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{
"abstract": "Case Report: We report here on a 58-year-old patient with abnormal findings in the left breast on screening mammography (October 2012). In May 2008 the patient was diagnosed with rectal cancer, subsequently treated by surgical resection followed by radiochemotherapy. In September 2011 the patient was diagnosed with peritoneal cancer. Extravasation of folinic acid occurred during palliative chemotherapy, which was delivered through a surgically implanted port, placed prepectorally on the left side. The patient had not previously undergone breast surgery. The abnormal finding in the left breast was located at the 1-2 o'clock position. The mammogram showed extensive hyperdense nodules with predominantly round, fine granular calcifications. On sonography, the findings presented as a hypoechogenic, inhomogenous, partially diffuse, partly solid, partly cystic mass with individual calcifications and reduced echogenicity in the dorsal aspect. Strong densification of the left breast was found at the corresponding position on palpation. On computed tomography (CT) done during follow-up for rectal cancer, new streaky/pitted densifications were noted in the left breast. Based on the patient's previous history and the results of the breast diagnostics a diagnosis of extensive fat necrosis after folinic acid extravasation was made. No further measures were taken. The patient will continue to be screened using mammography. Conclusion: A good knowledge of the mammographic and sonographic features of fat necrosis can reduce the number of unnecessary biopsies. Careful consideration of the patient's prior medical history is very important in breast diagnostics and may often be decisive for the correct diagnosis.",
"affiliations": "Radiologisches Institut, Universitätsklinikum Erlangen, Erlangen.;Radiologie, Radiologiezentrum Roth, Roth.;Radiologisches Institut, Universitätsklinikum Erlangen, Erlangen.",
"authors": "Hammon|M|M|;Dilbat|G|G|;Schulz-Wendtland|R|R|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0032-1328191",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5751",
"issue": "73(2)",
"journal": "Geburtshilfe und Frauenheilkunde",
"keywords": "Fat necrosis; breast; extravasation; mammography; sonography",
"medline_ta": "Geburtshilfe Frauenheilkd",
"mesh_terms": null,
"nlm_unique_id": "0370732",
"other_id": null,
"pages": "148-151",
"pmc": null,
"pmid": "24771912",
"pubdate": "2013-02",
"publication_types": "D016428:Journal Article",
"references": "11522417;16198567;18945303;19890780;15175436;8577961;9423681;16000102;18181095",
"title": "Fat Necrosis of the Breast Following Folinic Acid Extravasation.",
"title_normalized": "fat necrosis of the breast following folinic acid extravasation"
} | [
{
"companynumb": "DE-PFIZER INC-1667395",
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"occurcountry": "DE",
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"actiondrug": "1",
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"activesubstancename": "LEUCOVORIN CALCIUM"
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"drugindication": "PERITONEAL CARCINOMA METASTATIC",
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"medicinalproduct": "CALCIUM FOLINATE"
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"reaction": [
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"reactionmeddrapt": "Breast necrosis",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Extravasation",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
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"literaturereference": "HAMMON M.. FAT NECROSIS OF THE BREAST FOLLOWING FOLINIC ACID EXTRAVASATION. GEBURTSHILFE FRAUENHEILKD. 2013;73(2):148-151",
"literaturereference_normalized": "fat necrosis of the breast following folinic acid extravasation",
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"receiptdate": "20170720",
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}
] |
{
"abstract": "Progressive and/or unresectable pilocytic astrocytomas (PAs) carry a poor prognosis compared to typical PA. Early radiotherapy (RT) may have severe long-term neurocognitive side effects in this patient population. Intra-arterial (IA) chemotherapy is a viable alternative or addition to intravenous (IV) chemotherapy, which may be beneficial in avoidance of early RT.\n\n\n\nTo evaluate the safety and efficacy of IA chemotherapy in this subset of patients.\n\n\n\nThis is a retrospective review of medical records of PA patients who are treated with IA chemotherapy at Oregon Health & Science University from 1997 until 2019. Response to treatment was categorized as complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD). Progression free survival (PFS) and overall survival (OS) are also reported.\n\n\n\nTwelve patients were identified. All patients experienced progression prior to initiation of IA chemotherapy. The most common grade 3 or 4 toxicities related to chemotherapy were thrombocytopenia (66%), neutropenia (66%), leukopenia (50%), anemia (33%), and lymphopenia (16%). Responses achieved were CR in 1, PR in 3, SD in 7, and PD in 1. Median PFS and median OS were 16.5 and 83.5 mo, respectively. A total of 112 procedures (IA injections) were performed and 250 arteries were catheterized. There were 3 minor and no major complications attributable to procedures.\n\n\n\nThis study demonstrates that IA chemotherapy can be safely used in patients with unresectable or progressive PA.",
"affiliations": "Department of Neurology, Oregon Health & Science University, Portland, Oregon.;Department of Neurology, Oregon Health & Science University, Portland, Oregon.;Ponce Health Sciences University, Ponce, Puerto Rico.;Department of Neurology, Oregon Health & Science University, Portland, Oregon.;Department of Radiology, Providence St Joseph, Portland, Oregon.;School of Nursing, Oregon Health & Science University, Portland, Oregon.;Department of Neurology, Oregon Health & Science University, Portland, Oregon.;Department of Neurology, Oregon Health & Science University, Portland, Oregon.;Department of Neurology, Oregon Health & Science University, Portland, Oregon.;Department of Neurology, Oregon Health & Science University, Portland, Oregon.",
"authors": "Uluc|Kutluay|K|;Siler|Dominic A|DA|;Lopez|Ricardo|R|;Varallyay|Csanad|C|;Netto|Joao Prola|JP|;Firkins|Jenny|J|;Lacy|Cindy|C|;Huddleston|Amy|A|;Ambady|Prakash|P|;Neuwelt|Edward A|EA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/neuros/nyaa588",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0148-396X",
"issue": "88(4)",
"journal": "Neurosurgery",
"keywords": "Intra-arterial chemotherapy; Pilocytic astrocytoma; Radiotherapy; Unresectable tumors",
"medline_ta": "Neurosurgery",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001254:Astrocytoma; D001932:Brain Neoplasms; D002648:Child; D018450:Disease Progression; D005260:Female; D006801:Humans; D007223:Infant; D007261:Infusions, Intra-Arterial; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D013125:Spinal Neoplasms; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "7802914",
"other_id": null,
"pages": "E336-E342",
"pmc": null,
"pmid": "33548921",
"pubdate": "2021-03-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": "12943571;19364965;24482038;19451444;2709111;22367412;11337321;26819758;20061938;16195800;12426683;25792358;2924326;3696394",
"title": "Long-Term Outcomes of Intra-Arterial Chemotherapy for Progressive or Unresectable Pilocytic Astrocytomas: Case Studies.",
"title_normalized": "long term outcomes of intra arterial chemotherapy for progressive or unresectable pilocytic astrocytomas case studies"
} | [
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"literaturereference": "Uluc K, Siler DA, Lopez R, Varallyay C, Netto JP, Firkins J, et al. Long-Term Outcomes of Intra-Arterial Chemotherapy for Progressive or Unresectable Pilocytic Astrocytomas: Case Studies. Neurosurgery 2021;88(4):E336-E342.",
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{
"abstract": "Adrenaline infiltration is a widely used technique in head-neck and ENT surgeries to provide bloodless surgical field. However, use of adrenaline has been associated with hemodynamic changes which can be life threatening at times. Therefore, use of higher concentrations of adrenaline should be avoided and a close hemodynamic monitoring is required with use of other vasopressors. In the present case report, a young male died because of intraventricular bleeding caused by adrenaline infiltration during rhinoplasty.",
"affiliations": "Senior Resident, Department of Anaesthesiology, King George Medical University , Lucknow, U.P, India .;Senior Resident, Department of General Surgery, King George Medical University , Lucknow, U.P, India .;Senior Resident, Department of Anaesthesiology, King George Medical University , Lucknow, U.P, India .;Senior Resident, Department of Anaesthesiology, King George Medical University , Lucknow, U.P, India .;Senior Resident, Department of Anaesthesiology, King George Medical University , Lucknow, U.P, India .",
"authors": "Gautam|Shefali|S|;Kumar|Sanjeev|S|;Prakash|Ravi|R|;Mandhar|Vikas|V|;Srivastava|Vinod Kumar|VK|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.7860/JCDR/2015/11419.5657",
"fulltext": null,
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"issn_linking": "0973-709X",
"issue": "9(3)",
"journal": "Journal of clinical and diagnostic research : JCDR",
"keywords": "Anesthesia; Rhinoplasty; Vasopressors",
"medline_ta": "J Clin Diagn Res",
"mesh_terms": null,
"nlm_unique_id": "101488993",
"other_id": null,
"pages": "UD01-2",
"pmc": null,
"pmid": "25954684",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports",
"references": "16959188;24963201;21431060;18566202;5081938",
"title": "Intraventricular haemorrhage as a complication of sub mucosal infiltration of adrenaline.",
"title_normalized": "intraventricular haemorrhage as a complication of sub mucosal infiltration of adrenaline"
} | [
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{
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},
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{
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{
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"literaturereference": "GAUTAM S., KUMAR S., PRAKASH R., MANDHAR V., SRIVASTAVA V.K.. INTRAVENTRICULAR HAEMORRHAGE AS A COMPLICATION OF SUB MUCOSAL INFILTRATION OF ADRENALINE. JOURNAL OF CLINICAL AND DIAGNOSTIC RESEARCH. 2015;9 (3):UD01-UD02",
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{
"abstract": "Discontinuation of denosumab is associated with the risk of rebound in bone turnover and rebound-associated spontaneous clinical vertebral fractures. This case report presents an 86-year-old woman with rheumatoid arthritis who experienced rebound-associated spontaneous clinical vertebral fractures at 9 months after denosumab discontinuation. Following 5-year bisphosphonate treatment, the patient had 9 injections of 60-mg denosumab every 6 months. Because of tooth extraction, denosumab treatment was discontinued, and raloxifene was administered. At 9 months after the last denosumab injection, the patient experienced severe low back pain. Magnetic resonance imaging (MRI) and radiograph demonstrated clinical fracture at the fourth lumbar vertebra. MRI performed at 3 months after first fracture showed two additional fractures at the second and third lumbar vertebrae. Teriparatide was administered for management of rebound-associated spontaneous clinical, multiple vertebral fractures. Teriparatide was effective for accelerating the fracture healing and suppressing the occurrence of new fractures. However, 2-year treatment of teriparatide did not have suppressive effect of rebound in bone turnover and general bone loss. This case suggested that teriparatide was effective for suppression of new rebound-associated spontaneous clinical vertebral fractures, but not effective in prevention of general bone loss after denosumab discontinuation.",
"affiliations": "Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine.;Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine.;Department of Diagnostic Radiology, Tohoku University Graduate School of Medicine.;Department of Orthopaedic Surgery, Tohoku University Graduate School of Medicine.",
"authors": "Mori|Yu|Y|;Izumiyama|Takuya|T|;Mori|Naoko|N|;Aizawa|Toshimi|T|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1620/tjem.254.57",
"fulltext": null,
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"issn_linking": "0040-8727",
"issue": "254(1)",
"journal": "The Tohoku journal of experimental medicine",
"keywords": "denosumab discontinuation; osteoporosis; rebound effect; spontaneous multiple vertebral fracture; teriparatide",
"medline_ta": "Tohoku J Exp Med",
"mesh_terms": null,
"nlm_unique_id": "0417355",
"other_id": null,
"pages": "57-61",
"pmc": null,
"pmid": "34053968",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The Effect of Teriparatide for the Treatment of Multiple Spontaneous Clinical Vertebral Fractures after Discontinuation of Denosumab in a Female Patient with Rheumatoid Arthritis: A Case Report.",
"title_normalized": "the effect of teriparatide for the treatment of multiple spontaneous clinical vertebral fractures after discontinuation of denosumab in a female patient with rheumatoid arthritis a case report"
} | [
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],
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"reaction": [
{
"reactionmeddrapt": "Periodontal disease",
"reactionmeddraversionpt": "24.0",
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},
{
"reactionmeddrapt": "Lumbar vertebral fracture",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20180920"
}
},
"primarysource": {
"literaturereference": "YU MORI, TAKUYA IZUMIYAMA, NAOKO MORI, TOSHIMI AIZAWA. THE EFFECT OF TERIPARATIDE FOR THE TREATMENT OF MULTIPLE SPONTANEOUS CLINICAL VERTEBRAL FRACTURES AFTER DISCONTINUATION OF DENOSUMAB IN A FEMALE PATIENT WITH RHEUMATOID ARTHRITIS: A CASE REPORT. TOHOKU UNIVERSITY MEDICAL PRESS. 2021?254(1):57?61",
"literaturereference_normalized": "the effect of teriparatide for the treatment of multiple spontaneous clinical vertebral fractures after discontinuation of denosumab in a female patient with rheumatoid arthritis a case report",
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},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20211014"
}
] |
{
"abstract": "MSB11455 is a proposed biosimilar to the currently licensed reference pegfilgrastim (Neulasta® ). This study was designed primarily to compare the immunogenicity of MSB11455 and Neulasta® . As secondary objectives, the safety and tolerability of MSB11455 and Neulasta® were also compared. Healthy adult subjects were randomized to either MSB11455 or Neulasta® , stratified by antipolyethylene glycol (PEG) antibody status at screening and study site. Subjects received a single subcutaneous dose of MSB11455 or Neulasta® (both 6 mg/0.6 mL) on day 1 of each of two study periods (same product in both periods), separated by a washout of 28-35 days. Immunogenicity samples were taken predose and up to day 84 post-first dose. Noninferiority was confirmed if the upper limit of the exact one-sided adjusted 95% confidence interval (CI) for the difference in antidrug antibody (ADA)-positive rates was < 10%. Safety was assessed throughout the study. Overall, 336 subjects were randomized and treated (N = 168 in each group). Noninferiority of MSB11455 over Neulasta® was demonstrated for immunogenicity; the difference in confirmed treatment-induced ADA-positive rate between MSB11455 and Neulasta® was -0.6% (upper limit of the exact one-sided adjusted 95% CI: 6.25%). ADAs were mostly directed against the PEG moiety of pegfilgrastim. No filgrastim-specific neutralizing antibodies were detected in either treatment group. Safety and tolerability were as expected for pegfilgrastim, and comparable between treatments. This study supports and strengthens the available evidence for the biosimilarity of MSB11455 to Neulasta® .",
"affiliations": "Christchurch Clinical Studies Trust Ltd, Christchurch, New Zealand.;Auckland Clinical Studies Ltd, Auckland, New Zealand.;Fresenius Kabi SwissBioSim GmbH, Eysins, Switzerland.;Biostatistics, Merck Healthcare, Darmstadt, Germany.;SVAR Life Science - Wieslab AB, Lund, Sweden.;Fresenius Kabi SwissBioSim GmbH, Eysins, Switzerland.;Fresenius Kabi SwissBioSim GmbH, Eysins, Switzerland.;Fresenius Kabi SwissBioSim GmbH, Eysins, Switzerland.;Fresenius Kabi SwissBioSim GmbH, Eysins, Switzerland.",
"authors": "Wynne|Chris|C|;Schwabe|Christian|C|;Vincent|Emmanuelle|E|;Schueler|Armin|A|;Ryding|Janka|J|;Ullmann|Martin|M|0000-0002-3088-3209;Ghori|Vishal|V|;Kanceva|Radmila|R|;Stahl|Michael|M|0000-0002-7171-9691",
"chemical_list": "D000906:Antibodies; D059451:Biosimilar Pharmaceuticals; C455861:pegfilgrastim; D011092:Polyethylene Glycols; D000069585:Filgrastim",
"country": "United States",
"delete": false,
"doi": "10.1002/prp2.578",
"fulltext": "\n==== Front\nPharmacol Res Perspect\nPharmacol Res Perspect\n10.1002/(ISSN)2052-1707\nPRP2\nPharmacology Research & Perspectives\n2052-1707 John Wiley and Sons Inc. Hoboken \n\n10.1002/prp2.578\nPRP2578\nOriginal Article\nOriginal Articles\nImmunogenicity and safety of a proposed pegfilgrastim biosimilar MSB11455 versus the reference pegfilgrastim Neulasta® in healthy subjects: A randomized, double‐blind trial\nWYNNE et al.Wynne Chris \n1\n Schwabe Christian \n2\n Vincent Emmanuelle \n3\n Schueler Armin \n4\n Ryding Janka \n5\n Ullmann Martin https://orcid.org/0000-0002-3088-3209\n3\n Ghori Vishal \n3\n Kanceva Radmila \n3\n Stahl Michael https://orcid.org/0000-0002-7171-9691\n3\nm.stahl@fresenius-kabi.com \n1 \nChristchurch Clinical Studies Trust Ltd\nChristchurch\nNew Zealand\n\n\n2 \nAuckland Clinical Studies Ltd\nAuckland\nNew Zealand\n\n\n3 \nFresenius Kabi SwissBioSim GmbH\nEysins\nSwitzerland\n\n\n4 \nBiostatistics\nMerck Healthcare\nDarmstadt\nGermany\n\n\n5 \nSVAR Life Science – Wieslab AB\nLund\nSweden\n\n* Correspondence\n\nMichael Stahl, Fresenius Kabi SwissBioSim GmbH, Terre Bonne Business Park, Route de Crassier 23 – Bâtiment A3, CH – 1262 Eysins.\n\nEmail: m.stahl@fresenius-kabi.com\n\n25 4 2020 \n4 2020 \n8 2 10.1002/prp2.v8.2e0057816 12 2019 24 2 2020 01 3 2020 © 2020 The Authors. Pharmacology Research & Perspectives published by John Wiley & Sons Ltd, British Pharmacological Society and American Society for Pharmacology and Experimental Therapeutics.This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.Abstract\nMSB11455 is a proposed biosimilar to the currently licensed reference pegfilgrastim (Neulasta®). This study was designed primarily to compare the immunogenicity of MSB11455 and Neulasta®. As secondary objectives, the safety and tolerability of MSB11455 and Neulasta® were also compared. Healthy adult subjects were randomized to either MSB11455 or Neulasta®, stratified by antipolyethylene glycol (PEG) antibody status at screening and study site. Subjects received a single subcutaneous dose of MSB11455 or Neulasta® (both 6 mg/0.6 mL) on day 1 of each of two study periods (same product in both periods), separated by a washout of 28‐35 days. Immunogenicity samples were taken predose and up to day 84 post–first dose. Noninferiority was confirmed if the upper limit of the exact one‐sided adjusted 95% confidence interval (CI) for the difference in antidrug antibody (ADA)‐positive rates was < 10%. Safety was assessed throughout the study. Overall, 336 subjects were randomized and treated (N = 168 in each group). Noninferiority of MSB11455 over Neulasta® was demonstrated for immunogenicity; the difference in confirmed treatment‐induced ADA‐positive rate between MSB11455 and Neulasta® was −0.6% (upper limit of the exact one‐sided adjusted 95% CI: 6.25%). ADAs were mostly directed against the PEG moiety of pegfilgrastim. No filgrastim‐specific neutralizing antibodies were detected in either treatment group. Safety and tolerability were as expected for pegfilgrastim, and comparable between treatments. This study supports and strengthens the available evidence for the biosimilarity of MSB11455 to Neulasta®.\n\nantidrug antibodiesimmunogenicityMSB11455pegfilgrastimsafetytolerabilityFresenius Kabi SwissBioSim GmbHMerck Healthcare KGaA source-schema-version-number2.0cover-dateApril 2020details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.8.1 mode:remove_FC converted:25.04.2020\n\n\nWynne \nC \n, \nSchwabe \nC \n, \nVincent \nE \n, et al. Immunogenicity and safety of a proposed pegfilgrastim biosimilar MSB11455 versus the reference pegfilgrastim Neulasta® in healthy subjects: A randomized, double‐blind trial\n. Pharmacol Res Perspect . 2020 ;8 :e00578\n10.1002/prp2.578\n==== Body\nAbbreviations\nADAantidrug antibody\n\nAEadverse event\n\nANCabsolute neutrophil count\n\nBMIbody mass index\n\nCIconfidence interval\n\nCTCAECommon Terminology Criteria for Adverse Events\n\nDTLdrug tolerance limit\n\nECGelectrocardiogram\n\nEMAEuropean Medicines Agency\n\nFDAFood and Drug Administration\n\nGCPGood Clinical Practice\n\nG‐CSFgranulocyte colony‐stimulating factor\n\nICHInternational Council for Harmonisation\n\nITTintent‐to‐treat\n\nLPClow positive control\n\nMAbmonoclonal antibody\n\nMCSFmacrophage colony‐stimulating factor\n\nmPEGmethoxy‐polyethylene glycol\n\nNAbneutralizing antibody\n\nPEGpolyethylene glycol\n\nPPper protocol\n\nSAEserious adverse event\n\nSCsubcutaneous\n\nSDstandard deviation\n\nTEAEtreatment‐emergent adverse event\n\nWBCwhite blood cell\n\n1 INTRODUCTION\nMyelosuppressive chemotherapy is associated with the development of neutropenia, the consequences of which can be serious, with even minor infections potentially becoming life threatening. Clinically, chemotherapy‐induced neutropenia is defined as an absolute neutrophil count (ANC) of < 1.0x109/L; at this ANC, the risk of infection begins to rise.\n1\n Febrile neutropenia is defined as a temperature of > 38.2ºC on two determinations with severe neutropenia (ANC < 0.5 × 109/L), and this event indicates a high likelihood of localized or systemic infection.\n1\n Thus, persistent or severe neutropenia can be chemotherapy dose limiting, affecting the efficacy of these regimens. Treatment with a recombinant human granulocyte colony‐stimulating factor (G‐CSF), such as filgrastim, stimulates the proliferation, differentiation, and activation of neutrophils and reduces neutrophil maturation time.\n2\n\n\n\nPegfilgrastim is a pegylated form of filgrastim that requires administration only once per chemotherapy cycle.\n3\n High‐level evidence indicates that prophylactic use of either filgrastim or pegfilgrastim improves the likelihood of completing dose‐dense and dose‐intense chemotherapy and allows a broader range of patients to be treated.\n4\n Prophylactic use of G‐CSF in patients receiving myelosuppressive chemotherapy also reduces the risk of early mortality (ie, during the chemotherapy period), including that related to infection, in addition to reducing the risk of febrile neutropenia.\n5\n The risk of febrile neutropenia, and its associated complications, is generally lower in patients receiving prophylaxis with pegfilgrastim than in those receiving filgrastim.\n6\n Prophylactic use of these agents is, therefore, recommended in patients receiving a chemotherapy regimen with a high risk of febrile neutropenia and in situations where dose‐dense or dose‐intense chemotherapy strategies have survival benefits or when reductions in chemotherapy dose intensity or density are known to be associated with a poor prognosis.\n4\n, \n7\n\n\n\nNeulasta® (pegfilgrastim; Amgen, Inc), the US reference product, is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.\n3\n MSB11455 is a proposed biosimilar to the currently licensed pegfilgrastim, Neulasta®. As with all therapeutic proteins, there is a risk of immunogenic reactions associated with administration of filgrastim or pegfilgrastim. The United States Food and Drug Administration (FDA) and European Medicines Agency (EMA) have both issued guidance on the development of biosimilars.\n8\n, \n9\n In this guidance, the clinical development program of a biosimilar must include a comparative clinical immunogenicity assessment. MSB11455 and Neulasta® have analytical similarity of structural and functional attributes (data on file, Fresenius Kabi SwissBioSim GmbH, Switzerland), and have shown pharmacokinetic and pharmacodynamic equivalence in healthy volunteers.\n10\n Therefore, this biosimilar and the reference product were expected to demonstrate a similar immunogenicity and safety profile.\n\nThis study, therefore, compared the immunogenicity of MSB11455 and Neulasta® as the primary objective. As secondary objectives, the study also compared the safety and tolerability of the two pegfilgrastim products.\n\n2 MATERIALS AND METHODS\n2.1 Study design\nThis was a double‐blind, two‐dose, randomized, parallel‐group, group‐sequential, immunogenicity study (NCT03251339) in healthy subjects. The study was conducted at two sites in New Zealand during the period August 2017 to May 2018. Subjects were resident at a study site from day −1 to day 3 of each treatment period.\n\nSubjects were randomized in a double‐blind manner to one of the two pegfilgrastim products, MSB11455 or Neulasta® (Figure S1), stratified by antipolyethylene glycol (PEG) antibody status at screening (as preexisting PEG antibodies may be a confounding factor for antidrug antibodies [ADAs]). The study consisted of two treatment periods separated by a 28‐ to 35‐day washout period; during the first treatment period, subjects received either MSB11455 or Neulasta®, and during the second treatment period they received the same product. Subjects received a single subcutaneous injection of pegfilgrastim 6 mg/0.6 mL in the morning of day 1 of each of the two treatment periods, for a total of two injections. The end‐of‐treatment assessment visit occurred 28‐35 days after study drug administration in Period 2, whereas the end‐of‐study assessment visit was 84 ± 3 days after study drug administration in Period 1 or an early termination assessment visit.\n\nThe study was conducted in accordance with ethical principles of the International Council for Harmonisation (ICH) guideline for Good Clinical Practice (GCP) and the Declaration of Helsinki, as well as with applicable local regulations. All subjects provided written informed consent before study entry.\n\n2.2 Study population\nTo be included in the study, participants (healthy men or healthy nonpregnant women) had to be aged ≥ 18 to ≤ 55 years with body mass index (BMI) ≥18.0 to ≤ 29.9 kg/m2. Eligible participants were in good health based on comprehensive medical history, physical examination, vital signs, and clinical laboratory tests, and had no known hypersensitivity to any component of either pegfilgrastim product. All subjects were required to comply with the contraception requirements specified in the clinical study protocol.\n\nPotential participants were excluded based on usual exclusion criteria and the following: signs or symptoms of chronic obstructive pulmonary disease, smoking > 10 cigarettes/day, splenomegaly (spleen size > 13 cm in the craniocaudal dimension by ultrasound), prior exposure to any colony‐stimulating or growth factor in the 3 months before randomization, and prior exposure to therapeutic monoclonal antibodies (MAbs) targeting the bone marrow or blood cells; exposure to MAbs not affecting bone marrow or blood cells was allowed if the MAbs were discontinued > 3 months or five half‐lives (whichever was longer) before screening. Blood (≥500 mL) or plasma donation within 3 months, and stem cell or bone marrow donation within 12 months before screening were also not allowed.\n\n2.3 Assessments\nAt screening, samples to determine anti‐PEG status were collected and evaluated using a kit‐based enzyme‐linked immunosorbent assay (ELISA). Samples for evaluating immunogenicity were taken predose on day 1 of Period 1, and postdose on day 13 of Period 1, day 28 of Period 1 (which also provided the predose sample for Period 2), days 13 and 28 of Period 2, and at the end‐of‐study assessment visit (84 ± 3 days after first drug administration in Period 1) or early termination assessment visit. Subjects who were positive for treatment‐induced ADAs and who did not have two subsequent ADA samples at baseline levels by the end‐of‐study assessment visit continued into immunogenicity follow‐up. During this follow‐up, samples were taken every 5 weeks ± 7 days until two consecutive ADA samples had returned to baseline.\n\nAll immunogenicity samples were evaluated in a bioanalytical laboratory using a validated ELISA for ADA status. In this ELISA, labeled MSB11455 was employed as capture and detection reagent. The ability of the assay to detect antibodies against MSB11455 and Neulasta® was demonstrated during validation. All collected samples underwent a multitiered analytical approach to confirm the presence of ADA, collect semiquantitative information, and determine the binding specificity. First, a screening assay was used to detect potential ADA, followed by a confirmation assay, using MSB11455 as the competitive inhibitor, to reliably confirm the presence of ADA. Next, a titration assay was performed to collect semiquantitative information about the confirmed ADA, and finally a specificity assay was used to distinguish between ADAs binding to PEG and those binding to filgrastim. Relative sensitivity of the assay was determined using affinity‐purified polyclonal rabbit antipegfilgrastim and monoclonal mouse anti‐PEG antibodies. The determined relative sensitivities were 10 and 19 ng/mL, respectively. The determined drug tolerance limit (DTL) of the assay was 0.25 ng/mL MSB11455 at a low positive control (LPC) level of 15 ng/mL. Considering the half‐life of pegfilgrastim (15 to 80 hours), \n3\n the time between dosing and the first ADA sampling time point (13 days), and the results of a pharmacokinetic study (NCT03251248), the drug tolerance of the assay was considered adequate.