resinv.2015.12.005 27108018 \n20 Zhou XM Li P Zhao L Shi WJ . Lung carcinosarcoma masked by tracheobronchial aspergillosis . Intern Med (2015 ) 54 (15 ):1905 –7 .10.2169/internalmedicine.54.3945 26234234\n\n",
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"abstract": "The fetus is uniquely susceptible to carbon monoxide (CO) exposure. We present a case of severe unintentional CO poisoning in the first trimester of pregnancy.\nA 23-year-old G5P2022 female at 11 weeks' gestational age sat in a car with the engine idling. She was unaware that the vehicle's exhaust pipe was blocked with snow. She was found to be unresponsive, with an initial carboxyhemoglobin (COHb) concentration of 47.1%. She underwent emergent treatment with hyperbaric oxygen therapy. The remainder of her pregnancy was complicated by a diagnosis of myasthenia gravis. She delivered a full-term infant who was noted to have persistently small head circumference.\nFetal hemoglobin binds to CO more tightly than adult hemoglobin, and fetal carboxyhemoglobin concentrations are reported to exceed maternal levels. Fetal abnormalities may occur after CO poisoning in pregnancy and vary based on the gestational age of the fetus at the time of the exposure as well the chronicity of the exposure.\nFetal survival after maternal CO exposure is possible even with significantly elevated maternal COHb concentrations, although teratogenic effects may occur depending on the timing of exposure.",
"affiliations": "Georgetown University School of Medicine, Washington, DC U.S.;MedStar Georgetown University Hospital, Washington, DC U.S.;University of Virginia School of Medicine, Charlottesville, Virginia U.S.",
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"keywords": " carbon monoxide ; hyperbaric oxygen therapy ; myasthenia gravis ; pregnancy ",
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"mesh_terms": "D002249:Carbon Monoxide Poisoning; D002263:Carboxyhemoglobin; D005260:Female; D006801:Humans; D006931:Hyperbaric Oxygenation; D007231:Infant, Newborn; D008831:Microcephaly; D011247:Pregnancy; D011248:Pregnancy Complications; D011261:Pregnancy Trimester, First; D055815:Young Adult",
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"title": "Severe unintentional first trimester carbon monoxide poisoning: case report.",
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