\n\nFor ADA‐positive samples, NAb status was determined using a validated cell‐based assay that employed the cytokine‐dependent cell line M‐NFS‐60, a murine lymphoblastoid cell line derived from a myelogenous leukemia cell line and adapted to become filgrastim dependent (therefore, neutralization of filgrastim or pegfilgrastim will inhibit cell proliferation). However, macrophage colony‐stimulating factor (MCSF) neutralization also inhibits proliferation of this cell line. Thus, a tiered approach, as per regulatory guidance, was used to detect antibodies neutralizing pegfilgrastim and confirm their specificity toward filgrastim. In the first tier, ADA‐positive samples were assessed for neutralizing activity toward pegfilgrastim. In the second tier, neutralizing activity toward MCSF was tested to confirm the specificity of pegfilgrastim inhibition. Finally, samples neutralizing pegfilgrastim but not inhibiting MCSF‐induced cell proliferation were tested for their capacity to inhibit filgrastim. The determined DTL of this assay was 0.5 ng/mL MSB11455 and, based on the reasoning already presented for the ADA assay, the drug tolerance of the assay was considered adequate.\n\nTo avoid the confounding effect of pre‐existing antibodies, a subject was considered to have a confirmed treatment‐induced ADA‐positive status if one of two situations occurred. Firstly, if the predose sample was ADA negative and at least one postdose sample was positive in the ADA confirmatory assay. Secondly, if the predose sample was positive and at least one postdose sample was positive in the ADA confirmatory assay with a titer‐fold increase compared to predose above the minimum significant ratio (the minimum ratio between titers needed to declare a statistically significant difference), which was determined to be 3.6 during assay validation.\n\nSafety and tolerability, including treatment‐emergent adverse events (TEAEs), injection site reactions, physical examination findings, vital signs, results of routine laboratory testing and 12‐lead electrocardiograms (ECGs), and concomitant medication data, were assessed from the time of signing informed consent and throughout the study. TEAEs of special interest were acute hypersensitivity (occurring within 48 hours after study drug administration); clinically significant increase in spleen size; ANC ≥ 75 × 109/L (or white blood cell [WBC] count ≥ 90 × 109/L); or signs and symptoms of hyperviscosity syndrome. Abdominal ultrasound was performed to assess spleen size before each dose and at the end‐of‐treatment assessment visit (or early termination assessment visit, as appropriate); further assessments of spleen size were allowed during the study if clinical signs or symptoms suggestive of splenic enlargement were noted.\n\n2.4 Endpoints\nThe primary study endpoints were confirmed treatment‐induced ADA‐positive status to pegfilgrastim from predose on day 1 of Period 1 until the end‐of‐study assessment visit, and confirmed neutralizing antibody (NAb) status to pegfilgrastim from predose on day 1 of Period 1 until the end‐of‐study assessment visit. Secondary endpoints included safety and further immunogenicity endpoints.\n\nSafety endpoints were occurrence of TEAEs, serious AEs (SAEs), AEs of special interest, and abnormal laboratory values and vital signs in subjects from the first administered dose until the end‐of‐study assessment visit. Additional immunogenicity endpoints were ADA status by time point, ADA titer over time, and NAb status by time point.\n\n2.5 Statistical analyses\n2.5.1 Sample size and analysis population\nA group‐sequential design with an unblinded interim analysis was implemented. A maximum of 404 subjects were to be randomized 1‐to‐1 to each treatment arm, unless the study was stopped at the interim analysis, which was planned after 336 subjects had been randomized. This sample size was calculated to have 90% power to declare MSB11455 no worse than Neulasta®, either at the interim or final analysis if the true confirmed ADA‐positive rate by the end‐of‐study assessment visit in the Neulasta® arm was 12%, based on findings of a previous study (NCT02205320), and assuming a true difference in rates of 0%. Other key assumptions for these sample size calculations included a noninferiority margin of 10% and a type I error rate of ≤5% for a one‐sided test for noninferiority; this noninferiority margin corresponded to a maximum true confirmed ADA‐positive rate with MSB11455 of 22% under the assumption that the true confirmed ADA‐positive rate with Neulasta® was 12% by the end‐of‐study assessment visit.\n\nThe unblinded interim analysis for futility (nonbinding) and noninferiority took place when exactly 336 subjects were randomized and had completed the end‐of‐study assessment visit/early termination visit. After review of the interim analysis data, an Independent Data Monitoring Committee recommended that the study be stopped for noninferiority, and the interim analysis became the final analysis.\n\nThe primary analysis of treatment‐induced ADA‐positive status up to end‐of‐study assessment visit/early termination visit was performed on the intent‐to‐treat (ITT) population, defined as all randomized patients. Other immunogenicity outcomes and safety were analyzed in all subjects who received at least one administration of study drug (MSB11455 or Neulasta®).\n\n2.5.2 Main analyses\nBaseline subject demographics and characteristics were summarized descriptively. For the primary analysis of treatment‐induced ADA‐positive status up to end‐of‐study assessment visit/early termination visit, the difference in confirmed treatment‐induced ADA‐positive rates between MSB11455 and Neulasta® was estimated along with the corresponding exact one‐sided adjusted 95% confidence interval [CI].\n11\n, \n12\n Given that the primary endpoint was binary and the associated rates could be less than 10%, the power and type I error rate calculations of the study design were assessed using exact calculations.\n\nSecondary immunogenicity endpoints were reported as the proportion of subjects with confirmed treatment‐induced ADA‐positive status at each visit, with corresponding two‐sided 95% CI (using Clopper‐Pearson method); the denominator was the number of subjects with samples available at that visit. Summary statistics (median values) were used for ADA titers by visit. The proportion of subjects NAb positive to filgrastim for each visit was also calculated, the denominator being the number of subjects with samples analyzed (ie, subjects who were ADA positive). TEAEs were summarized by treatment and overall, as the number and proportion of subjects affected.\n\n2.5.3 Sensitivity analyses\nSensitivity analyses for the primary immunogenicity endpoint were conducted in the per protocol population (all subjects who received both doses of pegfilgrastim, had at least one ADA status available after day 1 of Period 2, and had no clinically important protocol deviations) and using a stratified analysis allowing for anti‐PEG antibody status at screening.\n\n3 RESULTS\n3.1 Patients\nA total of 336 subjects were randomized and treated (Figure 1). Baseline subject demographics and characteristics were well balanced between treatment arms (Table 1); overall, 4.8% of included subjects were anti‐PEG antibody positive at screening.\n\nFigure 1 Subject disposition\n\nTable 1 Subject demographics and characteristics at baseline by treatment group and overall\n\n \tMSB11455 (N = 168)\t\nNeulasta®\n\n\n\n(N = 168)\n\n\n\t\nOverall\n\n\n(N = 336)\n\n\n\t\nMale, n (%)\t100 (59.5)\t91 (54.2)\t191 (56.8)\t\nFemale, n (%)\t68 (40.5)\t77 (45.8)\t145 (43.2)\t\nRace, n (%)\t\nWhite\t120 (71.4)\t131 (78.0)\t251 (74.7)\t\nBlack/African American\t3 (1.8)\t2 (1.2)\t5 (1.5)\t\nAsian\t16 (9.5)\t13 (7.7)\t29 (8.6)\t\nNative Hawaiian or other Pacific Islander\t5 (3.0)\t2 (1.2)\t7 (2.1)\t\nAmerican Indian or Alaska Native\t1 (0.6)\t0\t1 (0.3)\t\nOther\t23 (13.7)\t20 (11.9)\t43 (12.8)\t\nEthnicity, n (%)\t\nHispanic\t9 (5.4)\t15 (8.9)\t24 (7.1)\t\nJapanese\t1 (0.6)\t2 (1.2)\t3 (0.9)\t\nAnti‐PEG antibody positive\na\n, n (%)\t8 (4.8)\t8 (4.8)\t16 (4.8)\t\nAge (years), mean ± SD\t26 ± 7.1\t28 ± 7.9\t27 ± 7.5\t\nWeight (kg), mean ± SD\t72.6 ± 11.4\t72.3 ± 10.8\t72.4 ± 11.1\t\nBMI (kg/m2), mean ± SD\t24.2 ± 2.7\t24.3 ± 2.8\t24.2 ± 2.8\t\nAbbreviations: BMI, body mass index; PEG, polyethylene glycol; SD, standard deviation.\n\na At screening.\n\nJohn Wiley & Sons, Ltd3.2 Immunogenicity\nNoninferiority of MSB11455 over Neulasta® was demonstrated for immunogenicity (upper limit of the exact one‐sided adjusted 95% CI < 10%). The confirmed treatment‐induced ADA‐positive rate was similar with both pegfilgrastim products (Figure 2), with a difference in rate between MSB11455 and Neulasta® of −0.6% (upper limit of the exact one‐sided adjusted 95% CI: 6.25). The overall postdose ADA‐positive rate, not constrained to a treatment‐induced ADA‐positive status, was also comparable between treatments. Over the entire study period, 15 subjects (8.9%) who received MSB11455 and 18 (10.7%) who received Neulasta® had an ADA‐positive status at any time.\n\nFigure 2 Proportion of healthy subjects with treatment‐induced ADA‐positive status at any time after the first of two single doses of MSB11455 or Neulasta® administered 28‐35 days apart until the end‐of‐study assessment visit/early termination visit\n\nTreatment‐induced ADA‐positive rates over time were also comparable between treatments (Figure 3). The highest positivity rate was observed on day 13 of Period 1, and rates decreased thereafter. Although there were numerically more ADA‐positive subjects in the MSB11455 group than in the Neulasta® group in period 2, the overall positivity rate in period 2 was low (<5.0% in each group). Overall, there were no relevant differences in median ADA titers over time between the two treatment groups among subjects with an ADA‐positive sample (Figure 3). At most visits, the ratio of median titers in each treatment group was below the minimum significant ratio (3.6), and hence not significantly different. On day 13 of Period 2, the difference for MSB1145 vs Neulasta® was above the minimum significant ratio, but that a single subject was ADA positive in the Neulasta® group prevents any conclusions regarding the clinical relevance of this finding. ADAs were mostly directed against the PEG moiety of pegfilgrastim, with no relevant differences in specificity observed between the two treatment groups (Table 2). No filgrastim‐specific NAbs were detected in either treatment group, but four subjects (three after MSB11455 and one after Neulasta®) had at least one postdose sample with detectable pegfilgrastim neutralizing activity.\n\nFigure 3 Summary of confirmed ADA‐positive status results over time from before the first of two single doses of MSB11455 or Neulasta® administered 28‐35 days apart until the end‐of‐study assessment visit/early termination visit in healthy subjects: proportion of ADA‐positive subjects,† with ADA titers in ADA‐positive subjects‡ presented below the figure\n\nTable 2 Specificity of ADAs in subjects who were ADA positive at any time after the first of two single doses of MSB11455 or Neulasta® administered 28‐35 days apart until the end‐of‐study assessment visit/early termination visit in healthy subjects\n\nn (%)\t\nMSB11455\n\n\n(N = 168)\n\n\n\t\nNeulasta®\n\n\n\n(N = 168)\n\n\n\t\nOverall\n\n\n(N = 336)\n\n\n\t\nmPEG‐positive\t10 (6.0)\t12 (7.1)\t22 (6.5)\t\nFilgrastim‐positive\t0\t1 (0.6)\t1 (0.3)\t\nmPEG‐ and filgrastim‐positive\na\n\n\t4 (2.4)\t1 (0.6)\t5 (1.5)\t\nmPEG‐ and filgrastim‐negative\na\n\n\t1 (0.6)\t4 (2.4)\t5 (1.5)\t\nAbbreviations: ADA, antidrug antibody; mPEG, methoxy‐polyethylene glycol.\n\na All ADAs associated with a low titer\n\nJohn Wiley & Sons, LtdSeven subjects identified as treatment‐induced ADA positive did not have two consecutive ADA samples that had returned to baseline by the end‐of‐study assessment visit, and therefore underwent immunogenicity follow‐up, consisting of a scheduled visit every 5 weeks (four subjects in the MSB11455 group and three in the Neulasta® group). All six evaluable subjects (one subject treated with Neulasta® was lost to follow‐up) had two consecutive ADA samples that returned to baseline (ie, subject completed follow‐up) within a maximum of five visits. In the MSB11455 group, one subject required a maximum of five follow‐up visits, two required three visits, and one required two visits. In the Neulasta® group, the two evaluable subjects each required one follow‐up visit.\n\n3.3 Sensitivity analyses\nSensitivity analyses conducted either in the per protocol population or with stratification for anti‐PEG antibody status at screening confirmed the primary analysis results, showing the noninferiority of MSB11455 over Neulasta® for immunogenicity (data not shown).\n\n3.4 Safety and tolerability\nSafety and tolerability were similar between treatments (Table 3). There were no deaths and the numbers of reported SAEs were small with no notable differences between treatments. TEAEs leading to discontinuation of study drug occurred with similar frequency in both treatment groups (Table 3) and were most commonly an increased WBC count to ≥ 50.0 × 109/L (9.5% of MSB11455 and 11.9% of Neulasta® recipients), which was initially a protocol prespecified treatment withdrawal criterion. TEAEs were generally mild to moderately severe, self‐limiting, and resolved without sequelae. No TEAEs were of National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade ≥ 4. The most common TEAEs were musculoskeletal and connective tissue disorders and nervous system disorders (Table 3).\n\nTable 3 Safety and tolerability of two single doses of MSB11455 or Neulasta® administered 28‐35 days apart in healthy subjects\n\n \t\nMSB11455\n\n\n(N = 168)\n\n\n\t\nNeulasta®\n\n\n\n(N = 168)\n\n\n\t\nAny TEAE\t167 (99.4)\t167 (99.4)\t\nAny study drug‐related TEAE\t166 (98.8)\t158 (94.0)\t\nAny serious TEAE\t1 (0.6)\t2 (1.2)\t\nAny study drug‐related serious TEAE\t1 (0.6)\na\n\n\t1 (0.6)\nb\n\n\t\nAny Grade ≥ 3\nc\n TEAE\t1 (0.6)\t2 (1.2)\t\nAny study drug‐related Grade ≥ 3\nc\n TEAE\t0\t0\t\nDeath\t0\t0\t\nAny TEAE leading to discontinuation of study drug\t25 (14.9)\t25 (14.9)\t\nAE of special interest\t25 (14.9)\t30 (17.9)\t\nSplenomegaly\t2 (1.2)\t0\t\nDrug hypersensitivity\t0\t2 (1.2)\t\nWhite blood cells increased\t23 (13.7)\t27 (16.1)\t\nDrug eruption\t0\t1 (0.6)\t\nMost common treatment‐emergent AEs (>5% of subjects)\t\nHeadache\t105 (62.5)\t120 (71.4)\t\nBone pain\t113 (67.3)\t101 (60.1)\t\nSpinal pain\t67 (39.9)\t68 (40.5)\t\nUpper respiratory tract infection\t32 (19.0)\t20 (11.9)\t\nNausea\t32 (19.0)\t19 (11.3)\t\nWhite blood cell count increased\nd\n\n\t23 (13.7)\t27 (16.1)\t\nMyalgia\t19 (11.3)\t17 (10.1)\t\nVomiting\t18 (10.7)\t9 (5.4)\t\nMusculoskeletal chest pain\t12 (7.1)\t17 (10.1)\t\nAbdominal pain\t9 (5.4)\t15 (8.9)\t\nDiarrhea\t8 (4.8)\t15 (8.9)\t\nOropharyngeal pain\t12 (7.1)\t14 (8.3)\t\nInjection site bruising\t12 (7.1)\t10 (6.0)\t\nArthralgia\t11 (6.5)\t11 (6.5)\t\nDizziness\t11 (6.5)\t11 (6.5)\t\nContusion\t11 (6.5)\t7 (4.2)\t\nFatigue\t7 (4.2)\t11 (6.5)\t\nBack pain\t8 (4.8)\t9 (5.4)\t\nNote\nData shown are n (%) of subjects.\n\nAbbreviations: AE, adverse event; TEAE, treatment‐emergent adverse event.\n\na Acute febrile neutrophilic dermatosis\n\nb Spontaneous abortion in partner\n\nc National Cancer Institute—Common Terminology Criteria for Adverse Events grade, Version 4.03\n\nd All events considered related to study drug\n\nJohn Wiley & Sons, LtdAEs of special interest were reported in similar proportions of subjects in the MSB11455 and Neulasta® groups (Table 3). Both instances of an increase in spleen size (coded as splenomegaly) (Grade 1 and 2, respectively) – only one of which was considered by the investigator as clinically significant on splenic ultrasound examination – resolved spontaneously and the subjects completed the study. Injection site reactions occurred in similar proportions of MSB11455 and Neulasta® recipients (11.9% vs 9.5%), the most common event being bruising.\n\nChanges in laboratory values and vital signs were similar between the two treatments. Eight subjects in each treatment group were anti‐PEG positive at screening; the frequency of TEAEs reported after administration of each pegfilgrastim product was comparable in these subjects. Similarly, there were no apparent differences in the pattern of TEAEs reported for ADA‐positive subjects among MSB11455 and Neulasta® recipients.\n\n4 DISCUSSION\nAs therapeutic proteins, both MSB11455 and Neulasta® were expected to induce ADAs.\n3\n Although, existing data suggest a low immunogenic potential for pegfilgrastim,\n3\n the ability to stimulate antibody formation can differ between structurally closely related molecules, with even minor changes affecting immunogenicity.\n13\n, \n14\n ADAs have the potential to adversely interfere with the therapeutic action of, or reduce or prolong exposure to, the therapeutic agent and/or predispose to adverse reactions.\n13\n, \n14\n In the case of filgrastim/pegfilgrastim, ADAs with filgrastim neutralizing capacity are particularly critical due to potential cross‐reactivity with the endogenous counterpart. Demonstration of immunogenic similarity of a biosimilar to the reference product in a head‐to‐head comparison is, therefore, a critical parameter for defining the safety of the biosimilar.\n13\n\n\n\nThe design of this study was appropriate for comparing the immunogenicity and safety profiles of MSB11455 and Neulasta®, with both the study design and population in line with regulatory guidance. The parallel‐group design of the study ensured that immunogenicity assessments were related to only one treatment. This study was conducted in healthy subjects because they are the most homogenous population for a sensitive assessment of immunogenicity; their immune system is not affected by chemotherapy (thereby improving sensitivity to detect differences in immunogenicity), and animal models have low predictive value with respect to immunogenicity in humans.\n13\n The dose of study drug administered is the approved dose for Neulasta® when used in sequence with cytotoxic chemotherapy.\n3\n The 28‐day period between doses was appropriate as pegfilgrastim is administered once per chemotherapy cycle, and given the half‐life of pegfilgrastim, the time between dosing and the first ADA sampling time point was considered adequate. Two injections were considered sufficient to assess immunogenicity based on unpublished historical data (from study NCT02205320), where the majority (approximately 95%) of immunogenicity occurred before a third dose of pegfilgrastim was given (ie, within 10 weeks of the first dose) and was mostly transient. Sampling time points were designed to identify potential early (Day 13) and late (Day 28) immune responses. In this study, ADA‐positive rates peaked within 2 weeks after the first dose of both pegfilgrastim products, with a later incidence and titer decline, suggesting that a longer study period would not be more informative.\n\nIn this study, noninferiority of MSB11455 over Neulasta® was demonstrated for the rate of confirmed treatment‐induced ADA‐positive status: the treatment‐induced confirmed immunogenicity rate was 8.9% for MSB11455% vs 9.5% for Neulasta® (difference in rate: −0.6%; upper limit of the exact one‐sided adjusted 95% CI: 6.25). Furthermore, no relevant differences in ADA characteristics such as onset, titer, and specificity were found between the treatment groups. Although there was a numerical difference in the number of ADA‐positive subjects in the MSB11455 group compared with the Neulasta® group in period 2, the small difference between the treatment arms in ADA incidence at individual visits (1.2% to 2.4%) was not conclusive and did not affect the demonstrated noninferiority in terms of immunogenicity of MSB11455 compared with Neulasta® at the overall study level. Most detected ADAs with both treatments were directed against the PEG moiety of pegfilgrastim. No filgrastim‐specific NAb was detected in either treatment arm, in line with the observed ADA specificity findings. Findings of the main analyses were supported by those of sensitivity analyses, including those performed in the per protocol population that included all subjects who received both doses of pegfilgrastim.\n\nStudy results also showed that the safety and tolerability of MSB11455 and Neulasta® were similar, and were as expected for administration of pegfilgrastim.\n3\n Bone pain and headache were among the most frequently reported TEAEs for both treatments, which is expected with pegfilgrastim treatment.\n3\n Pegfilgrastim is also associated with musculoskeletal pain because of bone marrow remodeling and increased precursor turnover.\n15\n Splenic rupture has been reported following administration of filgrastim\n16\n or pegfilgrastim\n3\n; therefore, the spleen was monitored throughout the study. Two subjects experienced a mild‐to‐moderate increase in spleen size; of these only one was deemed by the investigator as clinically significant on splenic ultrasound examination. In both instances, this spontaneously resolved. A relatively large number of subjects reported an increase in WBC count to ≥ 50.0 x 109/L as an AE of special interest, which resulted in treatment discontinuations in these subjects (as per corresponding withdrawal criterion prespecified in the initial version of the clinical study protocol). However, all these events were self‐limiting, returning spontaneously to normal levels within 10 days. The initial WBC count ‘safety threshold’ defined in the initial version of the clinical study protocol was at a level too low for healthy volunteers who had intact bone marrow. The study protocol was, therefore, amended to reflect the pronounced increment in WBC count expected in healthy subjects following stimulation by pegfilgrastim (to a WBC count ≥ 90.0 x 109/L) and no further events of this nature were reported after this amendment.\n\n5 CONCLUSION\nMSB11455 and Neulasta® showed comparable immunogenicity, safety, and tolerability in healthy subjects, and MSB11455 was noninferior to Neulasta® for immunogenicity, in terms of treatment‐induced ADA‐positive rates. This study supports and strengthens available evidence for the biosimilarity of MSB11455 to Neulasta®.\n\nDISCLOSURES\nChris Wynne is a shareholder in Christchurch Clinical Studies Trust Ltd; Christian Schwabe is an employee and shareholder in ACS; Emmanuelle Vincent, Michael Stahl, Martin Ullmann, Radmila Kanceva, and Vishal Ghori are employees of Fresenius Kabi SwissBioSim GmbH, Switzerland; Janka Ryding was employed by Fresenius Kabi SwissBioSim GmbH at the time of study conduct and is currently an employee of SVAR Life Science AB, Sweden; Armin Schueler is an employee of Merck Healthcare, Darmstadt, Germany.\n\nAUTHOR CONTRIBUTIONS\nChris Wynne: Study design, acquisition and interpretation of data, critical revision of the manuscript for important intellectual content, final approval, and has participated sufficiently in the work to agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Christian Schwabe: Acquisition of data, critical revision of the manuscript for important intellectual content, final approval, and has participated sufficiently in the work to agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Emmanuelle Vincent: Conception and study design, acquisition, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, final approval, and has participated sufficiently in the work to agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Armin Schueler: Study design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, final approval, and has participated sufficiently in the work to agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Janka Ryding: Conception and study design, acquisition and analysis of data, critical revision of the manuscript for important intellectual content, final approval, and has participated sufficiently in the work to agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Martin Ullmann: Study design, analysis and interpretation of data, critical revision of the manuscript for important intellectual content, final approval, and has participated sufficiently in the work to agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Vishal Ghori: Analysis and interpretation of data, critical revision of the manuscript for important intellectual content, final approval, and has participated sufficiently in the work to agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Radmila Kanceva: Acquisition, analysis and interpretation of data, drafting and critical revision of the manuscript for important intellectual content, final approval, and has participated sufficiently in the work to agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. Michael Stahl: Conception of work, acquisition, analysis, and interpretation of data, critical revision of the manuscript for important intellectual content, final approval, and has participated sufficiently in the work to agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.\n\nSupporting information\nFig S1\n\nClick here for additional data file.\n\n ACKNOWLEDGMENTS\nThis study was sponsored by Merck Healthcare KGaA (Darmstadt, Germany) and Fresenius Kabi SwissBioSim GmbH. Medical writing support was provided by Caroline Spencer and Dr Sue Chambers (Rx Communications, Mold, UK), funded by Fresenius Kabi SwissBioSim.\n==== Refs\nREFERENCES\n1 \n\nSchwartzberg \nLS \n. Management of chemotherapy‐induced neutropoenia\n. European Oncology . 2008 ;4 :26 ‐29\n.\n2 \n\nWelte \nK \n, \nGabrilove \nJ \n, \nBronchud \nMH \n, \nPlatzer \nE \n, \nMorstyn \nG \n. Filgrastim (r‐metHuG‐CSF): the first 10 years\n. Blood . 1996 ;88 (6 ):1907 ‐1929\n.8822908 \n3 \nAmgen Inc \n. NEULASTA® (pegfilgrastim) injection, for subcutaneous use\n. Prescribing Information. https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/neulasta/neulasta_pi_hcp_english.pdf. Accessed May 7, 2019\n4 \n\nRenwick \nW \n, \nPettengell \nR \n, \nGreen \nM \n. Use of filgrastim and pegfilgrastim to support delivery of chemotherapy: twenty years of clinical experience\n. BioDrugs . 2009 ;23 :175 ‐186\n.19627169 \n5 \n\nCooper \nKL \n, \nMadan \nJ \n, \nWhyte \nS \n, \nStevenson \nMD \n, \nAkehurst \nRL \n. Granulocyte colony‐stimulating factors for febrile neutropenia prophylaxis following chemotherapy: systematic review and meta‐analysis\n. BMC Cancer . 2011 ;11 :404 .21943360 \n6 \n\nMitchell \nS \n, \nLi \nX \n, \nWoods \nM \n, et al. Comparative effectiveness of granulocyte colony‐stimulating factors to prevent febrile neutropenia and related complications in cancer patients in clinical practice: A systematic review\n. Journal of Oncology Pharmacy Practice . 2016 ;22 :702 ‐716\n.26769697 \n7 \n\nAapro \nMS \n, \nBohlius \nJ \n, \nCameron \nDA \n, et al. 2010 update of EORTC guidelines for the use of granulocyte‐colony stimulating factor to reduce the incidence of chemotherapy‐induced febrile neutropenia in adult patients with lymphoproliferative disorders and solid tumours\n. Eur J Cancer. \n2011 ; 47 :8 ‐32\n.21095116 \n8 \nUS Food and Drug Administration \n. Scientific considerations in demonstrating biosimilarity to a reference product\n. Guideline for Industry. Rockville, MD, April 2015. https://www.fda.gov/media/82647/download. Accessed May 15, 2019.\n9 \nEuropean Medicines Agency \n. Guideline on similar biological medicinal products containing biotechnology‐derived proteins as active substance: non‐clinical and clinical issues\n. London, UK 2014. https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-similar-biological-medicinal-products-containing-biotechnology-derived-proteins-active_en-2.pdf. Accessed November 6, 2019.\n10 \n\nLickliter \nJD \n, \nGriffin \nP \n, \nVincent \nE \n, et al. Pharmacokinetic/pharmacodynamic assessment of a proposed biosimilar MSB11455 versus the currently licensed pegfilgrastim: A randomized, double‐blind trial\n. J Clin Oncol . 2019 ;37 (15 Suppl ):e14514.\n11 \n\nLin \nDY \n, \nWei \nLJ \n, \nDeMets \nDL \n. Exact statistical inference for group sequential trials\n. Biometrics . 1991 ;47 :1399 ‐1408\n.1786325 \n12 \n\nJennison \nC \n, \nTurnbull \nBW \n. Group sequential methods with applications to clinical trials . Boca Raton, Florida : Chapman & Hall/CRC , 1st ed , 2000 . \n13 \nWorld Health Organization \n. Guidelines on evaluation of similar biotherapeutic products (SBPS) Annex 2, WHO Technical Report Series No 977\n. http://www.who.int/entity/biologicals/publications/trs/areas/biological_therapeutics/TRS_977_Annex_2.pdf?ua=1. Accessed May 28, 2019.\n14 \n\nWadhwa \nM \n, \nKnezevic \nI \n, \nKang \nHN \n, \nThorpe \nR \n. Immunogenicity assessment of biotherapeutic products: An overview of assays and their utility\n. Biologicals . 2015 ;43 (5 ):298 ‐306\n.26144595 \n15 \n\nLambertini \nM \n, \nDel Mastro \nL \n, \nBellodi \nA \n, \nPronzato \nP \n. The five \"Ws\" for bone pain due to the administration of granulocyte‐colony stimulating factors (G‐CSFs)\n. Crit Rev Oncol Hematol . 2014 ;89 (1 ):112 ‐128\n.24041627 \n16 \nAmgen Inc \n. NEUPOGEN® (filgrastim) injection, for subcutaneous or intravenous use\n. Prescribing Information. https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/neupogen/neupogen_pi_hcp_english.pdf. Accessed 28 May 2019.\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2052-1707",
"issue": "8(2)",
"journal": "Pharmacology research & perspectives",
"keywords": "MSB11455; antidrug antibodies; immunogenicity; pegfilgrastim; safety; tolerability",
"medline_ta": "Pharmacol Res Perspect",
"mesh_terms": "D000328:Adult; D000906:Antibodies; D059451:Biosimilar Pharmaceuticals; D004311:Double-Blind Method; D005260:Female; D000069585:Filgrastim; D064368:Healthy Volunteers; D006801:Humans; D008297:Male; D011092:Polyethylene Glycols; D055815:Young Adult",
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"references": "26769697;21095116;21943360;19627169;8822908;32333641;24041627;26144595;1786325",
"title": "Immunogenicity and safety of a proposed pegfilgrastim biosimilar MSB11455 versus the reference pegfilgrastim Neulasta® in healthy subjects: A randomized, double-blind trial.",
"title_normalized": "immunogenicity and safety of a proposed pegfilgrastim biosimilar msb11455 versus the reference pegfilgrastim neulasta in healthy subjects a randomized double blind trial"
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"abstract": "Pyridoxine-dependent epilepsy (PDE) is a genetic metabolic disease caused by inborn errors affecting vitamin B6 metabolism, which typically presents with neonatal seizures resistant to antiepileptic drugs (AEDs). Treatment with pyridoxine terminates seizures and prevents neurological decline. We describe a case in which the diagnosis was established at the age of 22 years. Birth and development were normal, but there was a history of three isolated tonic-clonic seizures during childhood and adolescence. At the age of 18 years, she developed frequent focal motor seizures, many evolving into tonic-clonic seizures. Electroencephalography identified a focus in the posterior right hemisphere, but magnetic resonance imaging of the brain was normal. Over the next 3 years, she was hospitalized with uncontrolled seizures on six occasions and spent a total of 121 days in intensive care. The seizures proved resistant to 12 different AEDs. Exome sequencing revealed two pathogenic mutations in ALDH7A1. Since starting on pyridoxine 50 mg once daily, she has been seizure-free, all AEDs have been withdrawn, and cognition has improved to premorbid levels. This case illustrates the importance of considering PDE in drug-resistant epilepsy in adults.",
"affiliations": "Southampton General Hospital, Southampton, UK.;Southampton General Hospital, Southampton, UK.;Southampton General Hospital, Southampton, UK.;Southampton General Hospital, Southampton, UK.;Southampton General Hospital, Southampton, UK.",
"authors": "Osman|Chinar|C|0000-0001-8245-0942;Foulds|Nicola|N|;Hunt|David|D|;Jade Edwards|Casidhe|C|;Prevett|Martin|M|0000-0002-5809-1959",
"chemical_list": "C089507:ALDH7A1 protein, human; D000444:Aldehyde Dehydrogenase; D011736:Pyridoxine",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.16408",
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"issue": "61(1)",
"journal": "Epilepsia",
"keywords": "genetic; metabolic; pyridoxine",
"medline_ta": "Epilepsia",
"mesh_terms": "D000293:Adolescent; D017668:Age of Onset; D000444:Aldehyde Dehydrogenase; D004827:Epilepsy; D005260:Female; D006801:Humans; D009154:Mutation; D011736:Pyridoxine; D013226:Status Epilepticus; D055815:Young Adult",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "e1-e6",
"pmc": null,
"pmid": "31849043",
"pubdate": "2020-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Diagnosis of pyridoxine-dependent epilepsy in an adult presenting with recurrent status epilepticus.",
"title_normalized": "diagnosis of pyridoxine dependent epilepsy in an adult presenting with recurrent status epilepticus"
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"reaction": [
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},
{
"reactionmeddrapt": "Cognitive disorder",
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{
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"literaturereference": "OSMAN C, FOULDS N, HUNT D, EDWARDS CJ, PREVETT M.. DIAGNOSIS OF PYRIDOXINE-DEPENDENT EPILEPSY IN AN ADULT PRESENTING WITH RECURRENT STATUS EPILEPTICUS.. EPILEPSIA.. 2020?61(1):E1-E6",
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"abstract": "Objective: Due to the extensive use of diazepam worldwide, self-induced intoxication is very common, yet rarely fatal. Nevertheless, the management of intoxication caused by extremely high doses of diazepam is not known, as well as the effectiveness of flumazenil, a specific benzodiazepine (BDZ) antagonist. Here we present the first report on the enhanced elimination (clearance) of diazepam using the Molecular Adsorbents Recirculating System (MARS) following autointoxication with an extremely high dose as part of a suicide attempt. Case: A 44-year-old male patient was admitted to the ICU because of impaired consciousness following the ingestion of 20 g of diazepam. Blood and urine samples revealed high benzodiazepine levels. Repeated doses of flumazenil were without effect on consciousness. Following deterioration of the patient's clinical condition, including unconsciousness, hypoventilation, and decreased SpO2 (88%), the patient was intubated and mechanically ventilated. On the fourth day after admission, the patient was unresponsive, with no attempt to breath spontaneously. The plasma level of benzodiazepines was 1,772 μg/l. The elimination of benzodiazepines by MARS was attempted, continuing for 5 days, with one session per day. Five sessions of MARS effectively enhanced benzodiazepine elimination. After the first MARS treatment, the plasma level of benzodiazepines dropped from 1,772 to 780 μg/l. After the final MARS treatment on the eighth day, the patient was weaned from mechanical ventilation and extubated. Two days later, the patient was discharged to the internal medicine department and subsequently to the psychiatry department. Conclusions: To the best of our knowledge, this is the first case reporting successful treatment of diazepam intoxication using MARS. In severe cases of diazepam intoxication, with prolonged unconsciousness and the necessity of mechanical ventilation, we suggest considering the use of MARS elimination therapy together with the monitoring of the BDZ plasma level.",
"affiliations": "Faculty of Medicine, University Hospital Bratislava, Nemocnica Ruzinov, ICU, KAIM, Clinic of Anesthesiology and Intensive Care Medicine, Comenius University in Bratislava, Bratislava, Slovakia.;Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia.;Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia.;Faculty of Medicine, University Hospital Bratislava, Nemocnica Ruzinov, ICU, KAIM, Clinic of Anesthesiology and Intensive Care Medicine, Comenius University in Bratislava, Bratislava, Slovakia.;Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands.;Faculty of Medicine, University Hospital Bratislava, Nemocnica Ruzinov, ICU, KAIM, Clinic of Anesthesiology and Intensive Care Medicine, Comenius University in Bratislava, Bratislava, Slovakia.",
"authors": "Dobisova|Anna|A|;Vavrinec|Peter|P|;Vavrincova-Yaghi|Diana|D|;Gebhardtova|Andrea|A|;Henning|Robert H|RH|;Yaghi|Aktham|A|",
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"doi": "10.3389/fmed.2021.633250",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.633250\nMedicine\nCase Report\nCase Report: Enhanced Diazepam Elimination With the Molecular Adsorbents Recirculating System (MARS) in Severe Autointoxication: A Survival Case Report\nDobisova Anna 1\n\nVavrinec Peter 2*\n\nVavrincova-Yaghi Diana 2\n\nGebhardtova Andrea 1\nHenning Robert H. 3\n\nYaghi Aktham 1\n1Faculty of Medicine, University Hospital Bratislava, Nemocnica Ruzinov, ICU, KAIM, Clinic of Anesthesiology and Intensive Care Medicine, Comenius University in Bratislava, Bratislava, Slovakia\n2Department of Pharmacology and Toxicology, Faculty of Pharmacy, Comenius University in Bratislava, Bratislava, Slovakia\n3Department of Clinical Pharmacy and Pharmacology, University of Groningen, University Medical Center Groningen, Groningen, Netherlands\nEdited by: Marcelo Arruda Nakazone, Faculty of Medicine of São José do Rio Preto, Brazil\n\nReviewed by: Silvia Regina Cavani Jorge Santos, University of São Paulo, Brazil; Rafael Bañares, Gregorio Marañón Hospital, Spain; Pierre-André Dubé, Institut National de Santé Publique du Québec, Canada\n\n*Correspondence: Peter Vavrinec vavrinec@fpharm.uniba.sk\nThis article was submitted to Intensive Care Medicine and Anesthesiology, a section of the journal Frontiers in Medicine\n\n09 3 2021\n2021\n8 63325025 11 2020\n05 2 2021\nCopyright © 2021 Dobisova, Vavrinec, Vavrincova-Yaghi, Gebhardtova, Henning and Yaghi.\n2021\nDobisova, Vavrinec, Vavrincova-Yaghi, Gebhardtova, Henning and Yaghi\nThis 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(s) 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.\nObjective: Due to the extensive use of diazepam worldwide, self-induced intoxication is very common, yet rarely fatal. Nevertheless, the management of intoxication caused by extremely high doses of diazepam is not known, as well as the effectiveness of flumazenil, a specific benzodiazepine (BDZ) antagonist. Here we present the first report on the enhanced elimination (clearance) of diazepam using the Molecular Adsorbents Recirculating System (MARS) following autointoxication with an extremely high dose as part of a suicide attempt.\n\nCase: A 44-year-old male patient was admitted to the ICU because of impaired consciousness following the ingestion of 20 g of diazepam. Blood and urine samples revealed high benzodiazepine levels. Repeated doses of flumazenil were without effect on consciousness. Following deterioration of the patient's clinical condition, including unconsciousness, hypoventilation, and decreased SpO2 (88%), the patient was intubated and mechanically ventilated. On the fourth day after admission, the patient was unresponsive, with no attempt to breath spontaneously. The plasma level of benzodiazepines was 1,772 μg/l. The elimination of benzodiazepines by MARS was attempted, continuing for 5 days, with one session per day. Five sessions of MARS effectively enhanced benzodiazepine elimination. After the first MARS treatment, the plasma level of benzodiazepines dropped from 1,772 to 780 μg/l. After the final MARS treatment on the eighth day, the patient was weaned from mechanical ventilation and extubated. Two days later, the patient was discharged to the internal medicine department and subsequently to the psychiatry department.\n\nConclusions: To the best of our knowledge, this is the first case reporting successful treatment of diazepam intoxication using MARS. In severe cases of diazepam intoxication, with prolonged unconsciousness and the necessity of mechanical ventilation, we suggest considering the use of MARS elimination therapy together with the monitoring of the BDZ plasma level.\n\ndiazepam\nmars\npharmacokinetics\nelimination\nautointoxication\n==== Body\nIntroduction\n\nBecause of the extensive use of diazepam worldwide, self-induced intoxication is highly prevalent (1, 2). While common, single compound benzodiazepine (BDZ) intoxication rarely produces significant morbidity or mortality, the management of intoxication caused by extremely high doses of diazepam is not known, as well as the effectiveness of flumazenil, a specific BDZ antagonist. Because diazepam has a relatively long half-life (20–50 h), contains active metabolites (with a half-life of 36–200 h for the main active metabolite nordiazepam) and is highly bound to proteins (98%), the preferred strategy would encompass removal of the compound from circulation. Consequently, measures to enhance diazepam clearance may significantly shorten the duration of intoxication. The Molecular Adsorbents Recirculating System (MARS) is a removal strategy based on the principle of albumin dialysis and may therefore be especially useful in enhancing the clearance of (protein-bound) diazepam; however, its effectiveness in enhancing diazepam clearance following severe intoxication has not yet been explored. Here, we demonstrate for first time the effective enhancement of diazepam clearance by MARS, as used in a unique case of autointoxication featuring an extreme overdose of diazepam.\n\nCase\n\nA 44-year-old male was admitted to the ICU because of impaired consciousness, with a Glasgow Coma Score of 11 (GCS: E4, M5, V2), after reported ingestion of diazepam. The intoxication occurred at the pharmacy during the evening hours. The patient was found unconsciousness by an employee, next to an emptied pharmaceutical powder canister that had contained diazepam.\n\nAttempted suicide was suspected because of a letter left by the patient. Circumstances thus indicated that the patient had ingested 2,000 mg (20 g; 250 mg/kg) of diazepam, some 2–4 h prior to presentation at the ICU. The patient has no relevant medical, family, or psychosocial history, as well as no past interventions. No medical report about depressive disorder or previous suicide attempts exists. The patient worked as an economist in the pharmacy. On ICU admission, the patient's blood pressure was 110/70 mmHg, heart rate 90/min, with regular rhythm. The SpO2 was 90%, and the patient was hypothermic (35.5°C). The patient's weight was 80 kg, height 175 cm, and BMI 26.12 kg/m2. The patient had no renal or liver dysfunction. Plasma analyses revealed no changes in urea (3.27 mmol/L), creatinine (52.9 μmol/L), bilirubin (6.39 μmol/L), AST (0.37 ucat/l), ALT (0.21 ucat/l), and AMS (1.38 ucat/l). Further physical examination revealed no abnormalities. Blood and urine samples were taken for toxicology investigation. According to protocol, the patient was administered 75 g of activated charcoal and 20 g of MgSO4 by nasogastric tube every 6 h. I.v. flumazenil (0.5 mg) administration was without effect. Because of agitation, intermittent i.v. administration of propofol (50 mg) was used. BDZ intoxication was confirmed from blood and urine samples 5 h after admission, with plasma concentration above the upper detection limit of 2,000 μg/l. Plasma and urine BDZs were measured using DRI® Benzodiazepine Serum Tox Assay and Emit® II Plus Benzodiazepine Assay for urine. Because of hypoventilation and irregular breathing, decreased SpO2 (to 88%) and impaired GCS (to 3), the patient was intubated and mechanically ventilated starting from 5 h after admission without the need for additional sedation. Subsequent repetitive administration of flumazenil (0.5 mg i.v.; three times) was without effect.\n\nDuring the subsequent days, the patient remained unconsciousness with an absence of spontaneous breathing. Plasma BDZ remained above the upper detection limit, which prompted the start of MARS on the fourth day of admission and its continuation for 5 days, one session per day. Informed consent was obtained from the patient's relatives.\n\nThroughout the course of MARS, plasma levels of BDZ were measured twice daily—at 6:00 (before the MARS session) and at around 14:00 (after the MARS session). The first MARS session lowered the plasma level of BDZ from 1,772 to 780 μg/L, and subsequent sessions further lowered the BDZ levels (Figure 1, Table 1). By day eight, the plasma level of BDZ had dropped to 191.2 μg/L. The patient regained consciousness and was weaned from mechanical ventilation and extubated. Two days later, the patient was discharged to the department of internal medicine and subsequently to the department of psychiatry.\n\nFigure 1 Plasma level of benzodiazepines throughout the study expressed as μg/L. The five MARS sessions are indicated by gray vertical bars. Dotted curve represents estimated plasma level of benzodiazepines calculated using t1/2 of 52 h. Total plasma benzodiazepines were assessed by the DRI® Benzodiazepine Serum Tox Assay.\n\nTable 1 Benzodiazepines plasma levels before and after the MARS sessions.\n\nDay\tBDZ plasma before MARS (μg/L)\tBDZ plasma after MARS (μg/L)\tDecrease by MARS (%)\tIncrease after MARS (%)\tAbsolute increase after MARS (μg/L)\tEstimated removal (mg)\t\n4\t1,772\t780\t56\t\t\t119\t\n5\t943\t656\t30\t21\t163\t34\t\n6\t862\t413\t52\t31\t206\t29\t\n7\t616\t259\t58\t49\t203\t43\t\n8\t267\t191\t28\t3\t8\t9\t\n9\t161\t112\t30\t−16\t−30\t\t\nThe effectiveness of MARS is expressed as the percent of plasma level decrease and tissue release expressed as the percent increase after mars. The absolute increase after MARS and estimated removal by MARS were calculated from volume of distribution of 1.5 L/kg, body weight of 80 kg. Total plasma benzodiazepines were assessed by the DRI® Benzodiazepine Serum Tox Assay. Total plasma benzodiazepines were assessed by the DRI® Benzodiazepine Serum Tox Assay.\n\nAs a result of MARS, plasma BDZ levels were effectively lowered by a similar percentage at each session, averaging 45% (Figure 1, Table 1). In contrast, changes in the plasma BDZ level following each MARS session showed a different pattern, with a substantial and increasing percentage of nightly rebound following the initial three MARS sessions, followed by an abrupt halting of the increase, and even a net removal of BDZ following the last MARS session (Table 1). Of note, when expressed as ug/L change, the nightly rebound following the first three MARS sessions was similar.\n\nPlasma BDZ levels during the last measurements, when MARS had been stopped, allowed calculation of the elimination half-life (t1/2; assuming a volume of distribution 1.5 L/kg and a body weight of 80 kg). During the first time interval, the BDZ level dropped from 191 to 161 μg/l in 17 h; consequently the calculated elimination t1/2 was 69 h. During the last 24 h of measurements, the BDZ level dropped from 161 to 111 μg/l; therefore, calculated t1/2 was 45 h. Overall, calculation of the elimination half-life over the last three time points, when the plasma BDZ level dropped from 191 to 111 μg/l in 41 hours, rendered a similar result, with a t1/2 of 52 h.\n\nDiscussion\n\nMARS is a system of extracorporeal albumin dialysis that is mostly used in patients with established liver damage. The concept of albumin dialysis depends on the elimination of protein-bound molecules and can also be used with intoxication in order to remove toxicants. To the best of our knowledge, this is the first case reporting accelerated elimination of diazepam using MARS.\n\nGiven the excessive dose of diazepam taken by the patient, a poor prognosis was foreseen. Because of reported high diazepam albumin binding (98%) (3, 4), it was hypothesized that albumin dialysis would enhance the clearance of the plasma protein-bound diazepam. However, both in-vivo and in-vitro evidence on the impact of MARS on BDZ elimination is scarce. Specifically, one in-vitro study focuses on the impact of albumin stabilizers (5) and another on the impact of the dialysate albumin concentration on removal efficacy (6), rather than on the impact of MARS on diazepam elimination itself. Thus far, one porcine in-vivo study reported MARS to have efficiently removed midazolam in the setting of induced acute liver failure (7). This experimental in-vivo study supported our decision to use MARS to eliminate BDZs from the patient's body.\n\nOur data show that MARS efficiently lowers plasma BDZ levels, as single sessions resulted in an average drop in plasma BDZ of 43%. However, we also observed a significant rebound of plasma BDZ levels following the initial MARS sessions, which may have been the result of accumulated drug recirculation from plasma protein binding sites or redistribution from peripheral compartments, such as adipose and muscle tissue. Interestingly, absolute plasma BDZ levels increased similarly after the three initial MARS sessions, resulting in an increasing percentage of nightly plasma level rebound. This likely represents a release of accumulated drug from peripheral compartments at zero-order kinetics. This novel finding not only reflects the release mechanism of diazepam from tissue but may also have clinical implications, with the cessation of the rebound increase in BDZ plasma level being a useful indicator of the end of intoxication. However, up to our best knowledge, we cannot compare this finding with any literature. Based on this observation, we recommend routine plasma level sampling both prior to and after MARS.\n\nThe calculated patient's BDZ elimination half-life of 52 h, based on the last time points without MARS, is well in line with half-lives reported for diazepam, which range from 20 to 56 h. Based on this calculation, elimination of BDZ without MARS would take 16 days; therefore, MARS shortened the recovery of patient for 7 days. This would shorten the stay at ICU, decreased the risks of infections, ventilation-associated lung damage, etc.\n\nHowever, diazepam is metabolized into the active metabolites nordiazepam and oxazepam, which have substantially longer elimination half-lives of more than 200 h and high protein binding (8, 9). Consequently, the match between calculated BDZ and diazepam half-lives may be explained by the metabolites not being formed at high concentrations and/or complete removal by MARS without substantial accumulation in peripheral tissue. Unfortunately, metabolite levels cannot be discerned by the immunoassay method used.\n\nTo the best of our knowledge, our case represents the highest dose of diazepam intoxication ever reported. Greenblatt et al. reported a diazepam poisoning with a 10-fold lower dose, that is, 2,000 mg (10). While they report high concentrations of all metabolites present in early samples, which subsequently declined slowly over the next 2 weeks, the patient had fully recovered and was discharged within 48 h of ingestion. Because of this rapid clinical recovery, Greenblatt et al. propose that recovery from the diazepam overdose was not attributable to rapid elimination of active compounds from the body, but more likely grounded in adaptation or tolerance to the depressant effects. In contrast, the currently reported patient, who took a 10-fold higher dose, remained unconscious until the last MARS session (in the absence of additional sedating medication). Therefore, a rapid spontaneous recovery, as in case of Greenblatt et al., was clearly absent in our case. Additional data are obviously needed to resolve this issue.\n\nOur study has strengths but also limitation: Measurements of plasma BDZ concentration was assessed prior to and following every MARS session, allowing us to show clearly the beneficial effect of MARS. Based on our further calculation (Figure 1) moreover, the patient's recovery with MARS would be 1 week earlier than without MARS, pointing to the important role of MARS in severe BDZ intoxications. However, only total level of BDZ and not the levels of metabolites were estimated, which is the main limitation of our study.\n\nCollectively, based on the observations and favorable outcome of the current case and in absence of official guidelines for severe flumazenil irresponsive BDZ poisoning, we suggest considering the use of MARS elimination treatment with daily sessions together with twice daily monitoring of BZD plasma levels.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nEthical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nAD, AG, AY, and RH made substantial contributions to the conception or design of the manuscript. PV and DV-Y to the acquisition, analysis, and interpretation of the data. RH revised it critically. All authors participated in drafting the manuscript.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nFunding. This work was partially supported by the grant VEGA 1/0027/20 from the scientific grant agency of Ministry of Education, Science, Research and Sport of the Slovak Republic.\n==== Refs\nReferences\n\n1. Votaw VV Geyer R Rieselbach MM McHugh RK . The epidemiology of benzodiazepine misuse: a systematic review. Drug Alcohol Depend. (2019) 200 :95–114. 10.1016/j.drugalcdep.2019.02.033 31121495\n2. Bachhuber MA Hennessy S Cunningham CO Starrels JL . Increasing benzodiazepine prescriptions and overdose mortality in the United States, 1996–2013. Am J Public Health. (2016) 106 :686–8. 10.2105/AJPH.2016.303061 26890165\n3. Thiessen JJ Sellers EM Denbeigh P Dolman L . Plasma protein binding of diazepam and tolbutamide in chronic alcoholics. J Clin Pharmacol. (1976) 16 :345–51. 10.1002/j.1552-4604.1976.tb01531.x 947967\n4. Dhillon S Richens A . Serum protein binding of diazepam and its displacement by valproic acid in vitro. Br J Clin Pharmacol. (1981) 12 :591–2. 10.1111/j.1365-2125.1981.tb01273.x 6794588\n5. De Bruyn T Meijers B Evenepoel P Laub R Willems L Augustijns P . Stability of therapeutic albumin solutions used for molecular adsorbent recirculating system-based liver dialysis. Artificial Organs. (2012) 36 :29–41. 10.1111/j.1525-1594.2011.01310.x 21955219\n6. Drexler K Baustian C Richter G Ludwig J Ramlow W Mitzner S . Albumin dialysis molecular adsorbents recirculating system: impact of dialysate albumin concentration on detoxification efficacy. Therap Apheresis Dialysis. (2009) 13 :393–8. 10.1111/j.1744-9987.2009.00757.x 19788455\n7. Sen S Ytrebø LM Rose C Fuskevaag OM Davies NA Nedredal GI . Albumin dialysis: a new therapeutic strategy for intoxication from protein-bound drugs. Intensive Care Med. (2004) 30 :496–501. 10.1007/s00134-003-2141-0 14735236\n8. Allen MD Greenblatt DJ . Comparative protein binding of diazepam and desmethyldiazepam. J Clin Pharmacol. (1981) 21 :219–23. 10.1002/j.1552-4604.1981.tb02551.x 6790582\n9. Boudinot FD Homon CA Jusko WJ Ruelius HW . Protein binding of oxazepam and its glucuronide conjugates to human albumin. Biochem Pharmacol. (1985) 34 :2115–21. 10.1016/0006-2952(85)90404-6 4004929\n10. Greenblatt DJ Woo E Allen MD Orsulak PJ Shader RI . Rapid recovery from massive diazepam overdose. JAMA. (1978) 240 :1872–4. 10.1001/jama.240.17.1872 357765\n\n",
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"issn_linking": "2296-858X",
"issue": "8()",
"journal": "Frontiers in medicine",
"keywords": "autointoxication; diazepam; elimination; mars; pharmacokinetics",
"medline_ta": "Front Med (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101648047",
"other_id": null,
"pages": "633250",
"pmc": null,
"pmid": "33791324",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "14735236;947967;357765;26890165;19788455;6790582;6794588;21955219;31121495;4004929",
"title": "Case Report: Enhanced Diazepam Elimination With the Molecular Adsorbents Recirculating System (MARS) in Severe Autointoxication: A Survival Case Report.",
"title_normalized": "case report enhanced diazepam elimination with the molecular adsorbents recirculating system mars in severe autointoxication a survival case report"
} | [
{
"companynumb": "SK-NUVO PHARMACEUTICALS INC-2109985",
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"occurcountry": "SK",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
"drugadditional": null,
"drugadministrationroute": "048",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "DIAZEPAM."
}
],
"patientagegroup": null,
"patientonsetage": "44",
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"reaction": [
{
"reactionmeddrapt": "Hypothermia",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Irregular breathing",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Oxygen saturation decreased",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypoventilation",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Loss of consciousness",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Suicide attempt",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "VAVRINEC P, DOBISOVA A, VAVRINCOVA?YAGHI D, GEBHARDTOVA A, HENNING RH, YAGHI A, ET AL. CASE REPORT: ENHANCED DIAZEPAM ELIMINATION WITH THE MOLECULAR ADSORBENTS RECIRCULATING SYSTEM (MARS) IN SEVERE AUTOINTOXICATION: A SURVIVAL CASE?REPORT. FRONTIERS IN MEDICINE 8: 9 MAR 2021.HTTP://DOI.ORG/10.3389/FMED.2021.633250.",
"literaturereference_normalized": "case report enhanced diazepam elimination with the molecular adsorbents recirculating system mars in severe autointoxication a survival case report",
"qualification": "3",
"reportercountry": "SK"
},
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"receivedate": "20210429",
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},
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
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"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20210717"
},
{
"companynumb": "SK-BAUSCH-BL-2021-024999",
"fulfillexpeditecriteria": "1",
"occurcountry": "SK",
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{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIAZEPAM"
},
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"drugdosagetext": "INGESTED; 20 G; 250 MG/KG",
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"medicinalproduct": "DIAZEPAM."
}
],
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"reaction": [
{
"reactionmeddrapt": "Poisoning",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Suicide attempt",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Intentional overdose",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DOBISOVA A, VAVRINEC P, VAVRINCOVA?YAGHI D, GEBHARDTOVA A, HENNING R, YAGHI A. CASE REPORT: ENHANCED DIAZEPAM ELIMINATION WITH THE MOLECULAR ADSORBENTS RECIRCULATING SYSTEM (MARS) IN SEVERE AUTOINTOXICATION: A SURVIVAL CASE REPORT. FRONTIERS IN MEDICINE. 2021 MAR 09?8:1?4. DOI:10.3389/FMED.2021.633250",
"literaturereference_normalized": "case report enhanced diazepam elimination with the molecular adsorbents recirculating system mars in severe autointoxication a survival case report",
"qualification": "3",
"reportercountry": "SK"
},
"primarysourcecountry": "SK",
"receiptdate": "20210727",
"receivedate": "20210727",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportid": 19617777,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20211014"
}
] |
{
"abstract": "BACKGROUND\nLevofloxacin is routinely used for the prevention of invasive bacterial infections during autologous peripheral blood stem cell transplantation (APBSCT). However, increasing rates of bacterial sepsis were noted at our institution among multiple myeloma (MM) patients undergoing outpatient APBSCT with melphalan-based chemotherapy and levofloxacin prophylaxis. We assessed the impact of a change in antibacterial prophylaxis from oral levofloxacin (Period 1) to sequential oral levofloxacin followed by ertapenem (Period 2).\n\n\nMETHODS\nElectronic medical records were reviewed to identify MM patients who underwent APBSCT in the outpatient clinic between October 2007 and April 2012.\n\n\nRESULTS\nOver a 4.5-year period, 165 outpatient APBSCTs were eligible for the analysis. Fewer overall bacteremias occurred during Period 2 as compared with Period 1 (0.5 cases per 100 person-days vs. 2.4 cases per 100 person-days, P<0.001). In addition, fewer patients were hospitalized for neutropenic fever while receiving sequential prophylaxis (45.7% vs. 75.7% of outpatient APBSCT recipients during Periods 2 and 1, respectively; P<0.001). In Kaplan-Meier analysis, receipt of sequential prophylaxis (Period 2) was significantly associated with overall bacteremia-free survival within 30 days after the APBSCT (P<0.001). No significant differences were seen in the number of patients developing Clostridium difficile infection or ertapenem-resistant gram-negative bacteremia between study periods.\n\n\nCONCLUSIONS\nIn conclusion, sequential prophylaxis may effectively prevent episodes of bacteremia and hospitalizations in neutropenic MM outpatient APBSCT recipients. Prospective studies that involve larger numbers of MM patients with extended periods of follow-up are ultimately required to define the safety and efficacy of sequential antibacterial prophylaxis.",
"affiliations": "Division of Infectious Diseases, Department of Internal Medicine, University of Utah, Salt Lake City, Utah, USA.",
"authors": "Kim|J H|JH|;Goulston|C|C|;Zangari|M|M|;Tricot|G|G|;Boyer|M W|MW|;Hanson|K E|KE|",
"chemical_list": "D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D047090:beta-Lactams; D064704:Levofloxacin; D000077727:Ertapenem",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.12225",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "16(3)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "antibacterial prophylaxis; autologous peripheral blood stem cell transplantation; multiple myeloma",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D016470:Bacteremia; D000077727:Ertapenem; D005260:Female; D006760:Hospitalization; D006801:Humans; D064704:Levofloxacin; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D010045:Outpatients; D036102:Peripheral Blood Stem Cell Transplantation; D012189:Retrospective Studies; D047090:beta-Lactams",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "421-9",
"pmc": null,
"pmid": "24797543",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Impact of a change in antibacterial prophylaxis on bacteremia and hospitalization rates following outpatient autologous peripheral blood stem cell transplantation for multiple myeloma.",
"title_normalized": "impact of a change in antibacterial prophylaxis on bacteremia and hospitalization rates following outpatient autologous peripheral blood stem cell transplantation for multiple myeloma"
} | [
{
"companynumb": "US-JNJFOC-20140613198",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": null,
"drugadministrationroute": "048",
"drugauthorizationnumb": "020634",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ANTIBIOTIC PROPHYLAXIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LEVOFLOXACIN."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KIM JH, GOULSTON C, ZANGARI M, TRICOT G, BOYER M, HANSON K. IMPACT OF A CHANGE IN ANTIBACTERIAL PROPHYLAXIS ON BACTEREMIA AND HOSPITALIZATION RATES FOLLOWING OUTPATIENT AUTOLOGOUS PERIPHERAL BLOOD STEM CELL TRANSPLANTATION FOR MULTIPLE MYELOMA. TRANSPLANT INFECTIOUS DISEASE 2014;16(3):421-429.",
"literaturereference_normalized": "impact of a change in antibacterial prophylaxis on bacteremia and hospitalization rates following outpatient autologous peripheral blood stem cell transplantation for multiple myeloma",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150525",
"receivedate": "20150412",
"receiver": {
"receiverorganization": "FDA",
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},
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},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150821"
}
] |
{
"abstract": "CONCLUSIONS\nA systematic review of eight ulnar fractures in seven patients with bisphosphonate therapy was performed to describe the characteristics and predisposing factors. The proximal ulna is likely to be fractured, especially in the dominant limb of elderly female patients using walking aids after 7 to 15 years of bisphosphonate use.\n\n\nBACKGROUND\nLong-term bisphosphonate use has been suggested to result in decreased bone remodelling and increased risk of atypical fractures. While the relationship between bisphosphonate use and atypical femoral fractures has been extensively studied, there is relative rarity and unawareness of these fractures in the forearm. We conducted a systematic review of existing case reports to better describe the characteristics and predisposing factors for fractures occurring in patients with bisphosphonate therapy.\n\n\nMETHODS\nThe systematic review was conducted according to PRISMA guidelines. All studies with ulnar fractures in individuals with history of bisphosphonate use were included, with data extracted and analysed in totality.\n\n\nRESULTS\nSeven patients with eight fractures are included. Predisposing factors include elderly females requiring walking aids. There is a propensity for the proximal ulna to be fractured, especially in the dominant limb used for ambulation or transfer. All patients were on bisphosphonate for 7 to 15 years. All fractures were atraumatic, non-comminuted, transverse in configuration, had localised periosteal or endosteal thickening at the fracture site and generalised cortical thickening of the diaphysis.\n\n\nCONCLUSIONS\nUlnar fractures in patients with bisphosphonate therapy demonstrate features similar to those described for atypical femoral fractures, suggesting that these fractures could also possibly be due to bisphosphonate use. However, the ulna appears to be able to tolerate longer periods of alendronate use prior to fracture development. The mechanism and characteristics of these fractures additionally suggest the presence of repetitive stress that accumulates over time due to suppressed bone remodelling in patients on bisphosphonates, eventually resulting in these fractures.",
"affiliations": "Yong Loo Lin School of Medicine, National University of Singapore (NUS), 1E Kent Ridge Road, NUHS Tower Block, Level 11, Yong Loo Lin School of Medicine Dean's Office, Singapore, 119228, Singapore, sharontansiheng@gmail.com.",
"authors": "Tan|S H S|SH|;Saseendar|S|S|;Tan|B H M|BH|;Pawaskar|A|A|;Kumar|V P|VP|",
"chemical_list": "D050071:Bone Density Conservation Agents; D004164:Diphosphonates",
"country": "England",
"delete": false,
"doi": "10.1007/s00198-014-2885-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0937-941X",
"issue": "26(2)",
"journal": "Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA",
"keywords": null,
"medline_ta": "Osteoporos Int",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D005260:Female; D015775:Fractures, Stress; D006801:Humans; D010024:Osteoporosis; D012307:Risk Factors; D012656:Self-Help Devices; D013997:Time Factors; D016896:Treatment Outcome; D014458:Ulna Fractures; D016138:Walking",
"nlm_unique_id": "9100105",
"other_id": null,
"pages": "421-9",
"pmc": null,
"pmid": "25227921",
"pubdate": "2015-02",
"publication_types": "D016428:Journal Article; D016454:Review; D000078182:Systematic Review",
"references": "10999794;20493982;23426763;10780852;21991914;14758927;22184174;10986368;24878550;18259679;23712442;19925895;15028823;24120384;22716221;17704999;24833031;23619919;19568963;22850908;19113923;17190893;20130483;19419297;15984412;23999510;14583585;20842676;5040757;21625058;22903294;11783614;22571169;24933347;18448990;22696319;24980895;18769963;11344045;19419303;22066557;22571168",
"title": "Ulnar fractures with bisphosphonate therapy: a systematic review of published case reports.",
"title_normalized": "ulnar fractures with bisphosphonate therapy a systematic review of published case reports"
} | [
{
"companynumb": "SG-CIPLA LTD.-2014SG01453",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "TABLET",
"drugdosagetext": "UNK",
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"medicinalproduct": "ALENDRONATE"
}
],
"patientagegroup": null,
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"patientonsetageunit": null,
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"reaction": [
{
"reactionmeddrapt": "Stress fracture",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TAN S.H.S, SASEENDAR S, TAN B.H.M, PAWASKAR A, KUMAR VP. ULNAR FRACTURES WITH BISPHOSPHONATE THERAPY: A SYSTEMATIC REVIEW OF PUBLISHED CASE REPORTS. OSTEOPOROSIS INTERNATIONAL. 2014",
"literaturereference_normalized": "ulnar fractures with bisphosphonate therapy a systematic review of published case reports",
"qualification": "3",
"reportercountry": "SG"
},
"primarysourcecountry": "SG",
"receiptdate": "20141001",
"receivedate": "20141001",
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150528"
},
{
"companynumb": "JP-CIPLA LTD.-2014JP01452",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALENDRONATE SODIUM"
},
"drugadditional": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "TABLET",
"drugdosagetext": "5 MG, QD",
"drugenddate": null,
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"drugrecurreadministration": "3",
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"drugstructuredosagenumb": "5",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
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"medicinalproduct": "ALENDRONATE"
}
],
"patientagegroup": null,
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"patientonsetageunit": null,
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"reaction": [
{
"reactionmeddrapt": "Atypical fracture",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TAN S.H.S, SASEENDAR S, TAN B.H.M, PAWASKAR A, KUMAR VP. ULNAR FRACTURES WITH BISPHOSPHONATE THERAPY: A SYSTEMATIC REVIEW OF PUBLISHED CASE REPORTS. OSTEOPOROSIS INTERNATIONAL. 2014",
"literaturereference_normalized": "ulnar fractures with bisphosphonate therapy a systematic review of published case reports",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "JP",
"receiptdate": "20141001",
"receivedate": "20141001",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10485710,
"safetyreportversion": 2,
"sender": {
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"sendertype": "2"
},
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"seriousnesscongenitalanomali": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150528"
}
] |
{
"abstract": "Idiopathic orbital inflammation (IOI) is a noninfectious inflammatory disease whose etiology remains unknown. Treatment is focused on reducing inflammation, which becomes challenging in nonresponding cases. We report the case of a 59-year-old woman with refractory IOI that showed a positive response to tocilizumab therapy. The patient was diagnosed with a unilateral sclerosing IOI for 9 years and showed a negative control with previous oral steroids, peribulbar steroid injections, radiotherapy, immunosuppressors, and intravenous rituximab. After the initiation of 8 mg/kg intravenous tocilizumab, a complete reduction of the pain and the orbital inflammation signs was observed and her condition remained stable for the following 6 years under a monthly dose of 4 mg/kg. In recalcitrant IOI cases, tocilizumab could be considered a possible treatment to reduce inflammatory signs and symptoms with positive long-term outcomes as in our case.",
"affiliations": "Department of Ophthalmology, Hospital Universitario Fundación Jiménez Diaz, Madrid, Spain.;Department of Ophthalmology, Hospital Universitario Fundación Jiménez Diaz, Madrid, Spain.",
"authors": "Artaechevarria Artieda|June|J|;Tapias Elias|Ignacio|I|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000508237",
"fulltext": "\n==== Front\nCase Rep Ophthalmol\nCase Rep Ophthalmol\nCOP\nCase Reports in Ophthalmology\n1663-2699 S. 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.com \n\n10.1159/000508237\ncop-0011-0299\nCase Report\nTocilizumab in a Case of Refractory Idiopathic Orbital Inflammation: 6-Year Follow-Up Outcomes\nArtaechevarria Artieda June * Tapias Elias Ignacio Department of Ophthalmology, Hospital Universitario Fundación Jiménez Diaz, Madrid, Spain\n*June ArtaechevarriaArtieda, Hospital Universitario Fundación Jiménez Diaz, Avenida Reyes Católicos 2, ES–28040 Madrid (Spain), junearta@gmail.com\nMay-Aug 2020 \n6 7 2020 \n6 7 2020 \n11 2 299 305\n17 12 2019 26 4 2020 2020 Copyright © 2020 by S. Karger AG, Basel2020This 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.Idiopathic orbital inflammation (IOI) is a noninfectious inflammatory disease whose etiology remains unknown. Treatment is focused on reducing inflammation, which becomes challenging in nonresponding cases. We report the case of a 59-year-old woman with refractory IOI that showed a positive response to tocilizumab therapy. The patient was diagnosed with a unilateral sclerosing IOI for 9 years and showed a negative control with previous oral steroids, peribulbar steroid injections, radiotherapy, immunosuppressors, and intravenous rituximab. After the initiation of 8 mg/kg intravenous tocilizumab, a complete reduction of the pain and the orbital inflammation signs was observed and her condition remained stable for the following 6 years under a monthly dose of 4 mg/kg. In recalcitrant IOI cases, tocilizumab could be considered a possible treatment to reduce inflammatory signs and symptoms with positive long-term outcomes as in our case.\n\nKeywords\nIdiopathic orbital inflammationTocilizumabOrbitInflammationEye\n==== Body\nIntroduction\nIdiopathic orbital inflammation (IOI) or orbital pseudotumor is an orbital noninfectious inflammatory disease caused by a polymorphic lymphoid infiltration with varying degrees of fibrosis and without any local or systemic identifiable cause [1].\n\nTreatment is based on reducing the underlying inflammation. Systemic corticosteroids followed by descendent oral steroids are the first-line therapy and a positive response is usually observed [1, 2]. However, many cases of nonresponders and recurrences are to be considered. In such cases, the use of radiotherapy, immunosuppressive agents (methotrexate, azathioprine, mycophenolate mofetil, cyclosporine A, cyclophosphamide), and biologic antibodies (rituximab, daclizumab, infliximab) has been reported [3]. Unfortunately, there are no other alternatives described when all these therapies fail to control the disease.\n\nTocilizumab is a humanized monoclonal antibody against interleukin-6 (IL-6) receptor that has been widely used in systemic and ocular inflammatory diseases with positive outcomes [4]. Despite showing good response in other inflammatory diseases, there is no evidence in the literature of positive responses to tocilizumab in cases of IOI [5]. To date, only one article mentions a negative response and persistence of the inflammation after 9 months under tocilizumab therapy, but no clinical nor radiological evidence is provided [6].\n\nThe aim of this case is to report the clinical and radiologic outcomes after 6 years of follow-up in a woman affected with severe IOI who showed no response to multiple therapies and was successfully treated with intravenous tocilizumab.\n\nCase Report\nA 59-year-old woman with a previous diagnosis 9 years before of IOI in her right orbit consulted our hospital in 2014 for disabling pain that affected her daily life activities. During the last 6 years, she had had several clinical manifestations including dacryoadenitis, episcleritis, myositis of the external rectus muscle, anterior uveitis, and perineuritis in her right eye (RE). Secondary to the compressive neuropathy, visual acuity was no light perception in her RE for the last years. A biopsy of the right tear gland and orbital fat tissue revealed scarce interstitial lymphoplasmacytic cells in the fat tissue and adjacent to the gland lobes, as well as some dense fibrotic tissue. A complete blood test was performed (including a complete blood count and biochemical profile, C-reactive protein, erythrocyte sedimentation rate, levels of IgG4, antineutrophil cytoplasmic antibodies, complement, angiotensin converting enzyme, and serologic profile) to rule out the presence of an underlying systemic inflammatory disease such as IgG4 disease, vasculitis, sarcoidosis, and other infectious diseases. At that moment she was under 375 mg/m2 of intravenous rituximab perfusions every week. She had been treated several times with corticosteroid boluses (500 mg of methylprednisolone daily for 3 days) and with oral and topical corticosteroids in descending protocols, but the responses were always short term. Due to the high recurrences, she had also received peribulbar injections of triamcinolone (1 mL Trigon© 40 mL/mg), 10 sessions of local radiotherapy, subcutaneous injections of methotrexate (10-15-20 mg per week), and intravenous perfusions of rituximab (3 cycles of Mabthera© 375 mg/m2 of body surface, once a week for 4 weeks). However, all these treatments failed to control the inflammatory activity in the long term. Secondary to the long steroid treatment, hypertension arose and was well controlled with oral antihypertensives.\n\nAt the ophthalmological examination, the patient presented a diffuse right upper-lid edema with a thickening of the tear gland and a mild ptosis (Fig. 1). Visual acuity was no light perception in her RE and 1.0 in her left eye (LE). A relative afferent pupillary defect was observed in her RE. A binocular eye movement test, which was performed by asking the patient to follow the explorer's finger and employing a scoring system from 0 to −4 (from normal to a lack of muscle function, in 25% increments per grade), revealed a restriction of −3 in the RE in all positions, whereas the LE was preserved (grade 0). Proptosis of the RE was measured by the Hertel exophthalmometer (Oculus, Wetzlar, Germany), resulting in 22 mm in the RE and 20 mm in the LE (previous measurement a year before was 21 mm and 20 mm, respectively). The slit-lamp examination showed a mild hyperemia and chemosis in her RE. Intraocular pressure was within normal limits in both eyes. The fundoscopy of the RE showed a pale optic nerve secondary to previous compressive neuropathy with no other fundus alterations. Anterior and posterior pole examination was normal in the LE. Findings in the orbital MRI were compatible with sclerosant IOI and described an overall moderate radiologic worsening of the right orbit compared to the previous one a year ago. A 1-mm increase of the exophthalmos of the RE was measured and the intra- and extraconal orbital fat fibrosis presented a more intense inflammatory compound (Fig. 2a–c). Due to the clinical, histological, and radiological findings, sclerosing type of IOI was diagnosed [7].\n\nWith this situation, together with the Rheumatology service, it was decided to initiate oral steroids to stop the acute inflammation and the addition of a new immunosuppressor. Treatment consisted of 60 mg of oral prednisone daily in a weekly descendent protocol and 8 mg/kg of intravenous tocilizumab (Roactembra©) every month. High doses of oral NSAIDs and analgesia were necessary to control the pain. No adverse events of this drugs were noticed. During the next 6 months, an important progressive clinical and symptomatic improvement was objectivized. The eyelid edema and the hyperemia were reduced completely and extraocular movements of the RE improved remarkably to −1 in the grading score. Proptosis was slightly reduced in the RE, with an exophthalmos of 21 mm in the RE and 20 mm in the LE, measured by the Hertel exophthalmometer. Orbital MRI showed a diffuse reduction of the intraorbital inflammation (Fig. 2d–f). Oral analgesia and NSAIDs were no longer needed as the pain ceased. Oral steroids were stopped after 6 months, and tocilizumab was continued in a maintenance dose of intravenous perfusions of 4–6 mg/kg every 6 weeks up to the present time. The patient is currently asymptomatic and only one relapse was observed when treatment was stopped for a dental implant 2 years ago. No side effects of tocilizumab have been identified so far. Routine blood tests are performed every 3–6 months in order to detect any disorder.\n\nDiscussion\nTo our knowledge, this is the first case in the literature to report a positive response to tocilizumab in the treatment of IOI and to describe the results of a 6-year follow-up.\n\nTocilizumab is a recombinant humanized monoclonal IgG1 antibody that binds to the soluble and membrane-bound IL-6 receptor. By blocking the IL-6 signal, it has shown efficacy in immuno-mediated diseases such as rheumatoid arthritis, juvenile idiopathic arthritis, Crohn's disease, Castleman disease, and more recently, giant cell arteritis [8]. With regard to ocular diseases, the efficacy of this drug has been widely studied in Grave's orbitopathy [9, 10]. Moreover, a recent review by Ruiz-Medrano et al. [11] describes the good response to tocilizumab in other ocular inflammatory diseases such as anterior uveitis associated with juvenile idiopathic arthritis, uveitis in association to Castleman disease, uveitis-related refractory macular edema, Birdshot chorioretinopathy, Behçet disease, and in retinal vasoproliferative tumors. Despite all these diseases showing a positive response to the treatment, there is no evidence of a favorable response in IOI. Only one article, published by Silpa-Archa et al. [6], reports the outcomes of tocilizumab in 10 cases of uveitis, 6 cases of scleritis, and 1 case of orbital pseudotumor refractory to corticosteroids and immunosuppressants. In that study, poor clinical and radiological response is mentioned in the case of the orbital pseudotumor, but specific clinical, radiologic, and response data are absent. Therefore, we consider that our case reports the first positive case with specific and detailed data on the effects of tocilizumab in a case of refractory IOI.\n\nThe mechanism of tocilizumab in IOI is still not well defined. Recent studies have demonstrated an elevation of cytokines such as IL-2, −8, −10, −12, gamma interferon, and tumor necrosis factor alpha in IOI biopsy specimens and describe a T-helper 1 leucocyte disorder in the pathogenesis of IOI [12], but the involvement of IL-6 is yet to be defined. Another study documented the strong expression of CD20 and CD25 in IOI specimens, suggesting a possible benefit of rituximab (anti-CD20 monoclonal antibody) and daclizumab (anti-CD25 monoclonal antibody) in this disease [13]. However, our patient's condition was not controlled enough with infliximab, and daclizumab was not available. The involvement of IL-6 in inflammatory cascades and the good response of tocilizumab in other inflammatory diseases previously mentioned could explain the positive response in cases of IOI, where orbital inflammation is the landmark.\n\nTocilizumab can be used alone or in association with methotrexate [14]. In our case, monotherapy was preferred due to the poor response shown previously to methotrexate. Side effects of this biologic agent have been well described in the literature. The most common adverse events are upper respiratory tract infections, followed by headache, skin and soft tissue infections, hepatic enzymes elevation, hypercholesterolemia, and neutropenia [15]. Hypersensitivity reactions and anaphylaxis are rare but severe side effects that have been related to the development of anti-tocilizumab antibodies [14]. Thus, routine blood-tests are necessary during the follow-up for the early diagnosis and treatment of these possible adverse events.\n\nIn our experience, tocilizumab presented positive long-term clinical and radiological outcomes in a case of sclerosant IOI that was refractory to corticosteroids and other immunosuppressive treatments such as methotrexate and rituximab, and therefore could be considered a therapeutic option in nonresponding patients. Follow-up should be carried out between Ophthalmology and Rheumatology services and should include complete ophthalmological examinations as well as routine blood analysis in order to detect any early alteration. However, results from an isolated case such as this should be taken cautiously. Further research and the performance of clinical trials in this area would provide more information about the efficacy and safety profile of tocilizumab in IOI.\n\nStatement of Ethics\nThe patient gave her written informed consent to publish the case (including publication of images).\n\nConflict of Interest Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThe authors have no funding sources to disclose.\n\nAuthor Contributions\nJune ArtaechevarriaArtieda made substantial contribution to the design of the work, the acquisition and interpretation of data, and drafting the work. Ignacio TapiasElias made substantial contribution to the design of the work, the acquisition and interpretation of data, and revising the work critically for important intellectual content. Both authors agree to be accountable for all aspects of the work.\n\nAcknowledgments\nWe thank Dr. Olga Sánchez-Pernaute, PhD, for substantial contribution in the management of the therapy with tocilizumab and supervision of the clinical evolution of the patient, and Dr. Jose Fortes, PhD, for substantial contribution in the analysis and description of the histopathological specimens.\n\nFig. 1 a Acute stage of IOI presenting right upper lid edema and ptosis. Temporary mild hyperemia is observed. b Photograph 3 years after tocilizumab therapy. Eyelid edema is absent and the interpalpebral aperture is similar in both eyes.\n\nFig. 2 a–c Multimodal images captured during the acute stage before treatment with tocilizumab in 2014. a Orbital T1-weighted axial MRI showing bilateral asymmetric exophthalmos with progression in the right eye in respect to the previous image (1 mm). Diffuse alteration of intra- and extraconal orbital fat pushing the posterior part of the globe can be observed. b T2-weighted axial MRI presenting hypointense signal of the orbital fat, translating a major fibrous compound compatible with sclerosant subtype of IOI. c T1-weighted contrast-enhanced MRI. High-contrast caption is objectivized. d–f Multimodal images taken 1 year after initiation of tocilizumab in 2015. d T1-weighted axial MRI, showing mild bilateral symmetric exophthalmos, with important reduction of the proptosis in the right eye. Intra- and extraconal fat presenting notorious improvement. e T2-weighted axial MRI presenting hypointense signal of the orbital fat due to the high fibrotic tissue but with remarkable improvement in comparison to the previous image. f T1-weighted contrast-enhanced MRI in which intravenous contrast capture is clearly reduced.\n==== Refs\nReferences\n1 Yuen SJ Rubin PA Idiopathic orbital inflammation: distribution, clinical features, and treatment outcome Arch Ophthalmol 2003 4 121 (4) 491 9 12695246 \n2 Swamy BN McCluskey P Nemet A Crouch R Martin P Benger R Idiopathic orbital inflammatory syndrome: clinical features and treatment outcomes Br J Ophthalmol 2007 12 91 (12) 1667 70 17620331 \n3 Yeşiltaş YS Gündüz AK Idiopathic orbital inflammation: review of literature and new advances Middle East Afr J Ophthalmol 2018 Apr-Jun 25 (2) 71 80 30122852 \n4 Nishimoto N Kishimoto T Humanized antihuman IL-6 receptor antibody, tocilizumab Handb Exp Pharmacol 2008 181 151 60 \n5 American academy of Ophthalmology Nonspecific Orbital Inflammation (Idiopathic orbital inflammation, Orbital inflammatory syndrome, Orbital pseudotumor) [cited 2019 June 27>] Available from: https://eyewiki.aao.org/Nonspecific_Orbital_Inflammation_(Idiopathic_orbital_inflammation,_Orbital_inflammatory_syndrome,_Orbital_pseudotumor) \n6 Silpa-Archa S Oray M Preble JM Foster CS Outcome of tocilizumab treatment in refractory ocular inflammatory diseases Acta Ophthalmol 2016 9 94 (6) e400 6 27010181 \n7 Zakir R Manners RM Ellison D Barker S Crick M Idiopathic sclerosing inflammation of the orbit: a new finding of calcification Br J Ophthalmol 2000 11 84 (11) 1322 4 \n8 Rubbert-Roth A Furst DE Nebesky JM Jin A Berber E A review of recent advances using Tocilizumab in the treatment of Rheumatic Disease Rheumatol Ther 2018 6 5 (1) 21 42 29502236 \n9 Pérez-Moreiras JV Gómez-Reino JJ Maneiro JR Pérez-Pampin E Romo López A Rodríguez Alvarez FM Tocilizumab in Graves Orbitopathy Study Group Efficacy of Tocilizumab in Patients With Moderate-to-Severe Corticosteroid-Resistant Graves Orbitopathy: A Randomized Clinical Trial Am J Ophthalmol 2018 11 195 181 90 30081019 \n10 Pérez-Moreiras JV Alvarez-López A Gómez EC Treatment of active corticosteroid-resistant graves' orbitopathy Ophthal Plast Reconstr Surg 2014 Mar-Apr 30 (2) 162 7 \n11 Ruiz-Medrano J Díaz-Valle D Cuiña R Gegúndez JA Chhablani J Majumder PD The role of tocilizumab in the treatment of inflammatory diseases of the eye and orbit: A useful alternative J Fr Ophtalmol 2018 10 41 (8) 759 66 30217605 \n12 Wladis EJ Iglesias BV Gosselin EJ Characterization of the molecular biologic milieu of idiopathic orbital inflammation Ophthal Plast Reconstr Surg 2011 Jul-Aug 27 (4) 251 4 \n13 Ho VH Chevez-Barrios P Jorgensen JL Silkiss RZ Esmaeli B Receptor expression in orbital inflammatory syndromes and implications for targeted therapy Tissue Antigens 2007 8 70 (2) 105 9 17610415 \n14 European Medicines Agency Assessment report for RoActembra. EMA/742879/2018 \n15 H. Venkiteshwaran A. Tocilizumab MAbs 2009 1 (5) 432 8 20065633\n\n",
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"abstract": "Eptifibatide is an inhibitor of the platelet glycoprotein (GP) IIb/IIIa receptor that is commonly used in patients undergoing percutaneous coronary intervention (PCI).\nWe describe a case of a 62-year-old female patient admitted with acute ST-elevation myocardial infarction (STEMI) treated by primary coronary intervention (primary PCI) with a drug-eluting stent placement. She developed profound thrombocytopenia within 8 hours of first administration of eptifibatide and subsequent acute stent thrombosis next day. Other causes of thrombocytopenia were excluded and intravascular ultrasound (IVUS) showed good stent expansion and opposition to the coronary wall. Platelet count gradually returned to normal after discontinuation of eptifibatide.\nAlthough Eptifibatide has been associated with the development of thrombocytopenia, to the best of our knowledge, this is the first case report in the medical literature that associates acute stent thrombosis and eptifibatide-induced thrombocytopenia.",
"affiliations": "Pharmacy Department, Heart Hospital, Hamad Medical Corporation, Doha, Qatar.;Pharmacy Department, Heart Hospital, Hamad Medical Corporation, Doha, Qatar.;Cardiology and Cardiovascular Surgery Department, Heart Hospital, Hamad Medical Corporation, Doha, Qatar.",
"authors": "Aljundi|Amer|A|;Rahhal|Alaa|A|https://orcid.org/0000-0002-2631-0184;Dabdoob|Wafer|W|",
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"fulltext": "\n==== Front\nCase Rep Cardiol\nCase Rep Cardiol\nCRIC\nCase Reports in Cardiology\n2090-6404 2090-6412 Hindawi \n\n10.1155/2020/8386709\nCase Report\nAcute Stent Thrombosis Associated with Eptifibatide-Induced Profound Thrombocytopenia\nAljundi Amer \n1\n https://orcid.org/0000-0002-2631-0184Rahhal Alaa arahhal1@hamad.qa\n1\n Dabdoob Wafer \n2\n \n1Pharmacy Department, Heart Hospital, Hamad Medical Corporation, Doha, Qatar\n\n2Cardiology and Cardiovascular Surgery Department, Heart Hospital, Hamad Medical Corporation, Doha, Qatar\nAcademic Editor: Domingo A. Pascual Figal\n\n\n2020 \n9 6 2020 \n2020 838670915 1 2020 23 5 2020 2 6 2020 Copyright © 2020 Amer Aljundi et al.2020This 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.Background\n Eptifibatide is an inhibitor of the platelet glycoprotein (GP) IIb/IIIa receptor that is commonly used in patients undergoing percutaneous coronary intervention (PCI). \n\nCase\n We describe a case of a 62-year-old female patient admitted with acute ST-elevation myocardial infarction (STEMI) treated by primary coronary intervention (primary PCI) with a drug-eluting stent placement. She developed profound thrombocytopenia within 8 hours of first administration of eptifibatide and subsequent acute stent thrombosis next day. Other causes of thrombocytopenia were excluded and intravascular ultrasound (IVUS) showed good stent expansion and opposition to the coronary wall. Platelet count gradually returned to normal after discontinuation of eptifibatide. \n\nConclusion\n Although Eptifibatide has been associated with the development of thrombocytopenia, to the best of our knowledge, this is the first case report in the medical literature that associates acute stent thrombosis and eptifibatide-induced thrombocytopenia.\n==== Body\n1. Introduction\nThere are several agents that are used in the treatment of acute coronary syndromes (ACS) that were reported to cause drug-induced thrombocytopenia [1, 2]. Eptifibatide is a synthetic cyclic heptapeptide and a selective inhibitor of the platelet glycoprotein (GP) IIb/IIIa receptor that blocks the final common pathway of platelet aggregation. It is commonly used in patients with acute coronary syndromes and in those undergoing PCI to reduce the risk of acute cardiac ischemic events [3–6].\n\nRecent literature has suggested an association between eptifibatide exposure and the development of thrombocytopenia. However, to the best of our knowledge, this is the first case report in the medical literature that associates acute stent thrombosis and eptifibatide-induced thrombocytopenia.\n\n2. Case Presentation\nA 62-year-old female with a history of diabetes mellitus and hypertension presented to the emergency department with a two-hour history of retrosternal chest pain radiating to both shoulders and associated with profuse sweating and vomiting. She denied any previous history of blood dyscrasia or thrombocytopenia. She had no history of drug abuse and denied any history of a previous hospitalization where she may have received heparin or eptifibatide. She does not have any known allergies. Her past medication history included the use of amlodipine 5 mg daily, atorvastatin 20 mg daily, metformin 500 mg daily, aspirin 100 mg daily, carvedilol 25 mg twice daily, and lisinopril 20 mg/hydrochlorothiazide 12.5 mg daily.\n\nVital signs at presentation included a temperature of 36.8°C, regular pulse of 98 bpm, brachial blood pressure of 140/70 mmHg, respirations of 20 per minute, and oxygen saturation of 98% on room air. The physical exam demonstrated an alert and oriented patient in moderate distress from chest pain. There were no signs of peripheral edema or cyanosis. The patient had bilateral basilar crackles at the bases. The heart was regular, with no murmurs, rubs, and gallops. The abdomen was soft with no organomegaly.\n\nHer electrocardiogram (ECG) showed ST-segment elevation in lead II, III, aVF, Q wave in III, and reciprocal ST-segment depression in I and aVL (Figure 1). Transthoracic echocardiography showed inferior left ventricular (LV) wall motion akinesia with normal LV systolic function (as demonstrated by an LV ejection fraction of 55-60%) and mild concentric LV hypertrophy. Other findings included a mild mitral regurgitation with normal other valves and chambers. At baseline, the patient had a white blood cell count of 12.000/mm3, a hemoglobin level of 13.9 g/dL, and a platelet count of 378,000/mm3. Cardiac markers were creatine kinase myoglobin (CK MB) level of 87.40 ng/ml and troponin T level of 4040 ng/mL. The values of prothrombin time (PT) and activated partial thromboplastin time (aPTT) were within normal limits. Similarly, liver function tests and kidney function tests were within normal limits. Due to the patient's ischemic symptoms and ECG changes consistent with an acute inferior STEMI, she was taken for urgent cardiac catheterization. Coronary angiography revealed a dominant RCA with a 99% stenosis with a thrombolysis in myocardial infarction (TIMI) grade 0 flow and a 40% stenosis of the left circumflex artery (LCx). Angiography also showed normal left main coronary artery (LMCA) and left anterior descending (LAD) coronary artery.\n\nFollowing our local protocol, before catheterization, the patient received aspirin 300 mg; clopidogrel 600 mg; one dose of intravenous unfractionated heparin 7000 units; and eptifibatide 180 μg/kg as a bolus dose then 2-μg/kg/min infusion. A 3.0 × 24 mm XIENCE™ Everolimus Eluting Coronary stent was deployed in the distal RCA with a very satisfying angiographic result (TIMI grade 3 flow) with no complications. Once flow was restored in the RCA, the patient became pain-free with the resolution of her ST-segment elevation (Figure 2). She was then transferred in a stable condition to the coronary intensive care unit (CICU). Postpercutaneous coronary intervention (PCI) medications included dual antiplatelet therapy (DAPT) with aspirin 100 mg daily and clopidogrel 75 mg daily, ramipril 5 mg daily, metoprolol tartrate 25 mg twice daily, rosuvastatin 20 mg daily, and the eptifibatide intravenous infusion was to be continued for 18 hours.\n\nApproximately eight hours post-PCI and eptifibatide initiation, the patient developed a profound thrombocytopenia, with her platelet count dropping by over 90% from baseline to 17,000/mm3. The rest of her complete blood count at this time included hemoglobin 13.2 g/dL, hematocrit 39.6%, and white blood cell count 18.8 × 109/L. The platelet count trend through hospitalization is summarized in Figure 3.\n\nAfter the acute platelet drop, eptifibatide was discontinued. Intravenous lepirudin 14.5 mg/h was initiated due to a high clinical suspicion for heparin-induced thrombocytopenia (HIT).\n\nOn the next day (approximately 18 hours after primary PCI), our patient developed chest pain with nausea and vomiting. Her electrocardiogram (ECG) showed diffuse STEMI of the II, III, aVF, and reciprocal ST-segment depression in I and aVL (Figure 4). Urgent angiography revealed thrombosed mid and distal RCA with intravascular ultrasound (IVUS) study conforming thrombus formation (Figures 5 and 6). Export catheter™ was utilized to extract clot fragments with satisfying results (TIMI grade 2 flow). The subsequent IVUS study confirmed excellent stent expansion and apposition to the vessel indicating the optimal stent deployment (Figure 7).\n\n3. Discussion\nEptifibatide is a potent adjunct medication that significantly improves outcomes in patients undergoing PCI among those presenting with ACS [3–6]. Eptifibatide works by preventing the binding of fibrinogen, von Willebrand factor, and other ligands to the GP IIb/IIIa receptor, thereby reversibly inhibiting platelet aggregation and subsequent thrombosis [1, 2]. Drug-induced acute profound thrombocytopenia can be defined as a decrease in platelet count to below 20,000/mm3 within 24 hours of exposure to the drug, which was the case in our patient having reached a low as 17,000/mm3 [7].\n\nOur patient was exposed to several agents other than eptifibatide that are well known to be associated independently with profound thrombocytopenia, including heparin and clopidogrel [8]. These agents are usually coadministered before PCI which can make it difficult to discern causation in the setting of drug-induced thrombocytopenia.\n\nTreatment with GP IIb/IIIa antagonists has been reported to be associated with pseudothrombocytopenia [9]. Pseudothrombocytopenia is an artificial laboratory process resulting from the adherence of platelets to leukocytes. This process typically occurs when blood samples are collected in EDTA tubes. Pseudothrombocytopenia in our scenario was ruled out by confirmation of thrombocytopenia in an EDTA-free tube and by direct review of the peripheral blood smear which showed no signs of platelet clumping. Moreover, there was no evidence of microangiopathic hemolytic anemia consistent with thrombotic thrombocytopenic purpura–hemolytic uremic syndrome (TTP-HUS) due to the administration of clopidogrel [10]. Additionally, other than thrombocytopenia, our patient did not manifest any other hallmarks of the disease which include fever, neurologic manifestations, and renal insufficiency. Moreover, our patient received only one loading dose of clopidogrel 600 mg six hours before the drop in her platelet count making it unlikely that clopidogrel was the culprit for the observed thrombocytopenia.\n\nUse of the Naranjo scale to assess the probability of drug adverse events also indicated a probable relationship between the administration of eptifibatide and the development of profound thrombocytopenia (score of 5), while the relation was possible with heparin and clopidogrel (score 1) [11].\n\nHeparin is well known to be associated with thrombocytopenia; however, the timing of thrombocytopenia in this patient was consistent with eptifibatide-induced thrombocytopenia as it occurred within less than 24 hours of stating eptifibatide. Heparin-induced thrombocytopenia (HIT) type I usually develops early within the first two days of starting heparin and is usually mild and transient (rarely <100,000 platelet/mm3). Heparin-induced thrombocytopenia type II, on the other hand, is an immune-mediated reaction with a typical onset of 5-10 days after the administration of heparin without previous heparin exposure and can be as early as hours due to circulating heparin/platelet factor 4 from a previous exposure [12]. Our patient had a severe form of thrombocytopenia ruling out HIT type I, while the time frame for developing thrombocytopenia was not consistent with HIT type II as our patient had no previous exposure to heparin. Additionally, ELISA immunoassay was performed and was negative for heparin-platelet factor 4 antibodies. The patient's platelet count started to improve after discontinuing eptifibatide. These factors suggested that eptifibatide was the most likely cause of thrombocytopenia associated with acute stent thrombosis.\n\nThe mechanisms by which GP IIb-IIIa inhibitors cause thrombocytopenia are poorly understood. One possible mechanism is the formation of antibodies to a group of epitopes, called ligand-induced binding sites (LIBSs), which are normally hidden on the surface of the platelet. Binding of the GP IIb-IIIa inhibitor to the receptor induces a conformational change exposing LIBSs in the platelet. This permits the binding of the anti-LIBS antibodies and can eventually lead to subsequent clearance of platelets by the reticuloendothelial system [13].\n\nA proposed mechanism for thrombosis, however, is that LIBS antibodies can activate platelets by stabilizing the open, or active, conformation of the GP IIb/IIIa receptor, enabling the binding of multivalent ligands such as fibrinogen. Antibody-mediated fibrinogen binding can lead to bridging of adjacent platelets and platelet activation responses with subsequent generation of cell-surface procoagulant activity [14].\n\n4. Conclusion\nEptifibatide is known to cause severe thrombocytopenia; however, this the first report of this being associated with subsequent acute stent thrombosis. Despite being uncommon, it is a clinically important complication of eptifibatide. This report highlights the importance of close monitoring platelet counts, before and after starting eptifibatide. A high index of suspicion of acute stent thrombosis should be raised if a patient develops new onset chest pain following successful PCI in the setting of eptifibatide-induced thrombocytopenia.\n\nData Availability\nThe data used to support the findings of this study are included within the article.\n\nConsent\nA written informed consent for publishing patient's information and images were obtained from the patient.\n\nConflicts of Interest\nThe authors declare that there is no conflict of interest.\n\nFigure 1 Electrocardiogram (ECG) showing ST-segment elevation in lead II, III, aVF, Q wave in III, and reciprocal ST-segment depression in I and aVL at presentation.\n\nFigure 2 ECG showing resolution of ST-segment elevation after PCI to RCA.\n\nFigure 3 Platelet count during hospital stay.\n\nFigure 4 ECG showing diffuse ST elevation in lead II, III, aVF, and reciprocal ST-segment depression in I and aVL.\n\nFigure 5 IVUS showing thrombus in mid RCA at 5 to 11 o'clock.\n\nFigure 6 IVUS showing thrombus at 3 to 8 o'clock within the stent.\n\nFigure 7 IVUS showing well-expanded and opposed stent.\n==== Refs\n1 Rizvi M. A. Kojouri K. George J. N. Drug-induced thrombocytopenia: an updated systematic review Annals of Internal Medicine 2001 134 4 10.7326/0003-4819-134-4-200102200-00030 2-s2.0-0035916289 11182857 \n2 Aster R. H. Drug-induced immune thrombocytopenia: an overview of pathogenesis Seminars in Hematology 1999 36 1 Suppl 1 2 6 \n3 Tcheng J. E. Impact of eptifibatide on early ischemic events in acute ischemic coronary syndromes: a review of the IMPACT II trial. Integrilin to Minimize Platelet Aggregation and Coronary Thrombosis The American Journal of Cardiology 1997 80 4 21B 28B 10.1016/S0002-9149(97)00573-0 2-s2.0-0031577353 9205014 \n4 The PURSUIT Trial Investigators Inhibition of platelet glycoprotein IIb/IIIa with Eptifibatide in patients with acute coronary syndromes New England Journal of Medicine 1998 339 7 436 443 10.1056/NEJM199808133390704 2-s2.0-0008926519 9705684 \n5 The ESPRIT investigators Novel dosing regimen of eptifibatide in planned coronary stent implantation (ESPRIT): a randomised, placebo-controlled trial The Lancet 2000 356 9247 2037 2044 10.1016/S0140-6736(00)03400-0 2-s2.0-0034676781 \n6 ADVANCE MI Investigators Facilitated percutaneous coronary intervention for acute ST-segment elevation myocardial infarction: Results from the prematurely terminated ADdressing the Value of facilitated ANgioplasty after Combination therapy or Eptifibatide monotherapy in acute Myocardial Infarction (ADVANCE MI) trial American Heart Journal 2005 150 1 116 122 10.1016/j.ahj.2005.04.005 2-s2.0-23244449248 16084157 \n7 Berkowitz S. D. Harrington R. A. Rund M. M. Tcheng J. E. Acute Profound Thrombocytopenia After c7E3 Fab (Abciximab) Therapy Circulation 1997 95 4 809 813 10.1161/01.CIR.95.4.809 2-s2.0-0031055038 9054735 \n8 Fahdi I. E. Saucedo J. F. Hennebry T. Ghani M. Sadanandan S. Garza-Arreola L. Incidence and time course of thrombocytopenia with abciximab and eptifibatide in patients undergoing percutaneous coronary intervention The American Journal of Cardiology 2004 93 4 453 455 10.1016/j.amjcard.2003.10.041 2-s2.0-1242270514 14969621 \n9 Sane D. C. Damaraju L. V. Topol E. J. Occurrence and clinical significance of pseudothrombocytopenia during abciximab therapy Journal of the American College of Cardiology 2000 36 1 75 83 10.1016/S0735-1097(00)00688-4 2-s2.0-0033925843 10898416 \n10 Bennett C. L. Kim B. Zakarija A. Two mechanistic pathways for thienopyridine- associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP Research Group and the RADAR Project Journal of the American College of Cardiology 2007 50 12 1138 1143 10.1016/j.jacc.2007.04.093 2-s2.0-34548542028 17868804 \n11 Naranjo C. A. Busto U. Sellers E. M. A method for estimating the probability of adverse drug reactions Clinical Pharmacology and Therapeutics 1981 30 2 239 245 10.1038/clpt.1981.154 2-s2.0-0019799332 7249508 \n12 Warkentin T. E. Greinacher A. Koster A. Lincoff A. M. Treatment and Prevention of Heparin-Induced Thrombocytopenia Chest 2008 133 6 340S 380S 10.1378/chest.08-0677 2-s2.0-45949103154 18574270 \n13 Madan M. Berkowitz S. D. Understanding thrombocytopenia and antigenicity with glycoprotein IIb-IIIa inhibitors American Heart Journal 1999 138 4 S317 S326 10.1053/hj.1999.v138.a100465 2-s2.0-0032886666 \n14 Gao C. Boylan B. Bougie D. Eptifibatide-induced thrombocytopenia and thrombosis in humans require FcgammaRIIa and the integrin beta3 cytoplasmic domain The Journal of Clinical Investigation 2009 119 3 504 511 10.1172/JCI36745 2-s2.0-65649101237 19197137\n\n",
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"title": "Acute Stent Thrombosis Associated with Eptifibatide-Induced Profound Thrombocytopenia.",
"title_normalized": "acute stent thrombosis associated with eptifibatide induced profound thrombocytopenia"
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{
"abstract": "We report a case of neuroleptic malignant syndrome possibly caused by the combined administration of quetiapine and clarithromycin in a 75-year-old male patient. He was receiving quetiapine regularly. Two days before his admission to the hospital, he had been feverish and started receiving clarithromycin without consulting a doctor. Clarithromycin administration was interrupted 3 days after his admission because it was ineffective and because his clinical state was deteriorating. The patient presented altered level of consciousness and excessive muscular rigidity on his limbs, while he remained feverish (38.7 °C). Laboratory abnormalities included elevated serum creatine phosphokinase level (5.387 U/L), leukocytosis, and low serum iron. The patient was diagnosed with neuroleptic malignant syndrome, and quetiapine was immediately discontinued. After the following days, his muscle rigidity and mental status ameliorated, his fever withdrew, and his laboratory findings improved. The various features of the case are discussed in view of the fact that the concomitant administration of cytochrome 3A4 inhibitors, such as clarithromycin, is suggested to cause an increase of plasma concentrations of quetiapine. Thus, physicians should have a high index of suspicion of the interactions of commonly administered medications.",
"affiliations": "*Second Department of Psychiatry, and †Fourth Department of Internal Medicine, University of Athens Medical School, Attikon University General Hospital, Athens, Greece.",
"authors": "Christodoulou|Christos|C|;Margaritis|Dimitris|D|;Makris|Gerasimos|G|;Kavatha|Dimitra|D|;Efstathiou|Vasiliki|V|;Papageorgiou|Charalabos|C|;Douzenis|Athanasios|A|",
"chemical_list": "D014150:Antipsychotic Agents; D003987:Dibenzothiazepines; D000069348:Quetiapine Fumarate; D017291:Clarithromycin",
"country": "United States",
"delete": false,
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"issue": "38(1)",
"journal": "Clinical neuropharmacology",
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"medline_ta": "Clin Neuropharmacol",
"mesh_terms": "D000368:Aged; D014150:Antipsychotic Agents; D017291:Clarithromycin; D003131:Combined Modality Therapy; D003987:Dibenzothiazepines; D006801:Humans; D008297:Male; D009459:Neuroleptic Malignant Syndrome; D000069348:Quetiapine Fumarate",
"nlm_unique_id": "7607910",
"other_id": null,
"pages": "36-7",
"pmc": null,
"pmid": "25580921",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Quetiapine and clarithromycin-induced neuroleptic malignant syndrome.",
"title_normalized": "quetiapine and clarithromycin induced neuroleptic malignant syndrome"
} | [
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{
"abstract": "We present a case of a patient who ingested excessive amounts of the antidepressant Venlafaxine, a Selective Serotonin-Norepinephrine Reuptake Inhibitor (SNRI). She developed cardiogenic shock with clinical and echocardiographic signs of takotsubo syndrome, TTS; a life-threatening condition characterized by a transient regional cardiac dysfunction not solely caused by coronary artery occlusion. The pathogenesis remains unclear but catecholamines play a key role. Venlafaxine increases plasma catecholamine levels and with high probability it was judged to be the trigger for our patient's serious state. Our case study included clinical and laboratory data, as well as a literature review on published cases of SNRI associated TTS. Most cases of TTS fortunately show spontaneous recovery of cardiac function with conservative management and supportive treatment. No evidence-based treatment recommendations exist, but traditional inotropic and vasoactive drugs are considered potentially harmful, which can be a dilemma for the treating clinician, when facing an acutely decompensated TTS patient.",
"affiliations": "ST-läkare, akutkliniken, Vrinnevisjukhuset, Norrköping.;överläkare, anestesi och intensivvårdskliniken, Vrinnevisjukhuset, Norrköping.",
"authors": "Elhami|Nima|N|;Engerström|Lars|L|",
"chemical_list": "D002395:Catecholamines; D017367:Serotonin Uptake Inhibitors; D000069470:Venlafaxine Hydrochloride",
"country": "Sweden",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0023-7205",
"issue": "118()",
"journal": "Lakartidningen",
"keywords": null,
"medline_ta": "Lakartidningen",
"mesh_terms": "D002395:Catecholamines; D004452:Echocardiography; D005260:Female; D006801:Humans; D017367:Serotonin Uptake Inhibitors; D054549:Takotsubo Cardiomyopathy; D000069470:Venlafaxine Hydrochloride",
"nlm_unique_id": "0027707",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34100266",
"pubdate": "2021-06-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Venlafaxine was suspected to have triggered life-threatening takotsubo syndrome.",
"title_normalized": "venlafaxine was suspected to have triggered life threatening takotsubo syndrome"
} | [
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] |
{
"abstract": "BACKGROUND\nNilotinib is a highly effective tyrosine kinase inhibitor in the treatment of chronic myeloid leukemia (CML). However, reports of cardiovascular toxicities caused by nilotinib have recently raised critical concerns. The aim of the present study was to evaluate the incidence of cardiovascular events (CVEs) and frequency of asymptomatic peripheral arterial disease (PAD) after long-term exposure to nilotinib.\n\n\nMETHODS\nIn the present retrospective cohort, we evaluated the incidence of CVEs in 63 CML patients treated with nilotinib. The results of Doppler ultrasound examination of the carotid and vertebral and lower extremity arteries with ankle-brachial index measurements were collected in asymptomatic patients. The clinical outcome was a composite endpoint of PAD, acute coronary events, stroke, heart failure, and cardiovascular death.\n\n\nRESULTS\nSixty-three patients with a median age of 60 years were followed up for a median duration of 63 months. After a median nilotinib exposure of 49.30 months (range, 7.00-117.95 months), for a total exposure of 178.7 patient-years, 6 patients (9%) had experienced the clinical outcome. Four patients (8%) had abnormal arterial leg Doppler ultrasound findings. No significant lesions were reported in carotid/vertebral artery ultrasound examinations. Together, hypertension and low-density lipoprotein cholesterol > 2 mmol/L significantly increased the risk of CVEs or abnormal ultrasound findings (odds ratio, 37.65; 95% confidence interval, 4.06-348.9).\n\n\nCONCLUSIONS\nThe incidence of CVEs and the frequency of asymptomatic PAD in this population was low, and CVEs were associated with cardiovascular risk factors. Aggressive risk factor modification and applying standard definitions for measuring cardiovascular outcomes might have contributed to the findings. Further prospective and adequately powered studies are needed to explore the effect of the cardiovascular risk profile on CVEs in CML patients taking nilotinib.",
"affiliations": "Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada. Electronic address: Nazanin.Aghel@uhn.ca.;Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Department of Biostatistics, Princess Margaret Cancer Center, University Health Network, Toronto, ON, Canada.;Department of Medical Oncology and Hematology, Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada.;Division of Cardiology, Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, University of Toronto, Toronto, ON, Canada.",
"authors": "Aghel|Nazanin|N|;Lipton|Jeffrey Howard|JH|;Atenafu|Eshetu G|EG|;Kim|Dennis Dong Hwan|DDH|;Delgado|Diego Hernan|DH|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D011743:Pyrimidines; D011505:Protein-Tyrosine Kinases",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clml.2017.07.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2152-2669",
"issue": "17(12)",
"journal": "Clinical lymphoma, myeloma & leukemia",
"keywords": "Ankle-brachial index; BCR-ABL; Cardiovascular disease; Peripheral arterial disease; Tyrosine kinase inhibitor",
"medline_ta": "Clin Lymphoma Myeloma Leuk",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002318:Cardiovascular Diseases; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D017063:Outcome Assessment, Health Care; D058729:Peripheral Arterial Disease; D011505:Protein-Tyrosine Kinases; D011743:Pyrimidines; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors",
"nlm_unique_id": "101525386",
"other_id": null,
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"pmc": null,
"pmid": "28803825",
"pubdate": "2017-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Cardiovascular Events After Exposure to Nilotinib in Chronic Myeloid Leukemia: Long-term Follow-up.",
"title_normalized": "cardiovascular events after exposure to nilotinib in chronic myeloid leukemia long term follow up"
} | [
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{
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"reactionoutcome": "6"
}
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] |
{
"abstract": "Opioid-related mortality happens, even in healthcare settings. We describe serial postmortem fentanyl blood concentrations in a hospital inpatient who fatally abused transdermal fentanyl. This is a single-patient case report. A 42-year-old man with lymphoma was started on transdermal fentanyl therapy while hospitalized for chronic abdominal pain. The patient was last seen awake 1.3 h prior to being found apneic and cyanotic. During the resuscitation attempt, a small square-shaped film was removed from the patient's oropharynx. Femoral blood was collected 0.5 and 2 h postmortem, and the measured fentanyl concentration increased from 1.6 to 14 ng/mL. Study limitations include potential laboratory or collection errors and missing data. (i) Providers must be vigilant for signs of fentanyl patch abuse. (ii) Postmortem blood concentrations are not static postmortem, likely secondary to decreasing pH, increased aqueous solubility, and tissue redistribution, and are therefore unlikely to accurately represent antemortem blood concentrations.",
"affiliations": "Department of Internal Medicine, PinnacleHealth Hospitalists, 111 S. Front St, Harrisburg, PA, 17101; Department of Internal Medicine, PinnacleHealth Toxicology Center, 111 S. Front St, Harrisburg, PA, 17101; Department of Emergency Medicine, Penn State University College of Medicine, 500 University Dr, Hershey, PA, 17033.",
"authors": "Moore|Philip W|PW|;Palmer|Robert B|RB|;Donovan|Joseph Ward|JW|",
"chemical_list": "D000701:Analgesics, Opioid; D005283:Fentanyl",
"country": "United States",
"delete": false,
"doi": "10.1111/1556-4029.12559",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1198",
"issue": "60(1)",
"journal": "Journal of forensic sciences",
"keywords": "analgesics/opioid/fentanyl; forensic science; forensic toxicology; humans; necrokinetic; pharmacokinetics; postmortem; transdermal",
"medline_ta": "J Forensic Sci",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000701:Analgesics, Opioid; D062787:Drug Overdose; D005283:Fentanyl; D006760:Hospitalization; D006801:Humans; D008297:Male; D008409:Mastication; D009293:Opioid-Related Disorders; D011180:Postmortem Changes; D013391:Sucking Behavior; D057968:Transdermal Patch",
"nlm_unique_id": "0375370",
"other_id": null,
"pages": "243-6",
"pmc": null,
"pmid": "25041753",
"pubdate": "2015-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal fentanyl patch misuse in a hospitalized patient with a postmortem increase in fentanyl blood concentration.",
"title_normalized": "fatal fentanyl patch misuse in a hospitalized patient with a postmortem increase in fentanyl blood concentration"
} | [
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},
{
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"reactionoutcome": "5"
}
],
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},
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"literaturereference": "MOORE PW, PALMER RB, DONOVAN JW.. FATAL FENTANYL PATCH MISUSE IN A HOSPITALIZED PATIENT WITH A POSTMORTEM INCREASE IN FENTANYL BLOOD CONCENTRATION.. J-FORENSIC-SCI. 2015?60(1):243-6.",
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"qualification": "3",
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},
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnessother": 1,
"transmissiondate": "20160526"
},
{
"companynumb": "US-PFIZER INC-2015023570",
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"patient": {
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{
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"activesubstance": {
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},
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"drugdosageform": "TRANSDERMAL PATCH",
"drugdosagetext": "150 MCG/H (AS TWO 75 MCG/H NOVAPLUS_ FENTANYL RESERVOIR PATCHES) WAS STARTED 92 H (3.9 DAYS)",
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"drugdosagetext": "UNK, AT 8.5 H AFTER FENTANYL PATCH PLACEMENT",
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"drugdosagetext": "1 MG, AT 3, 7, AND 14 H",
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"drugindication": "CANCER PAIN",
"drugintervaldosagedefinition": "804",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Apnoea",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Drug abuse",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Cyanosis",
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"reactionoutcome": "5"
}
],
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},
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},
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"medicinalproduct": "FENTANYL."
}
],
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{
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},
{
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"reactionoutcome": "5"
},
{
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"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MOORE PW, PALMER RB, DONOVAN JW. FATAL FENTANYL PATCH MISUSE IN A HOSPITALIZED PATIENT WITH A POSTMORTEM INCREASE IN FENTANYL BLOOD CONCENTRATION. J-FORENSIC-SCI 2015? 60(1):243-6.",
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"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20151222",
"receivedate": "20151222",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11861522,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20160305"
},
{
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{
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},
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},
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"medicinalproduct": "FENTANYL UNKNOWN STRENGTH (WATSON LABORATORIES)"
},
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},
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"drugdosagetext": "3 MG, TOTAL (DOSES OF 1 MG WERE ADMINISTERED AT 3,7 AND 14H)",
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"medicinalproduct": "DILAUDID"
},
{
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},
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"drugdosagetext": "0.25 MG, UNKNOWN",
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}
],
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"patientweight": "77.6",
"reaction": [
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Apnoea",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Cyanosis",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Intentional product misuse",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Drug abuse",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MOORE PW, PALMER RB, DONOVAN JW. FATAL FENTANYL PATCH MISUSE IN A HOSPITALIZED PATIENT WITH A POSTMORTEM INCREASE IN FENTANYL BLOOD CONCENTRATION. J FORENSIC SCI. 2015?60(1):243-6.",
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"qualification": "1",
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},
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"receiptdate": "20151221",
"receivedate": "20151207",
"receiver": {
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"receivertype": "6"
},
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"safetyreportversion": 3,
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"sendertype": "2"
},
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"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20160305"
}
] |
{
"abstract": "For several decades, 5-Fluorouracil (5-FU) has been the backbone of many chemotherapy regimens for various tumor types. Its most common side effects are gastrointestinal disorders, mucositis, myelosuppression, hand-foot syndrome, and rarely cardiac toxicity. More rarely, 5-FU infusion can induce hyperammonemic encephalopathy. 5-FU toxicities can be worsened by complete or partial genetic and/or phenotypic dihydropyrimidine dehydrogenase deficiency. Here, we report the case of a patient who initially developed a 5-FU-induced hyperammonemic encephalopathy after receiving FOLFIRINOX (oxaliplatin, irinotecan, folinic acid, and 5-FU) chemotherapy with bevacizumab to treat a metastatic gastrointestinal cancer of unknown primary. Thereafter, the patient was rechallenged successfully by the same chemotherapy regimen (FOLFIRINOX) for more than 6 months with a protocol consisting in a free protein diet, and administration of ammonium chelators, and Krebs and urea cycle intermediates, to prevent further hyperammonemia. We also present a review of the literature on 5-FU rechallenge after 5-FU-induced hyperammonemic encephalopathy.",
"affiliations": "Medical Oncology Department, Gustave Roussy, Université Paris-Saclay.;Paris Descartes University.;Medical Oncology Department, Gustave Roussy, Université Paris-Saclay.;Medical Oncology Department, Gustave Roussy, Université Paris-Saclay.;Medical Oncology Department, Gustave Roussy, Université Paris-Saclay.;Intensive Care Unit, Bicêtre Hospital, Paris-Sud University, APHP, Le Kremlin-Bicêtre, Paris, France.;Paris Descartes University.;Paris Descartes University.;Paris Descartes University.;Medical Oncology Department, Gustave Roussy, Université Paris-Saclay.;Medical Oncology Department, Gustave Roussy, Université Paris-Saclay.",
"authors": "Boilève|Alice|A|;Wicker|Camille|C|;Verret|Benjamin|B|;Leroy|Florence|F|;Malka|David|D|;Jozwiak|Mathieu|M|;Pontoizeau|Clément|C|;Ottolenghi|Chris|C|;De Lonlay|Pascale|P|;Ducreux|Michel|M|;Hollebecque|Antoine|A|",
"chemical_list": "D000077150:Oxaliplatin; D000068258:Bevacizumab; D000077146:Irinotecan; D002955:Leucovorin; D005472:Fluorouracil",
"country": "England",
"delete": false,
"doi": "10.1097/CAD.0000000000000730",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0959-4973",
"issue": "30(3)",
"journal": "Anti-cancer drugs",
"keywords": null,
"medline_ta": "Anticancer Drugs",
"mesh_terms": "D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D001927:Brain Diseases; D005260:Female; D005472:Fluorouracil; D005770:Gastrointestinal Neoplasms; D006801:Humans; D022124:Hyperammonemia; D000077146:Irinotecan; D002955:Leucovorin; D009382:Neoplasms, Unknown Primary; D000077150:Oxaliplatin; D011379:Prognosis; D019233:Retreatment",
"nlm_unique_id": "9100823",
"other_id": null,
"pages": "313-317",
"pmc": null,
"pmid": "30531368",
"pubdate": "2019-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "5-Fluorouracil rechallenge after 5-fluorouracil-induced hyperammonemic encephalopathy.",
"title_normalized": "5 fluorouracil rechallenge after 5 fluorouracil induced hyperammonemic encephalopathy"
} | [
{
"companynumb": "FR-TEVA-2018-FR-963215",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
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},
{
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{
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},
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},
{
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"activesubstancename": "FLUOROURACIL"
},
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},
{
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},
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugdosageform": null,
"drugdosagetext": "FOLFIRINOX",
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"drugindication": "GASTROINTESTINAL CANCER METASTATIC",
"drugintervaldosagedefinition": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "FOLINIC ACID"
}
],
"patientagegroup": null,
"patientonsetage": "36",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hyperammonaemic encephalopathy",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BOILEVE A. 5-FLUOROURACIL RECHALLENGE AFTER 5-FLUOROURACIL-INDUCED HYPERAMMONEMIC ENCEPHALOPATHY. ANTI-CANCER DRUGS. 2019 MAR?30:313-317.",
"literaturereference_normalized": "5 fluorouracil rechallenge after 5 fluorouracil induced hyperammonemic encephalopathy",
"qualification": "3",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20190425",
"receivedate": "20190425",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16237549,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
}
] |
{
"abstract": "Atrial fibrillation (AF) is a frequent reason for emergency department visits. According to current guidelines either rate- or rhythm-control are acceptable therapeutic options in such situations. In this report, we present the complicated clinical course of a patient with AF and a rapid ventricular response. Because of paroxysmal AF, the patient was on chronic oral anticoagulation therapy with warfarin. Pharmacological treatment was ineffective to control ventricular rate, and immediate synchronized electrical cardioversion was performed. One hour later, the patient complained of chest pain in combination with marked ST-segment elevation in the anterior leads. Cardiac catheterization with optical coherence tomography disclosed plaque rupture in the left main coronary artery without other significant stenosis. Stent implantation was performed successfully. During the course of the hospital stay, the patient remained asymptomatic and the ST-segment elevations resolved. However, despite treatment with amiodarone it was not possible to keep the patient permanently in sinus rhythm. Therefore, a biventricular pacemaker was implanted and AV node ablation performed.",
"affiliations": "*Department of Internal Medicine,Jena University Hospital,Jena,Germany.;*Department of Internal Medicine,Jena University Hospital,Jena,Germany.;*Department of Internal Medicine,Jena University Hospital,Jena,Germany.;*Department of Internal Medicine,Jena University Hospital,Jena,Germany.;*Department of Internal Medicine,Jena University Hospital,Jena,Germany.;*Department of Internal Medicine,Jena University Hospital,Jena,Germany.",
"authors": "Prochnau|Dirk|D|;Surber|Ralf|R|;Hoyme|Matthias|M|;Otto|Sylvia|S|;Selle|Anna|A|;Poerner|Tudor C|TC|",
"chemical_list": "D000925:Anticoagulants",
"country": "England",
"delete": false,
"doi": "10.1017/cem.2016.352",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1481-8035",
"issue": "19(4)",
"journal": "CJEM",
"keywords": "STEMI; atrial fibrillation; emergency department; immediate cardioversion; left main artery; plaque rupture",
"medline_ta": "CJEM",
"mesh_terms": "D000369:Aged, 80 and over; D000925:Anticoagulants; D001281:Atrial Fibrillation; D017115:Catheter Ablation; D004554:Electric Countershock; D004636:Emergency Service, Hospital; D006801:Humans; D008297:Male; D009203:Myocardial Infarction; D010138:Pacemaker, Artificial; D058226:Plaque, Atherosclerotic; D012422:Rupture, Spontaneous; D015607:Stents; D041623:Tomography, Optical Coherence",
"nlm_unique_id": "100893237",
"other_id": null,
"pages": "312-316",
"pmc": null,
"pmid": "27619976",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "ST-segment Elevation Following Cardioversion of Atrial Fibrillation in the Emergency Department: Unmasked Myocardial Infarction due to Left Main Coronary Artery Plaque Rupture or Unspecific Finding?",
"title_normalized": "st segment elevation following cardioversion of atrial fibrillation in the emergency department unmasked myocardial infarction due to left main coronary artery plaque rupture or unspecific finding"
} | [
{
"companynumb": "DE-MYLANLABS-2019M1007405",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
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{
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"activesubstance": {
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},
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"drugdosagetext": "1000 MG, QD",
"drugenddate": null,
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"drugindication": "ATRIAL FIBRILLATION",
"drugintervaldosagedefinition": "804",
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},
{
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},
{
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},
{
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"drugtreatmentdurationunit": null,
"medicinalproduct": "WARFARIN"
},
{
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"activesubstancename": "AMIODARONE"
},
"drugadditional": "1",
"drugadministrationroute": "042",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "300 MG",
"drugenddate": null,
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"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"drugstructuredosagenumb": "300",
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"medicinalproduct": "AMIODARONE"
}
],
"patientagegroup": null,
"patientonsetage": "83",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Electrocardiogram ST segment elevation",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Chest pain",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "International normalised ratio increased",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DIRK PROCHNAU ET AL... ST-SEGMENT ELEVATION FOLLOWING CARDIOVERSION OF ATRIAL FIBRILLATION IN THE EMERGENCY DEPARTMENT: UNMASKED MYOCARDIAL INFARCTION DUE TO LEFT MAIN CORONARY ARTERY PLAQUE RUPTURE OR UNSPECIFIC FINDING?.. CANADIAN ASSOCIATION OF EMERGENCY PHYSICIANS. 2017?19(4):312-316",
"literaturereference_normalized": "st segment elevation following cardioversion of atrial fibrillation in the emergency department unmasked myocardial infarction due to left main coronary artery plaque rupture or unspecific finding",
"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20190319",
"receivedate": "20190129",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15884526,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
}
] |
{
"abstract": "Data on pediatric second-line antiretroviral treatment (ART) outcomes are scarce, but essential to evaluate second-line and design third-line regimens.\n\n\n\nChildren ≤12 years switching to second-line ART containing a protease inhibitor (PI) in Uganda were followed for 24 months. Viral load (VL) was determined at switch to second-line and every 6 months thereafter; genotypic resistance testing was done if VL ≥ 1000 cps/ml.\n\n\n\n60 children were included in the analysis; all had ≥1 drug resistance mutations at switch. Twelve children (20.0%) experienced treatment failure; no PI mutations were detected. Sub-optimal adherence and underweight were associated with treatment failure.\n\n\n\nNo PI mutations occurred in children failing second-line ART, which is reassuring as pediatric third-line is not routinely available in these settings. Poor adherence rather than HIV drug resistance is likely to be the main mechanism for treatment failure and should receive close attention in children on second-line ART.",
"affiliations": "Amsterdam Institute for Global Health and Development, Department of Global Health, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.;Joint Clinical Research Centre, Kampala, Uganda.;Amsterdam Institute for Global Health and Development, Department of Global Health, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.;Joint Clinical Research Centre, Kampala, Uganda.;Stichting HIV Monitoring, Amsterdam, the Netherlands.;Department of Pediatrics and Child Health, Makerere College of Health Sciences, Kampala, Uganda.;Stichting HIV Monitoring, Amsterdam, the Netherlands.;Stichting HIV Monitoring, Amsterdam, the Netherlands.;Stichting HIV Monitoring, Amsterdam, the Netherlands.;Stichting HIV Monitoring, Amsterdam, the Netherlands.;Stichting HIV Monitoring, Amsterdam, the Netherlands.;Global Child Health Group, Emma Children's Hospital, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.;Amsterdam Institute for Global Health and Development, Department of Global Health, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.;Amsterdam Institute for Global Health and Development, Department of Global Health, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.;Global Child Health Group, Emma Children's Hospital, Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.",
"authors": "Boerma|Ragna S|RS|;Kityo|Cissy|C|;Boender|T Sonia|TS|;Kaudha|Elizabeth|E|;Kayiwa|Joshua|J|;Musiime|Victor|V|;Mukuye|Andrew|A|;Kiconco|Mary|M|;Nankya|Immaculate|I|;Nakatudde|Lilian|L|;Mugyenyi|Peter N|PN|;Boele van Hensbroek|Michael|M|;Rinke de Wit|Tobias F|TF|;Sigaloff|Kim C E|KCE|;Calis|Job C J|JCJ|",
"chemical_list": "D044966:Anti-Retroviral Agents; D017320:HIV Protease Inhibitors",
"country": "England",
"delete": false,
"doi": "10.1093/tropej/fmw062",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0142-6338",
"issue": "63(2)",
"journal": "Journal of tropical pediatrics",
"keywords": "HIV drug resistance; HIV-1; antiretroviral treatment; genotypic resistance testing.; second-line",
"medline_ta": "J Trop Pediatr",
"mesh_terms": "D000293:Adolescent; D044966:Anti-Retroviral Agents; D044383:Blacks; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D024882:Drug Resistance, Viral; D005260:Female; D015658:HIV Infections; D017320:HIV Protease Inhibitors; D015497:HIV-1; D006801:Humans; D008297:Male; D009154:Mutation; D015995:Prevalence; D017211:Treatment Failure; D016896:Treatment Outcome; D014454:Uganda; D019562:Viral Load",
"nlm_unique_id": "8010948",
"other_id": null,
"pages": "135-143",
"pmc": null,
"pmid": "27634175",
"pubdate": "2017-04-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Second-line HIV Treatment in Ugandan Children: Favorable Outcomes and No Protease Inhibitor Resistance.",
"title_normalized": "second line hiv treatment in ugandan children favorable outcomes and no protease inhibitor resistance"
} | [
{
"companynumb": "UG-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-029005",
"fulfillexpeditecriteria": "1",
"occurcountry": "UG",
"patient": {
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{
"actiondrug": "5",
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"activesubstancename": "LAMIVUDINE"
},
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"drugindication": "HIV INFECTION",
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"medicinalproduct": "LAMIVUDINE."
},
{
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"medicinalproduct": "DIDANOSINE."
},
{
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},
{
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},
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"medicinalproduct": "STAVUDINE."
},
{
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},
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"drugindication": "HIV INFECTION",
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"medicinalproduct": "RITONAVIR-BOOSTED LOPINAVIR"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "NEVIRAPINE"
},
"drugadditional": "3",
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"drugindication": "HIV INFECTION",
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VIRAMUNE"
}
],
"patientagegroup": null,
"patientonsetage": "3",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Treatment failure",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KITYO C, BOENDER S, KAUDHA E, KAYIWA J, MUSIIME V. SECOND-LINE HIV TREATMENT IN UGANDAN CHILDREN: FAVORABLE OUTCOMES AND NO PROTEASE INHIBITOR RESISTANCE. JOURNAL OF TROPICAL PEDIATRICS. 2017;63:2:135-143.",
"literaturereference_normalized": "second line hiv treatment in ugandan children favorable outcomes and no protease inhibitor resistance",
"qualification": "5",
"reportercountry": "UG"
},
"primarysourcecountry": "UG",
"receiptdate": "20170524",
"receivedate": "20170524",
"receiver": {
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"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 13578671,
"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170830"
}
] |
{
"abstract": "Primary CNS PTLD is an extremely rare complication after allogeneic HSCT. At our centre, an 11-year-old patient developed nausea, vomiting, and diplopy on day +82 following HSCT. On brain MRI, multiple white matter lesions were seen. Histology showed a diffuse large B-cell lymphoma with high load of EBV in tissue. Despite stopping immunosuppression, treatment with EBV-specific cytotoxic T cells, systemic rituximab, HD-MTX, and intrathecal chemotherapy, progression was observed. With a combination of HD-MTX and cytarabine, only a partial response could be achieved. Having all conventional modalities not only failed but resulted in significant toxicity, a salvage monotherapy with biweekly nivolumab has been instituted. The starting dose was 1.1 mg/kg, later escalated to 2.2 mg/kg. After 8 months of nivolumab therapy, PET-CT showed complete metabolic remission. Subsequently, the patient has been switched to a maintenance dosage of 1.1 mg/kg. No cytopenias, graft failure, GvHD, or any other alloimmune complications were seen during nivolumab therapy. In conclusion, nivolumab may be considered as an effective and safe option for CNS PTLD therapy when all other modalities have failed.",
"affiliations": "Department of Pediatric Hematology and Stem Cell Transplantation, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary.;Department of Hematology and Stem Cell Transplantation, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary.;Department of Hematology and Stem Cell Transplantation, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary.;Department of Pediatric Hematology and Stem Cell Transplantation, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary.;Department of Pediatric Hematology and Stem Cell Transplantation, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary.;Department of Pediatric Hematology and Stem Cell Transplantation, Central Hospital of Southern Pest, National Institute of Hematology and Infectious Diseases, Budapest, Hungary.",
"authors": "Kassa|Csaba|C|0000-0003-4091-4926;Reményi|Péter|P|;Sinkó|János|J|;Kállay|Krisztián|K|;Kertész|Gabriella|G|;Kriván|Gergely|G|",
"chemical_list": "D000970:Antineoplastic Agents; D000074322:Antineoplastic Agents, Immunological; C581634:BCR-ABL1 fusion protein, human; D003561:Cytarabine; D000077594:Nivolumab; D000069283:Rituximab; D016044:Fusion Proteins, bcr-abl",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.13302",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1397-3142",
"issue": "22(8)",
"journal": "Pediatric transplantation",
"keywords": "central nervous system; diffuse large B-cell lymphoma; hematopoietic stem cell transplantation; nivolumab; post-transplant lymphoproliferative disorder",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D000970:Antineoplastic Agents; D000074322:Antineoplastic Agents, Immunological; D002648:Child; D003561:Cytarabine; D020031:Epstein-Barr Virus Infections; D005260:Female; D016044:Fusion Proteins, bcr-abl; D006801:Humans; D007165:Immunosuppression Therapy; D007278:Injections, Spinal; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D016393:Lymphoma, B-Cell; D008232:Lymphoproliferative Disorders; D008279:Magnetic Resonance Imaging; D000077594:Nivolumab; D000072078:Positron Emission Tomography Computed Tomography; D011184:Postoperative Period; D012074:Remission Induction; D000069283:Rituximab; D033581:Stem Cell Transplantation; D014184:Transplantation, Homologous; D016896:Treatment Outcome",
"nlm_unique_id": "9802574",
"other_id": null,
"pages": "e13302",
"pmc": null,
"pmid": "30345623",
"pubdate": "2018-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful nivolumab therapy in an allogeneic stem cell transplant child with post-transplant lymphoproliferative disorder.",
"title_normalized": "successful nivolumab therapy in an allogeneic stem cell transplant child with post transplant lymphoproliferative disorder"
} | [
{
"companynumb": "PHHY2018HU194504",
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"occurcountry": "HU",
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},
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"medicinalproduct": "RITUXIMAB."
},
{
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"drugdosagetext": "25 MG, UNK",
"drugenddate": null,
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"drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"medicinalproduct": "RITUXIMAB."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "3",
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"drugauthorizationnumb": "017469",
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"drugdosagetext": "10 MG, UNK",
"drugenddate": null,
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"drugindication": "POST TRANSPLANT LYMPHOPROLIFERATIVE DISORDER",
"drugintervaldosagedefinition": null,
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"drugrecurrence": null,
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"medicinalproduct": "PREDNISOLONE."
}
],
"patientagegroup": null,
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"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Malignant neoplasm progression",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Post transplant lymphoproliferative disorder",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Seizure",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
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{
"abstract": "Background: Checkpoint inhibitor immunotherapy or immuno-oncology (IO) treatment in refractory cervical cancer yielded an objective response rate (ORR) of 12% in tumors expressing the programmed cell death ligand-1 (PD-L1) in the KEYNOTE-158 phase II study. We hypothesized that the positive response might be associated with the level of PD-L1 expression and/or the tumor mutation burden (TMB). We also aimed to analyze if responses could be associated with platinum sensitivity. Methods: This is a retrospective study of all consecutive patients with cervical cancer who received pembrolizumab or nivolumab. Results: Ten patients were identified. Median age was 64.5 years old (range 48-80). The response rate was 70% and the median duration of response was 21.0 months (range 1.8-26.7) after 20.7 months of follow-up (range 2.0-31.0). The response rate was 80% in patients with PD-L1 combined positive score (CPS) ≥ 10, and 75% in patients with tumor mutation burden (TMB) ≥ 10 mut/Mb. The mean progression-free survival (PFS) for the entire cohort was 20.2 months (95% CI 12.0-28.5). Seven patients had treatment for >12 months (range 14.6-31.0). Five patients were platinum-sensitive and 5 patients were platinum-resistant at the time of immunotherapy, and the response rate was similar regardless of platinum sensitivity. Conclusions: The positive response to IO treatment in advanced cervical cancer in this study was higher than published, and a possible association with the level of PD-L1 expression and the TMB level was suggested. A PD-L1 CPS score ≥ 10 or TMB ≥ 10 may be biomarkers to correlate with response, which should be explored in large studies.",
"affiliations": "Department of Medicine, Maimonides Medical Center, Brooklyn, NY, United States.;Comparative Effectiveness Outcomes Research, Department of Sociomedical Sciences, Columbia University Mailman School of Public Health, New York, NY, United States.;Division of Hematology and Oncology, Department of Medicine, Maimonides Medical Center, Brooklyn, NY, United States.",
"authors": "Shieh|Kevin R|KR|;Huang|Anna|A|;Xu|Yiqing|Y|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fmed.2021.669587",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.669587\nMedicine\nBrief Research Report\nResponse to Immune Checkpoint Inhibitor Treatment in Advanced Cervical Cancer and Biomarker Study\nShieh Kevin R. 1\n\nHuang Anna 2\nXu Yiqing 3 *\n\n1Department of Medicine, Maimonides Medical Center, Brooklyn, NY, United States\n2Comparative Effectiveness Outcomes Research, Department of Sociomedical Sciences, Columbia University Mailman School of Public Health, New York, NY, United States\n3Division of Hematology and Oncology, Department of Medicine, Maimonides Medical Center, Brooklyn, NY, United States\nEdited by: Francesco Plotti, Campus Bio-Medico University, Italy\n\nReviewed by: Huri Güvey, Duzce University, Turkey; Nazan Yurtcu, Sivas Cumhuriyet University Faculty of Medicine, Turkey\n\n*Correspondence: Yiqing Xu yxu@maimonidesmed.org\nThis article was submitted to Obstetrics and Gynecology, a section of the journal Frontiers in Medicine\n\n12 8 2021\n2021\n8 66958719 2 2021\n29 6 2021\nCopyright © 2021 Shieh, Huang and Xu.\n2021\nShieh, Huang and Xu\nhttps://creativecommons.org/licenses/by/4.0/ This 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(s) 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.\nBackground: Checkpoint inhibitor immunotherapy or immuno-oncology (IO) treatment in refractory cervical cancer yielded an objective response rate (ORR) of 12% in tumors expressing the programmed cell death ligand-1 (PD-L1) in the KEYNOTE-158 phase II study. We hypothesized that the positive response might be associated with the level of PD-L1 expression and/or the tumor mutation burden (TMB). We also aimed to analyze if responses could be associated with platinum sensitivity.\n\nMethods: This is a retrospective study of all consecutive patients with cervical cancer who received pembrolizumab or nivolumab.\n\nResults: Ten patients were identified. Median age was 64.5 years old (range 48–80). The response rate was 70% and the median duration of response was 21.0 months (range 1.8–26.7) after 20.7 months of follow-up (range 2.0–31.0). The response rate was 80% in patients with PD-L1 combined positive score (CPS) ≥ 10, and 75% in patients with tumor mutation burden (TMB) ≥ 10 mut/Mb. The mean progression-free survival (PFS) for the entire cohort was 20.2 months (95% CI 12.0–28.5). Seven patients had treatment for >12 months (range 14.6–31.0). Five patients were platinum-sensitive and 5 patients were platinum-resistant at the time of immunotherapy, and the response rate was similar regardless of platinum sensitivity.\n\nConclusions: The positive response to IO treatment in advanced cervical cancer in this study was higher than published, and a possible association with the level of PD-L1 expression and the TMB level was suggested. A PD-L1 CPS score ≥ 10 or TMB ≥ 10 may be biomarkers to correlate with response, which should be explored in large studies.\n\ncervical cancer\nimmunotherapy\ncheckpoint inhibitor\nPD-L1\ntumor mutation burden\nbiomarker\n==== Body\nIntroduction\n\nCervical cancer is the 14th most common cancer among women in the United States of America and is associated with HPV infections (1). Worldwide, it ranks fourth in terms of incidence and mortality among women (2). HPV vaccination and early detection by the Papanicolaou test (also known as the Pap smear) have decreased incidence and promoted early detection (3, 4). Primary treatment with surgery or chemoradiation can cure about 70% of the early stage patients; however, about 30% of the patients ultimately recur after primary treatment with either surgery or definitive chemoradiation (5–7).\n\nUntil recently, the treatment for patients with recurrent and metastatic cervical center has been chemotherapy with limited efficacy (8). Combination chemotherapy using cisplatin and topotecan yields a median overall survival of 9.4 months compared to 6.5 months for cisplatin alone (9). Incorporating bevacizumab to the chemotherapy regimen has shown to further increase median overall survival to 16.8 months (10).\n\nA new generation of therapeutics, i.e., immune checkpoint inhibitors or immuno-oncology (IO) treatment, represents a major advance in the treatment of malignancies. Tumor cells evade immune destruction through various ways, such as downregulation of the T cell response and modulation of major histocompatibility antigen expression (11). Immune checkpoint inhibitors are monoclonal antibodies that most commonly target cytotoxic T-lymphocyte antigen 4 (CTLA-4), programmed cell death protein-1 (PD-1), or its ligand (PD-L1) by inhibiting the suppression of T cell activity and re-enabling the immune system to attack tumor cells (12). These therapies have shown antitumor activity in multiple tumor types. The activity of pembrolizumab in cervical cancer has been tested in the phase Ib KEYNOTE-028 and phase II KEYNOTE-158 studies (13, 14). In the latter, the response rate from single agent pembrolizumab was 12% and another 18% had stable disease. In addition, 80% of those who responded had more than 12 months of response. All patients who responded to pembrolizumab had PD-L1 expression of ≥1. Based on those results, pembrolizumab was approved by the FDA for the treatment of advanced cervical cancer that progressed on chemotherapy.\n\nImmune checkpoint inhibitor treatment is emerging as a promising treatment in cervical cancer, but an important unanswered question is the identification of predictive clinical factors or biomarkers associated with treatment response.\n\nIn this study, we reviewed our series of cervical cancer patients who received immunotherapy. We aimed to evaluate the correlation of response and progression-free survival with a number of clinical factors, including PD-L1 combined positive score (CPS), tumor mutation burden (TMB), platinum sensitivity, and sites of metastatic disease.\n\nMethods\n\nThis is a retrospective study including all patients with cervical cancer who were treated in Maimonides Cancer Center whose start date of receiving pembrolizumab or nivolumab treatment was before September 31, 2019. The last day of enrollment was August 31, 2019. The study protocol was approved by the Institutional Review Board. Electronic medical records were searched to collect demographics, treatment history and response. Tumor response was assessed by the investigators according to the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) (15). Patients were deemed to be platinum-sensitive if they had previously responded to a platinum-based therapy, and the treatment was given at least 6 months prior. Of note, some patients were given a chemotherapy break after being treated until best response with platinum-based treatment; if their subsequent recurrence was more than 6 months from the last platinum administration, they were deemed to be platinum-sensitive. Platinum-refractory was defined as those patients without a previous response to platinum, or with recurrence <6 months from the last platinum-based treatment. The cut-off day for follow up was April 30, 2021. PD-L1 expression was performed by Foundation Medicine (Cambridge, MA, USA) and Pathline Emerge (Ramsey, NJ, USA). Seven out of 10 patients had data on tumor molecular testing through next-generation sequencing (NGS) performed by Foundation Medicine. Duration of response was defined as time from beginning of response until objective progression or death; PFS was defined as time from start of treatment until objective tumor progression or death; and OS was defined as time from start of treatment until death.\n\nStatistical Methods\n\nThe predictor variables were all coded as binary with dummy variables and included the following: PD-L1 CPS ≥ 10 or PD-L1 CPS < 10, TMB ≥ 10 or TMB < 10, platinum sensitivity or resistance, and tumor site at only the lymph nodes or elsewhere.\n\nBoth a Fisher's exact test as well as an unadjusted linear regression were performed to analyze the differences between each of the binary predictor variables. The binary outcome variable in the Fischer's exact test was either a response to treatment or no response to treatment. A Fisher's exact test was performed because of the low cell count and small sample size. The test was first used to calculate the chi-square test statistic and the corresponding p-values between the identified predictors and outcome variables. Separate associations were analyzed between the binary outcome for PFS and PD-L1 CPS, TMB, platinum sensitivity, and tumor site. Similar analyses for the same four predictor variables were analyzed for associations with the binary outcome of response to treatment.\n\nSeparate unadjusted linear regressions were performed to determine estimates for differences in the continuous variables for PFS and response duration and the predictor variables for PD-L1 CPS, TMB, platinum sensitivity, and tumor site. An estimate in the difference between PFS for those who responded to treatment and those who did not was also analyzed using a linear regression to compare to the results and effectiveness of the treatment in existing literature. Adjusted linear regressions would have resulted in an overfit model because of the small sample size; however, only 2 samples are needed per variable in order to analyze linear regressions with an acceptable degree of internal validity (16). An alpha value of 0.05 and a 95% confidence interval was used to determine statistical significance.\n\nResults\n\nPatient Demographics\n\nTen patients were identified, and their demographics and clinical characteristics are summarized in Table 1 and Supplementary Table 1. Median age was 64.5 years (range 48–80). In terms of ethnic origin, 1 was Caucasian (Russian), 4 were Asian, 3 were Caribbean, and 2 were Latino. All were diagnosed with squamous cell carcinoma, with one transformed to small cell. All patients received platinum-based treatment. Other than 1 patient who had de novo metastatic disease, 9 patients had recurrent disease; among them, 7 patients received definitive platinum-based chemoradiation as primary treatment, and 2 patients received adjuvant chemoradiation after surgery. After developing recurrent/metastatic disease, and prior to IO therapy, 8 had received platinum again and 6 had received bevacizumab. At the time of starting IO treatment, 5 patients were still considered to be platinum-sensitive. Their primary sites of disease at the time of IO treatment were lymph node only (LN) (n = 3), pelvic organs (n = 2), visceral metastasis (n = 2), and mixed (n = 3).\n\nTable 1 Baseline demographics and disease characteristics.\n\nDisease characteristics\tNumber (N = 10)\t\nAge, years old\t\nMedian\t64.5\t\nRange\t48–80\t\nECOG status\t\n0\t3\t\n1\t6\t\n2\t0\t\n3\t1\t\nEthnicity\t\nAsian\t4\t\nCaribbean\t3\t\nLatino\t2\t\nRussian\t1\t\nFIGO stage at initial diagnosis\t\nI\t1\t\nII\t5\t\nIII\t3\t\nIV\t1\t\nHistology\t\nSquamous cell\t10\t\nAdenocarcinoma\t0\t\nSmall cell\t1 (transformed from squamous cell)\t\nPrevious treatment with platinum\t10\t\n Chemoradiation primary treatment\t7\t\n Chemoradiation adjuvant treatment\t2\t\nChemotherapy for metastatic disease\t\n Using platinum\t8\t\n Using bevacizumab\t6\t\nNo of previous lines of therapy for recurrence/metastasis before IO\t\n0\t2\t\n1\t5\t\n2\t1\t\n3\t2\t\nSites of metastatic lesions\t\nLN only\t3\t\nPelvic organs\t2\t\nVisceral metastases\t2\t\nOther\t3\t\nPlatinum sensitivity\t\nSensitive\t5\t\nResistant\t5\t\nImmunotherapy received\t\nPembrolizumab\t9\t\nNivolumab\t1\t\nPD-L1 combined positive score (CPS)\t\n0\t1\t\n1–9\t3\t\n10–100\t6\t\nMicrosatellite status (MS)\t\nMS stable\t7\t\nMS instability\t0\t\nNot assessed\t3\t\nTumor mutation burden (TMB)*\t\nTMB <10\t3\t\nTMB ≥ 10 mut/Mb\t4\t\nP16 status\t\nPositive\t6\t\nNegative\t1\t\nNot assessed\t3\t\n* Seven of the patients had tumor mutation burden measured.\n\nMolecular biomarker characteristics were extracted from the tumor genomic testing and pathology reports, shown in Table 1. PD-L1 combined positive score (CPS) was 0 in the patient whose tumor transformed to small cell cancer, 3 (30%) were 1–9, and 6 (60%) were CPS ≥ 10. All had microsatellite stable status. Of the 7 patients with molecular testing, all had TMB ≥ 6, and 4 of these had TMB ≥ 10. P16 was positive for 6, negative for 1.\n\nTreatment and Response\n\nNine patients received pembrolizumab and 1 received nivolumab treatment. The best response rate was 70%, with 3 complete response (CR), 4 partial response (PR), 1 stable disease (SD), and 2 progressive disease (PD). One of the two patients with progression was a transformed small cell case. While one patient had PR by clinical imaging, she underwent pelvic surgery and was found to have CR on pathological evaluation.\n\nAt the time of data cut-off, the median follow-up was 20.7 months. The median duration of treatment was 26 cycles (range 3–30 cycles) or 20.7 months (range 1.4–31.0 months), and 5 patients were still continuing treatment. One patient stopped treatment after being found to have pathological complete response during pelvic surgery after 21.2 months of treatment. The median duration for treatment for those who responded to treatment was 22.6 months (range 7.2–31.0). Eight patients had continued for >6 months, and 7 had continued for >12 months. Figure 1 depicts patients' best response, duration of response, and unique tumor characteristics.\n\nFigure 1 Individual patient disease characteristics, response, and durations.\n\nBoth platinum-sensitive patients and platinum-resistant patients demonstrated CR or PR to IO treatment, with response rates of 60 and 80%, respectively.\n\nThe mean progression-free survival (PFS) for the entire cohort was 20.2 months (95% CI 12.0–28.5). The mean overall survival (OS) was 21.7 months (95% CI 14.3–29.0) (Figure S1). Only 4 events have happened so we were unable to calculate the median.\n\nAssociation of Response With Biomarkers\n\nIn the entire cohort, the PD-L1 composite positive score has a median of 10 and a mean of 32.5 (95% CI 7.7–57.3), which indicates a right skew toward the higher expression scores. The overall TMB for the 7 patients included in this measure had a median of 14.0 and a mean of 15.6 (95% CI 5.0–26.1), also skewed toward a higher expression (Supplementary Table 2).\n\nWe further attempted to evaluate the association of response in patients with particular biomarker characteristics. Generally, the response rate was higher in patients with CPS ≥ 10 vs. CPS < 10 in PD-L1 expression level (83.3 vs. 50%); higher in TMB ≥ 10 vs. < 10 (75 vs. 33%); and higher in patients with LN only disease vs. non-LN disease (100 vs. 57.1%). It was also higher in patients with platinum refractory disease vs. platinum sensitive disease (80 vs. 60%) (Table 2).\n\nTable 2 Correlation of response rate with biomarkers.\n\n\tResponse rate\tFisher's exact test\t\n\tN (%)\tp-value\t\nPD-L1\t\t0.2598\t\nCPS ≥ 10 (N = 6)\t5 (83.3)\t\t\nCPS <10 (N = 4)\t2 (50)\t\t\nTumor mutation burden*\t\t0.2703\t\nTMB ≥ 10 mut/Mb (N = 4)\t3 (75)\t\t\nTMB <10 mut/Mb (N = 3)\t1 (33)\t\t\nPlatinum sensitivity\t\t0.4902\t\nSensitive (N = 5)\t3 (60)\t\t\nRefractory (N = 5)\t4 (80)\t\t\nTumor site\t\t0.1753\t\nLymph node only (N = 3)\t3 (100)\t\t\nOther [pelvic, visceral, or mixed] (N = 7)\t4 (57.1)\t\t\n* Seven of the patients had tumor mutation burden measured.\n\nUsing a Fisher's exact test to test the associations between response to treatment and each of the four predictor variables, as summarized in Table 2, the result showed that the associations were >0.05, indicating that at this sample size, there is no detectable statistical significance between response to treatment and PD-L1 CPS, TMB, or platinum sensitivity, or tumor site.\n\nThe association of PFS with each of the above four variables was studied using linear regressions method (Table 3). Although not reaching statistical significance, the median and mean PFS for patients with a PD-L1 CPS ≥ 10 was longer than those with a PD-L1 CPS < 10, and the difference in the mean PFS was 3.4 months (95% CI −4.3 to 11.1) longer. Patients with tumors only in the lymph nodes had a mean PFS of about 25.5 months (95% CI 13.8–37.3), which is ~12.9 months (95% CI 6.0–19.8) longer than patients with tumors at pelvic, visceral, or multiple sites. This difference was numerally large, but not statistically significant. However, the 95% confidence interval comparing tumor sites did not include 0, which indicates that there may be a significant difference in PFS given that the study was better powered with a larger sample size (Table 3).\n\nTable 3 Correlation of progression-free survival with biomarkers.\n\nProgression-free survival (months)\tN\tMedian\tMean (95% CI)\tParameter estimate (Unadjusted)\tp-value\t\nPD-L1 CPS ≥ 10\t6\t20.68\t17.88 (7.45 to 28.31)\t3.41 (−4.27 to 11.09)\t0.6684\t\nPD-L1 CPS <10\t4\t12.81\t14.46 (−8.74 to 27.67)\tReferent\t\t\nTMB ≥ 10\t4\t12.02\t12.42 (−4.58 to 29.42)\t−7.08 (−17.57 to 3.41)\t0.5387\t\nTMB <10\t3\t19.50\t19.50 (−120.97 to 159.97)\tReferent\t\t\nPlatinum-sensitive\t5\t20.14\t15.36 (3.81 to 26.90)\t−2.31 (−9.88 to 5.26)\t0.7678\t\nPlatinum-refractory\t5\t21.24\t17.67 (0.10 to 35.24)\tReferent\t\t\nTumor in lymph nodes only\t3\t23.06\t25.54 (13.81 to 37.26)\t12.89 (5.95 to 19.84)\t0.1006\t\nOther tumor sites\t7\t8.44\t12.64 (2.19 to 23.10)\tReferent\t\t\nResponded to treatment\t7\t22.57\t21.78 (13.45 to 30.10)\t17.55 (23.08 to 12.02)\t0.0131*\t\nNo response to treatment\t3\t2.56\t4.23 −4.91 to 13.36)\tReferent\t\t\n* Statistically significant at alpha = 0.05.\n\nThere was no significant difference in the median or mean PFS between patients with platinum-sensitive disease and platinum-refractory disease (Table 3). On the other hand, for patients with TMB < 10, the mean PFS was 7.1 months (95% CI −17.6 to 3.41) longer than patients with TMB ≥ 10.\n\nFor patients who responded to treatment, the PFS was significantly longer than those who did not respond to treatment (Table 3).\n\nOther Mutations\n\nAs seven patients had next-generation sequencing for tumor gene profiling, we also examined their common mutations. Among the patients who responded to treatment, PIK3CA mutations were seen in 3 patients, MLL2 mutations were seen in 2, and mutations in the TERT promoter were seen in 2 patients. Those recurrent mutations were not detected in the patients without treatment response. Instead, PALB2, DDR2, and BCL2 amplifications were found (Table S3).\n\nAdverse Events\n\nOnly one patient developed a severe treatment-related immune-associated adverse event while the other patients did not show notable side effects. She had presented with de novo metastatic disease with liver, renal and peritoneal metastases. Past medical history included hypertension and ventricular tachycardia and she was taking metoprolol and amiodarone. She was initially treated with paclitaxel and carboplatin for 6 cycles with early response but quick progression. PD-L1 CPS was 60%, so the treatment was switched to pembrolizumab with initial PR. During the response, she progressed to a mixed pattern. Imaging had demonstrated marked decrease of the liver and peritoneal lesions, but enlargement of a kidney lesion. She then developed worsening thrombocytopenia. Treatment was held when the platelet count decreased to 38,000/μL, and eventually reached a nadir of 10,000/μL. She was diagnosed with idiopathic thrombocytopenic purpura (ITP), as her peripheral smear revealed large platelets without clumping. She was admitted for intravenous immunoglobulin (IVIG) and glucocorticoid treatments, and her platelets responded with an increase to 23,000/μL. On day four of the hospital admission, she developed hypoxemia and unresponsiveness, and subsequently expired. Despite the thrombocytopenia, there were no obvious signs of bleeding.\n\nWith a median follow-up of 20.7 months, we have not observed other severe immune-related toxicities.\n\nDiscussion\n\nThe phase Ib KEYNOTE-028 study and the phase II KEYNOTE-158 study have demonstrated promising antitumor activity with pembrolizumab in patients with advanced cervical cancer who have become refractory to platinum-based chemotherapy (13, 14). However, the overall response rate was reported to be only 12.2%. This notion of low ORR with immunotherapy in this cancer was also shown in a study with nivolumab alone (26.3%) (17), while the combination of nivolumab with ipilimumab appeared to deliver a higher response rate of 46% (18). A significant benefit from immunotherapy is the durable response in the responders (14) (KEYNOTE-158), not only in cervical cancer, but also in other cancers (19, 20).\n\nOnly 12 of 98 patients showed overall response in the KEYNOTE-158 study. Although our cohort was smaller, we had a much higher proportion of responders (70%) and a longer follow up time with a median of 20.7 months. Our result should provide addition to the literature regarding the characteristics of the responders.\n\nWe have shown in this study that response can occur in both platinum-sensitive or platinum-refractory patients, and in patients with lymph node disease or widespread visceral disease. The treatment response was durable with a median of 21.0 months, which is comparable to published studies. Seven of these patients had responses > 12 months. Our results are consistent with the consensus observations from the vast publications on immunotherapy, in that responding patients may enjoy a long-term control with minimal side effects.\n\nIn the published studies, responses appeared to occur in PD-L1 CPS positive patients, but due to the low response rate, more biomarker studies are needed for patient selection and prediction of response. Our study showed a much higher response rate than reported, and it would be interesting to delve deeper into the underlying associations. For example, all our patients were non-US born immigrants. Moreover, the level of expression of PD-L1 had a median of 10 and a mean of 32.5 (95% CI 7.7–57.3), which indicates a right skew (i.e., higher expression). The overall TMB had a median of 14 and a mean of 15.6 (95% CI 5.0–26.1) (Supplementary Table 2), both of which are higher than the median TMB of 5–6 mut/Mb usually found in this disease (21, 22).\n\nIn our study, patients with PD-L1 CPS ≥ 10 demonstrated numerically higher response rate than those with CPS < 10, suggesting a higher PD-L1 score could be a biomarker. Such a correlation has also been found in the treatment of lung cancer and esophageal cancer. KEYNOTE-024 investigated non-small cell lung cancer patients who had PD-L1 expression of more than 50% and found that single-agent pembrolizumab induced higher response rates, PFS, and OS than chemotherapy alone (23). Similar treatment advantage was also revealed in patients with esophageal cancer in the KEYNOTE-181 study, (63% of patients with squamous cell histology) in which RR, PFS, and OS all increased with pembrolizumab compared to chemotherapy in patients with PD-L1 expression of at least 10 (24).\n\nThe significance of TMB is a rapidly evolving field. In June 2020, the FDA approved pembrolizumab treatment in patients with TMB ≥ 10 mut/Mb regardless of cancer type. The study was based on promising data from the KEYNOTE-158 study, which analyzed a subset of 102 patients (13.2%) whose tumor had a TMB-H signature, defined as TMB ≥ 10 mut/Mb. The ORR was 29% in this study. Among them, 16 patients had cervical cancer with a response rate of 31% (25). The 1-year PFS was also higher in the TMB-H group vs. the non-TMB-H group (26.4 vs. 14.1%, respectively) (26). As mentioned above, the median TMB in cervical cancer was estimated to be 5–6 mut/Mb from prior studies (21, 22); therefore, all our patients had TMB higher than the median. There were 4 patients in our study who had TMB ≥ 10, and their response rate was 75%. These patients would be defined as patients likely having response based on the new approval indication. Thus, the high response rate seen in our cohort could be attributed by the higher proportion of patients with intermediate or high TMB. We propose to further study the relationship of TMB 6–10 mut/Mb and response in future larger studies.\n\nClinical factors associated with response and PFS were studied. As patients enrolled in the KEYNOTE-158 study were predominantly platinum-refractory patients, our data on platinum-sensitive patients should be supplemental to the literature. Similar response rate and PFS were observed between platinum sensitive and platinum resistant patients. On the other hand, patients with LN-only disease showed a higher response rate, longer mean and median PFS than those with non-LN-only disease, suggesting that patients without hematological spread may fare better with immunotherapy.\n\nWe performed statistical analysis attempting to confirm the potential association of biomarkers with response and PFS. There was no statistical significance to satisfy a p-value of <0.05, which could be attributable to the small sample size. Furthermore, as our cohort had a relatively higher expression of the biomarkers, which itself may have been the overwhelming basis of the higher response rate, the binary cut off value that was chosen for the comparison between groups may not have been optimal. Nevertheless, the analysis suggests a possible difference in a study with greater power, which encourages further study with larger sample sizes.\n\nUndoubtedly, immunotherapy offers patients a therapeutic option of less toxic treatment with long-term control. The mean PFS of the entire group was 20.2 months, longer than that of the bevacizumab-paclitaxel-cisplatin arm (median PFS of 7.6 months) in a previous chemotherapy study (27). We have not had a chance to observe progression pattern after immunotherapy.\n\nOne patient died after developing ITP, which was considered to be IO-related. ITP as a side effect from PD-L1 blockade has been reported in the literature (28), although this complication is uncommon (29). Our patient was diagnosed with grade 4 ITP and treated accordingly and never showed any signs of bleeding. It is unknown if the death was related to the immunotherapy.\n\nConclusion\n\nThe response rate to IO treatment in cervical cancer was much higher than published data in this small cohort of patients who had TMB ≥ 6. A PD-L1 CPS score ≥ 10 or TMB ≥ 10 may be a biomarker to correlate with response, which should be explored in future large studies.\n\nData Availability Statement\n\nThe datasets presented in this article are not readily available because they consist of patient records. Requests to access the datasets should be directed to yxu@maimonidesmed.org.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the Maimonides Medical Center Institutional Review Board. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. Written informed consent was not obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nYX and AH designed the analysis. KS, YX, and AH performed the analysis and interpreted the results. KS, AH, and YX contributed to the manuscript. All authors approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nPublisher's Note\n\nAll claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.669587/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1. Siegel RL Miller KD Jemal A . Cancer statistics, 2020. CA Cancer J Clin. (2020) 70 :7–30. 10.3322/caac.21590 31912902\n2. Bray F Ferlay J Soerjomataram I Siegel RL Torre LA Jemal A . Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. (2018) 68 :394–424. 10.3322/caac.21492 30207593\n3. Drolet M Bénard É Pérez N Brisson M Ali H Boily M-C . Population-level impact and herd effects following the introduction of human papillomavirus vaccination programmes: updated systematic review and meta-analysis. Lancet. 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Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin Cancer Biol. (2015) 35 :S185–98. 10.1016/j.semcancer.2015.03.004 25818339\n12. Farkona S Diamandis EP Blasutig IM . Cancer immunotherapy: the beginning of the end of cancer? BMC Med. (2016) 14 :73. 10.1186/s12916-016-0623-5 27151159\n13. Frenel J-S Le Tourneau C O'Neil B Ott PA Piha-Paul SA Gomez-Roca C . Safety and efficacy of pembrolizumab in advanced, programmed death ligand 1–positive cervical cancer: results from the phase Ib KEYNOTE-028 trial. J Clin Oncol. (2017) 35 :4035–41. 10.1200/JCO.2017.74.5471 29095678\n14. Chung HC Ros W Delord J-P Perets R Italiano A Shapira-Frommer R . Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study. J Clin Oncol. (2019) 37 :1470–8. 10.1200/JCO.18.01265 30943124\n15. Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R . New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. (2009) 45 :228–47. 10.1016/j.ejca.2008.10.026 19097774\n16. Austin PC Steyerberg EW . The number of subjects per variable required in linear regression analyses. J Clin Epidemiol. (2015) 68 :627–36. 10.1016/j.jclinepi.2014.12.014 25704724\n17. Naumann RW Hollebecque A Meyer T Devlin M-J Oaknin A Kerger J . Safety and efficacy of nivolumab monotherapy in recurrent or metastatic cervical, vaginal, or vulvar carcinoma: results from the phase I/II CheckMate 358 trial. J Clin Oncol. (2019) 37 :2825–34. 10.1200/JCO.19.00739 31487218\n18. Naumann RW Oaknin A Meyer T Lopez-Picazo JM Lao C Bang Y-J . Efficacy and safety of nivolumab (Nivo) + ipilimumab (Ipi) in patients (pts) with recurrent/metastatic (R/M) cervical cancer: results from CheckMate 358. Ann Oncol. (2019) 30 (Suppl_5 ):v898–9. 10.1093/annonc/mdz394.059\n19. Borcoman E Kanjanapan Y Champiat S Kato S Servois V Kurzrock R . 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Kojima T Shah MA Muro K Francois E Adenis A Hsu CH . Randomized Phase III Keynote-181 study of Pembrolizumab Versus Chemotherapy in advanced esophageal cancer. J Clin Oncol. (2020) 38 :4138–48. 10.1200/JCO.20.01888 33026938\n25. Keytruda (pembrolizumab) . Whitehouse Station, NJ: Merck & Co., Inc. (2020). Available online at: https://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf\n26. Diaz LA Le D Maio M Ascierto PA Geva R Motola-Kuba D . Pembrolizumab in microsatellite instability high cancers: updated analysis of the phase II KEYNOTE-164 and KEYNOTE-158 studies. Ann Oncol. (2019) 30 :v475. 10.1093/annonc/mdz253\n27. Tewari KS Sill MW Long HJ Penson RT Huang H Ramondetta LM . Improved Survival with bevacizumab in advanced cervical cancer. J Eng J Med. (2014) 370 :734–43. 10.1056/NEJMoa1309748 28745937\n28. Le Roy A Kempf E Ackermann F Routier E Robert C Turpin A . Two cases of immune thrombocytopenia associated with pembrolizumab. Eur J Cancer. (2016) 54 :172–4. 10.1016/j.ejca.2015.10.073 26687374\n29. Hasegawa T Ozaki Y Inoue T Watanabe Y Fukuhara M Yamaura T . Nivolumab-related severe thrombocytopenia in a patient with relapsed lung adenocarcinoma: a case report and review of the literature. J Med Case Reports. (2019) 13 :1–6. 10.1186/s13256-019-2245-y 31647029\n\n",
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] |
{
"abstract": "As limited amounts of data are available regarding thrombolytic therapy for patients taking novel oral anticoagulants, thrombolytic therapy is not recommended in such cases. Here, we report an acute stroke patient taking rivaroxaban who received intravenous thrombolysis with recombinant tissue plasminogen activator (rt-PA). An 80-year-old man with a history of nonvalvular atrial fibrillation, who had been receiving 10 mg of rivaroxaban showed abrupt onset of aphasia and right hemiparesis. National Institutes of Health Stroke Scale score was 10. Onset of neurologic deficits occurred 4 hours after the last dose of rivaroxaban. Clinical data on admission were as follows: blood pressure, 170/90 mm Hg; prothrombin time (PT), 22.6 seconds (control, 12.9 seconds); international normalized ratio, 2.03; activated partial thromboplastin time, 46 seconds (normal, 23-32 seconds); and creatinine level, 1.11 mg/dL. Magnetic resonance angiography revealed occlusion of the superior trunk of the left middle cerebral artery. Intravenous infusion of .6 mg/kg of rt-PA (total dose, 36 mg) was performed 6 hours after the last rivaroxaban administration with informed consent. The neurologic deficit improved during infusion of rt-PA. Repeat brain computed tomography showed left frontal cortical infarction without hemorrhagic changes. In the case of rivaroxaban, it is difficult to accurately determine the drug activity. As the anticoagulant activity of rivaroxaban can be estimated from its pharmacokinetics and PT, it is clinically important to obtain accurate information about the timing of medication and blood sampling.",
"affiliations": "Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Japan. Electronic address: hishi@yamaguchi-u.ac.jp.;Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Japan.;Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Japan.;Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Japan.;Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Japan.;Department of Neurosurgery, Yamaguchi University School of Medicine, Ube, Japan.",
"authors": "Ishihara|Hideyuki|H|;Torii|Hiroaki|H|;Imoto|Hirochika|H|;Oka|Fumiaki|F|;Sadahiro|Hirokazu|H|;Suzuki|Michiyasu|M|",
"chemical_list": "D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009025:Morpholines; D011994:Recombinant Proteins; D013876:Thiophenes; D000069552:Rivaroxaban; D010959:Tissue Plasminogen Activator",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jstrokecerebrovasdis.2014.07.008",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1052-3057",
"issue": "23(10)",
"journal": "Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association",
"keywords": "Anticoagulant therapy; cardiogenic embolism; cerebral infarction; thrombolysis; tissue plasminogen activator",
"medline_ta": "J Stroke Cerebrovasc Dis",
"mesh_terms": "D000369:Aged, 80 and over; D001281:Atrial Fibrillation; D001777:Blood Coagulation; D002533:Cerebral Angiography; D038524:Diffusion Magnetic Resonance Imaging; D016903:Drug Monitoring; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D006801:Humans; D007262:Infusions, Intravenous; D018810:Magnetic Resonance Angiography; D008297:Male; D009025:Morpholines; D011237:Predictive Value of Tests; D011517:Prothrombin Time; D011994:Recombinant Proteins; D012307:Risk Factors; D000069552:Rivaroxaban; D020521:Stroke; D013876:Thiophenes; D015912:Thrombolytic Therapy; D010959:Tissue Plasminogen Activator; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
"nlm_unique_id": "9111633",
"other_id": null,
"pages": "e457-e459",
"pmc": null,
"pmid": "25280819",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with rivaroxaban.",
"title_normalized": "intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with rivaroxaban"
} | [
{
"companynumb": "JP-JNJFOC-20141013842",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
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"drugdosageform": "TABLET",
"drugdosagetext": null,
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"drugindication": "CEREBROVASCULAR ACCIDENT PROPHYLAXIS",
"drugintervaldosagedefinition": "804",
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"drugstructuredosagenumb": "10",
"drugstructuredosageunit": "003",
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"medicinalproduct": "RIVAROXABAN"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
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"drugadministrationroute": "065",
"drugauthorizationnumb": "202439",
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"drugdosageform": "TABLET",
"drugdosagetext": null,
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"drugenddateformat": null,
"drugindication": "ATRIAL FIBRILLATION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "2",
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
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"drugstructuredosagenumb": "10",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "RIVAROXABAN"
}
],
"patientagegroup": "6",
"patientonsetage": "80",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cerebral infarction",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Cerebral artery occlusion",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ISHIHARA H, TORII H, IMOTO H, OKA F, SADAHIRO H, SUZUKI M. INTRAVENOUS THROMBOLYSIS WITH RECOMBINANT TISSUE PLASMINOGEN ACTIVATOR IN A STROKE PATIENT TREATED WITH RIVAROXABAN.. JOURNAL OF STROKE AND CEREBROVASCULAR DISEASE 2014:1-3.",
"literaturereference_normalized": "intravenous thrombolysis with recombinant tissue plasminogen activator in a stroke patient treated with rivaroxaban",
"qualification": "1",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20141028",
"receivedate": "20141027",
"receiver": {
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"receivertype": "6"
},
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"safetyreportid": 10543101,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20150529"
}
] |
{
"abstract": "We report the case of a 47-year-old patient who developed acute myelogenous leukemia (AML) 18 months after receiving high-dose chemotherapy with peripheral blood progenitor cell support (PBPCT) for relapsed low-grade follicular non-Hodgkin's lymphoma (NHL). Cytogenetic analysis of the leukemic cells showed the translocation (9;22)(q34;q11). In three mitoses, an additional Philadelphia chromosome (Ph1) was present. In the literature, Philadelphia chromosome-positive secondary AML has been described only once before in a patient with multiple myeloma.",
"affiliations": "Department of Oncology and Hematology, University Hospital Eppendorf, Hamburg, Germany.",
"authors": "Stockschläder|M|M|;Fiedler|W|W|;Zander|A|A|;Weh|H J|HJ|;Hossfeld|D K|DK|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s002770050243",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0939-5555",
"issue": "73(6)",
"journal": "Annals of hematology",
"keywords": null,
"medline_ta": "Ann Hematol",
"mesh_terms": "D000208:Acute Disease; D000971:Antineoplastic Combined Chemotherapy Protocols; D015139:Blotting, Southern; D004305:Dose-Response Relationship, Drug; D064420:Drug-Related Side Effects and Adverse Reactions; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008228:Lymphoma, Non-Hodgkin; D008875:Middle Aged",
"nlm_unique_id": "9107334",
"other_id": null,
"pages": "291-3",
"pmc": null,
"pmid": "9003159",
"pubdate": "1996-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Philadelphia chromosome-positive secondary acute myeloid leukemia following high-dose chemotherapy with peripheral blood progenitor cell support for relapsed low-grade non-Hodgkin's lymphoma.",
"title_normalized": "philadelphia chromosome positive secondary acute myeloid leukemia following high dose chemotherapy with peripheral blood progenitor cell support for relapsed low grade non hodgkin s lymphoma"
} | [
{
"companynumb": "DE-PFIZER INC-2015399597",
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],
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"reaction": [
{
"reactionmeddrapt": "Acute myeloid leukaemia",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Second primary malignancy",
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}
],
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},
"primarysource": {
"literaturereference": "STOCKSCHLADER, M.. PHILADELPHIA CHROMOSOME-POSITIVE SECONDARY ACUTE MYELOID LEUKEMIA FOLLOWING HIGH-DOSE CHEMOTHERAPY WITH PERIPHERAL BLOOD PROGENITOR CELL SUPPORT FOR RELAPSED LOW-GRADE NON-HODGKIN^S LYMPHOMA. ANNALS OF HEMATOLOGY. 1996?73 (6):291-293",
"literaturereference_normalized": "philadelphia chromosome positive secondary acute myeloid leukemia following high dose chemotherapy with peripheral blood progenitor cell support for relapsed low grade non hodgkin s lymphoma",
"qualification": "3",
"reportercountry": "DE"
},
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"receiptdate": "20151217",
"receivedate": "20151125",
"receiver": {
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},
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},
"serious": 1,
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"seriousnessdeath": 1,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160304"
}
] |
{
"abstract": "X-linked recessive ectodermal dysplasia with immunodeficiency is a rare primary immunodeficiency caused by hypomorphic mutations of the IKBKG gene encoding the nuclear factor κB essential modulator (NEMO) protein. This condition displays enormous allelic, immunological, and clinical heterogeneity, and therapeutic decisions are difficult because NEMO operates in both hematopoietic and nonhematopoietic cells. Hematopoietic stem cell transplantation (HSCT) is potentially life-saving, but the small number of case reports available suggests it has been reserved for only the most severe cases. Here, we report the health status before HSCT, transplantation outcome, and clinical follow-up for a series of 29 patients from unrelated kindreds from 11 countries. Between them, these patients carry 23 different hypomorphic IKBKG mutations. HSCT was performed from HLA-identical related donors (n = 7), HLA-matched unrelated donors (n = 12), HLA-mismatched unrelated donors (n = 8), and HLA-haploidentical related donors (n = 2). Engraftment was documented in 24 patients, and graft-versus-host disease in 13 patients. Up to 7 patients died 0.2 to 12 months after HSCT. The global survival rate after HSCT among NEMO-deficient children was 74% at a median follow-up after HSCT of 57 months (range, 4-108 months). Preexisting mycobacterial infection and colitis were associated with poor HSCT outcome. The underlying mutation does not appear to have any influence, as patients with the same mutation had different outcomes. Transplantation did not appear to cure colitis, possibly as a result of cell-intrinsic disorders of the epithelial barrier. Overall, HSCT can cure most clinical features of patients with a variety of IKBKG mutations.",
"affiliations": "Study Center for Immunodeficiencies, Assistance Publique-Hopitaux de Paris, Necker Hospital for Sick Children, Paris, France.;Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.;Division of Pediatric Dermatology, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL.;Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.;Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Pediatrics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.;Pediatric Onco-Hemato-Immunology Unit, University Hospital, Angers, France.;Hospices Civils de Lyon, Genetic Unit, School of Medicine, University Lyon 1, Bron, France.;Study Center for Immunodeficiencies, Assistance Publique-Hopitaux de Paris, Necker Hospital for Sick Children, Paris, France.;Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.;Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.;Division of Immunology and.;Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.;Department of Biochemistry and Genetics, University Hospital, Angers, France.;Clinical Immunology Department and Program of Hematopoietic Stem Cell Transplantation, National Institute of Pediatrics, Mexico City, Mexico.;Clinical Immunology Department and Program of Hematopoietic Stem Cell Transplantation, National Institute of Pediatrics, Mexico City, Mexico.;University College London Great Ormond Street Institute of Child Health, London, United Kingdom.;Clinical Immunology Department and Program of Hematopoietic Stem Cell Transplantation, National Institute of Pediatrics, Mexico City, Mexico.;Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, CO.;Department of Pediatric Dermatology, Oregon Health & Science University, Portland, OR.;Paediatric Haematology, Starship Blood and Cancer Centre, Starship Hospital, Auckland, New Zealand.;Immunodeficiency Centre for Wales, University Hospital of Wales, Cardiff, United Kingdom.;Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.;Center for Chronic Immunodeficiency, University of Freiburg, Freiburg, Germany.;Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.;Primary Immunodeficiency Group, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom.;Division of Immunology and.;Department of Pediatrics and.;Department of Immunology, Institute of Biomedical Sciences, Federal University of São Paulo, São Paulo, Brazil.;Blood and Marrow Transplant Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom.;Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.;Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD.;Imagine Institute, Paris Descartes University, Paris, France.;Imagine Institute, Paris Descartes University, Paris, France.;Imagine Institute, Paris Descartes University, Paris, France.;Center for Chronic Immunodeficiency, University of Freiburg, Freiburg, Germany.;National Institute for Health Research, Cambridge Biomedical Research Centre, Cambridge, United Kingdom.;Oxford University Hospitals NHS Foundation Trust, National Institute for Health Research Oxford Biomedical Research Centre, Oxford, United Kingdom.;Imagine Institute, Paris Descartes University, Paris, France.;Study Center for Immunodeficiencies, Assistance Publique-Hopitaux de Paris, Necker Hospital for Sick Children, Paris, France.;Immunodeficiency Diagnosis and Treatment Program, Department of Pediatrics, National Jewish Health, Denver, CO.;Imagine Institute, Paris Descartes University, Paris, France.;Center for Human Immunobiology, Section of Immunology, Allergy and Rheumatology, Texas Children's Hospital, Baylor College of Medicine, Houston, TX.;Study Center for Immunodeficiencies, Assistance Publique-Hopitaux de Paris, Necker Hospital for Sick Children, Paris, France.",
"authors": "Miot|Charline|C|;Imai|Kohsuke|K|;Imai|Chihaya|C|;Mancini|Anthony J|AJ|;Kucuk|Zeynep Yesim|ZY|;Kawai|Tokomki|T|;Nishikomori|Ryuta|R|;Ito|Etsuro|E|;Pellier|Isabelle|I|;Dupuis Girod|Sophie|S|;Rosain|Jeremie|J|;Sasaki|Shinya|S|;Chandrakasan|Shanmuganathan|S|;Pachlopnik Schmid|Jana|J|;Okano|Tsubasa|T|;Colin|Estelle|E|;Olaya-Vargas|Alberto|A|;Yamazaki-Nakashimada|Marco|M|;Qasim|Waseem|W|;Espinosa Padilla|Sara|S|;Jones|Andrea|A|;Krol|Alfons|A|;Cole|Nyree|N|;Jolles|Stephen|S|;Bleesing|Jack|J|;Vraetz|Thomas|T|;Gennery|Andrew R|AR|;Abinun|Mario|M|;Güngör|Tayfun|T|;Costa-Carvalho|Beatriz|B|;Condino-Neto|Antonio|A|;Veys|Paul|P|;Holland|Steven M|SM|;Uzel|Gulbu|G|;Moshous|Despina|D|;Neven|Benedicte|B|;Blanche|Stéphane|S|;Ehl|Stephan|S|;Döffinger|Rainer|R|;Patel|Smita Y|SY|;Puel|Anne|A|;Bustamante|Jacinta|J|;Gelfand|Erwin W|EW|;Casanova|Jean-Laurent|JL|;Orange|Jordan S|JS|;Picard|Capucine|C|",
"chemical_list": "C491731:IKBKG protein, human; D016328:NF-kappa B; D051550:I-kappa B Kinase",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2017-03-771600",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0006-4971",
"issue": "130(12)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D002675:Child, Preschool; D015331:Cohort Studies; D018380:Hematopoietic Stem Cell Transplantation; D006579:Heterozygote; D006801:Humans; D051550:I-kappa B Kinase; D007223:Infant; D007231:Infant, Newborn; D007249:Inflammation; D015212:Inflammatory Bowel Diseases; D009154:Mutation; D016328:NF-kappa B; D010641:Phenotype; D015398:Signal Transduction; D016019:Survival Analysis; D014019:Tissue Donors; D019172:Transplantation Conditioning; D016896:Treatment Outcome",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "1456-1467",
"pmc": null,
"pmid": "28679735",
"pubdate": "2017-09-21",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "23708964;17361131;22078572;18277915;19663838;23864385;19225723;15337789;12042591;14523047;28597146;24579931;18851874;17417663;10839543;18412279;20345847;21734245;22156202;11047757;22139302;18179816;17322906;18794870;16769798;21755389;26269396;20652730;11242109;26691317;11224521;16636116;16177180;12045264;23870671;18313693;18347290;26482257;26812624;25068423;23405946;15356572;28086098;18851875;22566850;26117626;16647846;16333836;14734108;27391872;20542322;22635013;22517901;17931563",
"title": "Hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic IKBKG/NEMO mutations.",
"title_normalized": "hematopoietic stem cell transplantation in 29 patients hemizygous for hypomorphic ikbkg nemo mutations"
} | [
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"literaturereference": "MIOT C, IMAI K, IMAI C, MANCINI AJ, KUCUK ZY, KAWAI T, ET AL. HEMATOPOIETIC STEM CELL TRANSPLANTATION IN 29 PATIENTS HEMIZYGOUS FOR HYPOMORPHIC IKBKG/NEMO MUTATIONS. BLOOD 2017;130(12):1456-1467.",
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{
"abstract": "Accurate diagnosis of a distinct epilepsy syndrome is based on well-defined electroclinical features that differentiate separate nosological entities. In clinical practice, however, syndromes may overlap and cases may present with unusual manifestations posing a diagnostic challenge. This heterogeneity has been documented in several cases presenting with eyelid myoclonia with or without absences (EMA) diagnosed either as Jeavons syndrome (JS) variants or as genetic generalised epilepsies defined by the presence of this unique clinical entity. The hallmark of JS is the triad: (1) eyelid myoclonia with or without absences, (2) eye closure-induced paroxysms, and (3) photosensitivity. The presence of massive myoclonus, intellectual disability, or slowing of the EEG background are not typical features of the syndrome and may cause delay in making the correct diagnosis. Adding to the variability of clinical features, we describe two female paediatric patients with probable genetic epilepsy who presented with EMA but demonstrated clear atypical features, such as prominent myoclonic seizures, atonic components on video-EEG, and cognitive impairment. We also note the presence of interictal and ictal posterior discharges during eyelid myoclonia in one, supporting similar previous observations leading to consideration of EMA as an occipital cortex-initiated seizure activity. [Published with video sequences on www.epilepticdisorders.com].",
"affiliations": "Aristotle University of Thessaloniki, A' Department of Paediatrics, Hippokration General Hospital of Thessaloniki, Greece.;Young Epilepsy, Paediatric Neurology, Lingfield, Surrey.;Young Epilepsy, Neurophysiology, Lingfield, Surrey.;Young Epilepsy, Neurophysiology, Lingfield, Surrey.;Sheffield Children's Hospital, Sheffield.;Developmental Neurosciences, UCL Great Ormond Street Institute of Child Health, London, Great Ormond Street Hospital for Children, London, UK.;Great Ormond Street Hospital for Children, London, UK.",
"authors": "Dragoumi|Pinelopi|P|;Emery|Jacqueline|J|;Chivers|Fiona|F|;Brady|Megan|M|;Desurkar|Archana|A|;Cross|J Helen|JH|;Das|Krishna B|KB|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1684/epd.2017.0937",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1294-9361",
"issue": "20(1)",
"journal": "Epileptic disorders : international epilepsy journal with videotape",
"keywords": "Jeavons; atonia; eyelid myoclonia; myoclonic seizure; phenotypic heterogeneity",
"medline_ta": "Epileptic Disord",
"mesh_terms": "D000293:Adolescent; D002648:Child; D004569:Electroencephalography; D004831:Epilepsies, Myoclonic; D004829:Epilepsy, Generalized; D005260:Female; D006801:Humans; D009207:Myoclonus",
"nlm_unique_id": "100891853",
"other_id": null,
"pages": "35-41",
"pmc": null,
"pmid": "29171397",
"pubdate": "2018-02-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Crossing the lines between epilepsy syndromes: a myoclonic epilepsy variant with prominent eyelid myoclonia and atonic components.",
"title_normalized": "crossing the lines between epilepsy syndromes a myoclonic epilepsy variant with prominent eyelid myoclonia and atonic components"
} | [
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"narrativeincludeclinical": "CASE EVENT DATE: 2008"
}
},
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"literaturereference": "DRAGOUMI P, EMERY J, CHIVERS F, ET AL. CROSSING THE LINES BETWEEN EPILEPSY SYNDROMES: A MYOCLONIC EPILEPSY VARIANT WITH PROMINENT EYELID MYOCLONIA AND ATONIC COMPONENTS.. EPILEPTIC DISORDERS.. 2018 FEB?20(1):35-41.",
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{
"abstract": "Cerebellitis is a rarely encountered complication of isoniazid therapy. Its occurrence is usually associated with concomitant renal disease and haemodialysis. Herein, we report the case of a patient with this complication who presented with isolated bilateral symmetrical dentate nucleus T2 hyperintensities on magnetic resonance imaging. Isoniazid neurotoxicity has never been reported to cause bilateral dentate hyperintensities, for which the differentials are few and include metronidazole toxicity.",
"affiliations": "Department of Radiodiagnosis, Christian Medical College and Hospital, Ludhiana, Punjab, Pin-141008, India. prasant.peter@rediffmail.com.",
"authors": "Peter|Prasant|P|;John|Mary|M|",
"chemical_list": "D000995:Antitubercular Agents; D007538:Isoniazid",
"country": "Singapore",
"delete": false,
"doi": "10.11622/smedj.2013188",
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"issue": "55(1)",
"journal": "Singapore medical journal",
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"mesh_terms": "D000328:Adult; D000995:Antitubercular Agents; D002526:Cerebellar Diseases; D002529:Cerebellar Nuclei; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007538:Isoniazid; D008279:Magnetic Resonance Imaging; D006435:Renal Dialysis; D051437:Renal Insufficiency; D014376:Tuberculosis",
"nlm_unique_id": "0404516",
"other_id": null,
"pages": "e17-9",
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"pmid": "24452983",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "8439890;21042443;8321366;2260338;16032442;17885234;14968261",
"title": "Isoniazid-induced cerebellitis: a disguised presentation.",
"title_normalized": "isoniazid induced cerebellitis a disguised presentation"
} | [
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{
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}
],
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{
"abstract": "We present the case of a 53-year-old male with metastatic rectal cancer who was treatment resistant to FOLFOX and FOLFOXIRI. Due to a Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, regorafenib was given in the third line setting. Surprisingly, the patient had a prolonged partial response that lasted 27 months. Mutational status was extensively evaluated to identify potential alterations that might play a role as predictive markers for this unusual event. A poorly characterized but nontransforming mutation in Fms-like tyrosine kinase 4 (FLT4) was present in the tumor. Prior to and at the time of clinical progression, we found amplification of fibroblast growth factor receptor 1 (FGFR1) and epidermal growth factor receptor (EGFR), loss of the FLT4 mutation, and gain of KIT proto-oncogene receptor tyrosine kinase (KIT) G961S suggesting potential roles in acquired resistance.",
"affiliations": "Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (IPCT), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (IPCT), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (IPCT), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (IPCT), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (IPCT), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (IPCT), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.;Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.",
"authors": "Korphaisarn|Krittiya|K|;Loree|Jonathan M|JM|;Nguyen|Van|V|;Coulson|Ryanne|R|;Holla|Vijaykumar|V|;Litzenburger|Beate C|BC|;Chen|Ken|K|;Mills|Gordon B|GB|;Maru|Dipen M|DM|;Meric-Bernstan|Funda|F|;Shaw|Kenna R Mills|KRM|;Kopetz|Scott|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.18632/oncotarget.18357",
"fulltext": "\n==== Front\nOncotargetOncotargetOncotargetImpactJOncotarget1949-2553Impact Journals LLC 1835710.18632/oncotarget.18357Case ReportGenomic analysis of exceptional responder to regorafenib in treatment-refractory metastatic rectal cancer: a case report and review of the literature Korphaisarn Krittiya 12Loree Jonathan M. 1Nguyen Van 3Coulson Ryanne 1Holla Vijaykumar 4Litzenburger Beate C. 4Chen Ken 4Mills Gordon B. 4Maru Dipen M. 5Meric-Bernstan Funda 4Shaw Kenna R. Mills 4Kopetz Scott 11 Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA2 Department of Medicine, Division of Medical Oncology, Faculty of Medicine Siriraj Hospital, Bangkok, Thailand3 Department of Pharmacy, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA4 Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy (IPCT), The University of Texas MD Anderson Cancer Center, Houston, Texas, USA5 Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USACorrespondence to:Scott Kopetz,Skopetz@mdanderson.org22 8 2017 3 6 2017 8 34 57882 57888 29 3 2017 20 5 2017 Copyright: © 2017 Korphaisarn et al.2017This article is distributed under the terms of the Creative Commons Attribution License (CC-BY), which permits unrestricted use and redistribution provided that the original author and source are credited.We present the case of a 53-year-old male with metastatic rectal cancer who was treatment resistant to FOLFOX and FOLFOXIRI. Due to a Kirsten rat sarcoma viral oncogene homolog (KRAS) mutation, regorafenib was given in the third line setting. Surprisingly, the patient had a prolonged partial response that lasted 27 months. Mutational status was extensively evaluated to identify potential alterations that might play a role as predictive markers for this unusual event. A poorly characterized but nontransforming mutation in Fms-like tyrosine kinase 4 (FLT4) was present in the tumor. Prior to and at the time of clinical progression, we found amplification of fibroblast growth factor receptor 1 (FGFR1) and epidermal growth factor receptor (EGFR), loss of the FLT4 mutation, and gain of KIT proto-oncogene receptor tyrosine kinase (KIT) G961S suggesting potential roles in acquired resistance.\n\nmetastatic colorectal cancerregorafenibsurvivalbiomarkerresponse\n==== Body\nINTRODUCTION\nRegorafenib, an oral multikinase inhibitor, is used in treatment refractory metastatic colorectal cancer (mCRC) after failure of fluoropyrimidine, irinotecan, and oxaliplatin based therapies. In RAS wild type patients, progression following EGFR targeted therapy should also occur before use of regorafenib. The CORRECT clinical trial [1] demonstrated an overall survival (OS) benefit of regorafenib over placebo in treatment-refractory mCRC (6.4 months vs 5 months, Hazard ratio (HR) 0.77, 95% confidential interval (CI), 0.64-0.94, P = 0.0052). Mean duration of regorafenib treatment was 2.8 months with an objective response rate only being 1% (5/505). The benefit of regorafenib was also reported in Asian populations in the CONCUR trial [2], which demonstrated an extended OS in regorafenib treated patients compared to placebo (8.8 vs 6.3 months, HR = 0.55, 95%CI 0.44-0.77, P = 0.00016). However, there are no biomarkers predicting response to this drug and many patients suffer early progression during treatment with regorafenib. An extensive analysis of circulating tumor DNA and proteins from the CORRECT trial attempted to identify biomarkers able to predict response, however was unsuccessful [3]. Here, we report a case of an unusual deep and long-term response to regorafenib and present the molecular characterization of this patient to help elucidate potential determinants of this exceptional response.\n\nCASE REPORT\nA 53-year-old male presented with lower abdominal pain, constipation, intermittent episodes of bright red blood per rectum, and significant weight loss of 20 pounds over 3 months. He had no significant past medical or family history, and physical examination was normal. The patient underwent a colonoscopy which demonstrated an exophytic mass in the rectum causing partial obstruction. Biopsy revealed moderate to poorly differentiated adenocarcinoma arising from a villous adenoma with high grade dysplasia. Staging investigations revealed liver limited multiple metastases, with the largest mass measuring 12 centimeters. Carcinoembryonic antigen (CEA) was within normal limit.\n\nA 200 gene next generation sequencing (NGS) panel was performed on the biopsied primary and identified a KRAS mutation in codon G12S, a tumor protein p53 (TP53) mutation in codon R273C, an adenomatous polyposis coli (APC) mutation in codon R1450* and I742fs*, a protein phosphatase 1 regulatory subunit 3A (PPP1R3A) mutation in codon E271D, and a FLT4mutation, in codon F131S. FLT4, also known as vascular endothelial growth factor receptor 3 (VEGFR3)[4], is a member of the VEGFR family which can be targeted by regorafenib [5]. Since high VEGFR protein expression has been reported on colorectal cancer cells [6], we assessed the functional significance in the Ba/F3 cell reporter assay. This screen showed no IL-3 independent growth which is a surrogate for the transforming ability of this variant in FLT4. Molecular characterization of the tumor is shown in Table 1. CpG island methylator phenotype (CIMP) was high (abnormal methylation in 6/6 target genes) and microsatellite instability testing by immunohistochemistry demonstrated a microsatellite stable tumor.\n\nTable 1 NGS panel results as assessed longitudinally throughout the course of a patient with an exceptional response to regorafenib\nGene\tDiagnostic Biopsy (Pre-treatment)\tBiopsy of Primary Tumor after Partial Response\tBiopsy of Primary Tumor at Time of Discordant Response\tctDNA Sequencing at Time of Systemic Progression\t\nPlatform used\tT200\tT200.1\tT200.1\tGuardant 360\t\nKRAS G12S\t✓\t✓\t✓\t✓\t\nTP53 R273C\t✓\t✓\t✓\t✓\t\nTP53 R175H\tx\tx\tx\t✓(minor alteration)\t\nAPC R1450*\t✓\tx\tx\tx\t\nAPC I742fs*\t✓\t✓\t✓\t✓ (minor alteration)\t\nFLT4 F131S\t✓\tx\tx\tx\t\nPPP1R3A E271D\t✓\tx\tx\tx\t\nATR I774fs*\tx\t✓\tx\tx\t\nEP300 L1755V\tx\tx\t✓\tx\t\nWHSC1L1 E123Q\tx\tx\t✓\tx\t\nKIT G691S\tx\tx\tx\t✓\t\nMYCL amplification\tx\t✓ (7.4)*\t✓ (2.5)*\tx\t\nCDK4 amplification\tx\t✓ (3.1)*\t✓ (2.7)*\t✓ (2.4)*\t\nKRAS amplification\tx\t✓ (3.1)*\tx\t✓ (2.4)*\t\nFGFR1 amplification\tx\tx\t✓ (2.5)*\t✓ (2.46)*\t\nEGFR amplification\tx\tx\t✓ (2.7)*\t✓ (2.5)*\t\nMYC amplification\tx\tx\tx\t✓ (2.49)*\t\nPIK3CA amplification\tx\tx\tx\t✓ (2.58)*\t\nKRAS;Kirsten rat sarcoma viral oncogene homolog, TP53; tumor protein p53, APC; adenomatous polyposis coli, FT4; Fms-Related Tyrosine Kinase, PPP1R3A; protein phosphatase 1 regulatory subunit 3A, ATR; ataxia telangiectasia and Rad3 related, EP300; E1A binding protein p300, WHSC1L1; Wolf-Hirschhorn Syndrome Candidate 1-Like 1, KIT; KIT proto-oncogene receptor tyrosine kinase, MYCL; v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog, CDK4; cyclin dependent kinase 4, FGFR1; fibroblast growth factor receptor 1, EGFR; epidermal growth factor receptor, PIK3CA; phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, ctDNA; circulating tumor DNA, *copy number\n\nDue to the patient's prior rectal bleeding and in-situ primary malignancy, FOLFOX was initiated with bevacizumab omitted. After 4 cycles of treatment, interval CT scan showed progression of the hepatic metastases and rectal mass according to the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guideline [7]. The patient's treatment was changed to FOLFIRINOX, with an initial partial response (PR) after 4 cycles. However, after 8 cycles the patient once again demonstrated progressive disease in the liver and rectum. The patient was subsequently started on regorafenib at a dose of 120 mg per day for 3 weeks each 28-day cycle as per MD Anderson's institutional dosing practice. Interval CT scan of abdomen after 2 months showed a dramatic response. Hepatic metastases decreased in size from 9.8 to 7.7 in the left lobe and 11.6 to 9.3 centimeters (cm) in the right lobe which was confirmed after 4 months. He continued on treatment without any dosing modifications. After 10 months of regorafenib, he required a dose reduction due to grade 2 hand-foot skin reaction (HFSR) which was most pronounced on the third week of each cycle. Subsequently, his dose was changed to 120 mg per day for the first two weeks and 80 mg per day for the third week. After 15 months of treatment, a flexible sigmoidoscopy was performed and showed an ulcerative non-obstructive mass at the site of the primary tumor which was biopsied and confirmed residual poorly differentiated adenocarcinoma. A repeat 200 gene NGS panel was performed on this biopsy and identified KRAS G12S, TP53 R273C, and APC I742fs* which were previously reported at time of diagnosis. However, new gene alterations were identified in ataxia telangiectasia and Rad3 related (ATR) gene at codon I774fs*; and gene amplifications in v-myc avian myelocytomatosis viral oncogene lung carcinoma derived homolog (MYCL), cyclin dependent kinase 4 (CDK4), and KRAS. Figure 1 showed the maximum response of the liver metastases after 17 months of regorafenib treatment.\n\nFigure 1 Abdominal CT with contrast (A) at baseline showed multiple liver masses, largest 9.8×9.5 cm. in the left lobe and 11.6×9.8cm in the right lobe (B) At best response, the liver masses were 5.4×4 cm in the left lobe and 8.3×9.5 cm in the right lobe.\n\nTreatment with regorafenib was continued with good tolerance. After 20 months of regorafenib a CT scan of the abdomen showed stable liver metastases but increased size of the rectal mass. Re-biopsy of the rectal tumor was obtained to assess for mechanisms of resistance and sequencing identified FGFR1 and EGFR gene amplifications; and an E1A binding protein p300 (EP300) mutation in codon L1755V, and a Wolf-Hirschhorn Syndrome Candidate 1-Like 1 (WHSC1L1) mutation in codon E123Q. Concurrent chemo-radiation (CCRT) therapy with capecitabine 650mg/m2 twice daily with a total of 50.4Gy was initiated and regorafenib was placed on hold. Upon completion of CCRT, regorafenib was re-initiated with continued disease control in the liver. Unfortunately, after 27 months of regorafenib treatment, an abdominal CT revealed progression of the liver metastases. Re-biopsy of the liver was attempted but there were no viable cells to characterize. Therefore, circulating tumor DNA (ctDNA) sequencing was used to characterize alterations after regorafenib progression. Analysis revealed a mutation in KIT at codon G961S, PIK3CA and MYC gene amplifications that were not noted on prior testing and confirmed FGFR1 and EGFR amplifications which were previously identified in the progressed rectal tumor tissue. The mutational profile is summarized in Table 1 and Supplementary Table 1.\n\nAs the patient had not received any other prior anti-VEGF therapy, he was started on irinotecan plus aflibercept. Restaging CT scans after 2 and 4 months showed stable disease, however the patient developed grade III diarrhea during therapy leading to the omission of subsequent irinotecan after 4 months. The patient continued aflibercept for a further 2 months at which point he was found to have hepatic progression. The patient was subsequently transitioned to best supportive care.\n\nDISCUSSION\nWe report the case of an exceptional responder to regorafenib in mCRC and describe the alterations identified through molecular testing, anticipating to elucidate a potential mechanism of sensitivity in this patient.\n\nRegorafenib, an oral mutikinase inhibitor, can inhibit activity of several protein kinases, including those involved in tumor proliferation (KIT, PDGFR and RET), tumor angiogenesis (VEGFR1-3, TIE2), and tumor microenvironment (PDGFR-B, FGFR) [5, 8, 9]. The Food and Drug Administration approved regorafenib in 2012 for the treatment of mCRC after failure of standard therapies, including fluoropyrimidine, oxaliplatin, and irinotecan-based chemotherapy, anti-VEGR therapy, and anti-EGFR therapy in KRAS wild type tumors. Regorafenib showed benefit in both KRAS-wild-type and KRAS-mutant subgroups [1, 2].\n\nPrior attempts to identify a useful biomarker to select patients who will benefit from regorafenib have assessed stereotypic mCRC aberrant genes including KRAS, BRAF, PIK3CA, and MMR status and failed to correlate mutations in any of these genes to treatment response [2, 3]. Teufel et al suggested a benefit of regorafenib therapy in patients with high-risk molecular characteristics defined by gene expression clusters (HR = 0.10; 95%CI 0.02 - 0.35) compared to a lower-risk subgroup (HR = 0.58; 95%CI 0.44 - 0.77) although this has not yet been validated [3]. Moreover, markers of angiogenesis may have potential utility in identifying responders. Eisen et al reported higher baseline TIMP metallopeptidase inhibitor 2 (TIMP2) and soluble tyrosine kinase with immunoglobulin like and EGF like domains 1 (TIE1) which were correlated with regorafenib treatment response [10]. Data from CORRECT [3] also demonstrated that high levels of soluble protein TIE1 were associated with OS benefit in the regorafenib group. Additionally, Giampieri et al reported that patients who harbored VEGF-A rs2010963 germline polymorphism showed better PFS (HR = 0.49, 95%CI 0.33-0.81) and OS (HR 0.52, 95%CI 0.34-0.99) when treated with regorafenib compared to those without these polymorphisms [8]. While hypothesis generating, all of these angiogenic markers suffer from limited power due to multiple comparison and require further studies.\n\nThe patient reported here had an exceptional response to regorafenib of 27 months, which has never been reported previously. The most recent published data from Japan [11] reported 18 months of partial response in a patient with mCRC treated after progression on FOLFOX, FOLFIRI, and XELOX regimens. However, they did not report any molecular analysis. In this study, we utilized sequential molecular testing before, during, and upon progression of regorafenib treatment. We found several gene mutations, including KRAS codon G12S, TP53 codon R273C, and APC codon I742fs*which persisted from diagnosis through treatments. We also found several transient mutations that occurred during regorafenib treatment including APC codon R1450*, PPP1R3A codon E271D, ATR gene in codon I774fs*, EP300 codon L1755V, and WHSC1L1 codon E123Q. However, these genes do not have biologic rationale to support their use as a predictive biomarker, and instead likely reflect clonal diversity over time.\n\nFLT4 mutations are rare in CRC and have been reported in only 2.4 % (5/212) in sequenced CRC in the Cancer Genomic Atlas (TCGA) dataset [12, 13]. FLT4 F131S located within the extracellular region of FLT4 protein [14]. Previously FLT4 F131S has not been functionally characterized; therefore this mutation was functionally analyzed in the Ba/F3 system which revealed that this mutation does not induce growth factor independent cell growth and thus is characterized as likely non-transforming/benign. Nevertheless, it cannot be ruled out that FLT4 mutations might sensitize cells/tumors to regorafenib treatment. Further experiments that characterize this mutation with regards to its therapeutic effect might be needed.\n\nThe mechanisms of pre-existing and acquired resistance to regorafenib are unknown. Recent data from a pre-clinical study demonstrated Notch-I upregulation in regorafenib resistant tumor cells and inhibition of Notch-I in resistant cells partially restored sensitivity to the regorafenib treatment in vitro. These results suggest Notch as potential mechanism of acquired resistance [15]. Gene amplifications are a common mechanism of acquired resistance to targeted therapies in CRC. Examples include BRAF gene amplification in MEK inhibitor treated tumor [16] , HER2 and MET amplification in anti-EGFRab treated tumor [17, 18] . Many acquired gene amplifications were identified in the patient's tumor profile (Table 1); several of these amplifications were present in the responding tumor (MLCL, CDK4, and KRAS) and are less likely to be associated with resistance. Others such as MYC and PIK3CA were only present in the cfDNA but not seen in the progressing rectal primary. In contrast FGFR1 and EGFR were present at the time of progression of the rectal primary and later upon progression of the liver metastases, and are therefore candidate resistance mechanism.\n\nFGFR1 is a gene that encodes a member of FGFR family which includes four receptor tyrosine kinases, FGFR1-4 [19]. FGFR1 gene amplification has been reported in numerous malignancies including breast cancer and squamous cell carcinoma of lung cancer, head and neck cancer, and esophageal cancer [20–23]. FGFR1 amplifications have been reported in 2.8% (6 cases) of 212 sequenced CRC in the TCGA dataset [12, 13]. Although FGFR1 has recently emerged as a promising target in non-small cell lung cancer, data from CRC are limited. EGFR belongs to a family of cell signaling receptors and is known to activate a cascade of multiple signaling pathways. The presence of an EGFR abnormality; including mutation, amplification, and overexpression, can result in over activity of EGFR protein and excessive proliferation [24]. EGFR amplifications have been reported in 0.5% (1 case) of 212 sequenced CRC in the TCGA dataset [12, 13]. Although EGFR mutations have been reported to predict sensitivity to EGFR tyrosine kinase inhibitors in lung cancer [25], little is known about the impact of EGFR amplifications in either for selecting patient to anti-EGFR treatment or as a role in resistance.\n\nEach of the above amplifications were noted in pathways that are adjacent or in line with a pathway targeted by regorafenib and our molecular characterization shows multiple concurrent potential resistance mechanisms induced by regorafenib. However, to our knowledge, no gene amplification has previously been established as a potential resistance mechanism for regorafenib.\n\nKIT was the only mutation noted upon tumor progression during regorafenib. KIT encodes the human homolog of the proto-oncogene c-kit that belongs to the type III tyrosine kinase receptor family [26]. Binding of its endogenous ligand, stem cell factor (SCF) initiates multiple downstream signaling pathways [27–29]; including mitogen-activated protein kinase (MAPK) pathway, phosphatidylinositol 3-kinase (PI3K)/AKT pathway, Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway, PLC- γ signaling transduction pathway and Src kinase signaling transduction pathway, leading to cell proliferation, survival and migration. KIT mutations have been reported in 2.8% (6/212) of sequenced CRC in the TCGA dataset [12, 13]. KIT G961S alteration has not been functionally characterized. It is located at the C-terminal end of the protein, outside of any known function domain [14]. Although, KIT G916S has not been reported with any clinical significance, the acquisition of any mutation in a kinase targeted by regorafenib suggests that KIT G961S might play a role in acquired resistance.\n\nCONCLUSION\nWe report a case with an unusually prolonged response to regorafenib in mCRC and we highlight the development of FGFR1/EGFR amplifications and a KIT G961S mutation as potential mechanisms of acquired resistance in this patient. The molecular features of this exceptional responder may provide insight into genomic alterations that develop during regorafenib treatment which may lead to acquired resistance.\n\nAPPENDICES\nMethods\nT200 gene panel\nThe T200 is a next generation sequencing panel that provides sequencing coverage of all exons for 201 cancer related genes. The panel consists of 4874 exons encoding 938607 bases and was designed with a higher read depth in order to provide the ability to call mutations at lower allele frequencies (down to 1%). Detailed methods associated with this assay have been previously published [30].\n\nGuardant 360TM assays\nThe Guardant 360TM is a commercially available next generation sequencing panel developed for use with circulating tumor DNA (ctDNA). The panel consists of 68 cancer related genes and is able to identify mutations and copy number alterations. Cell free DNA is extracted from plasma and genomic alterations are analyzed by massively parallel sequencing of amplified target genes. The minimum detectable mutant allele is dependent on the concentration of ctDNA in a patient's serum at the time of blood draw [31].\n\nCIMP methylation\nAssay is performed using either formalin-fixed, paraffin-embedded tissue blocks or frozen tissue samples. DNA extracted from formalin-fixed, paraffin-embedded tissue or frozen tissue samples is treated with bisulfite to convert unmethylated cytosine to uracil. PCR amplification of both unmethylated and methylated MINT1, MINT2 and MINT31 loci, and promoter sequences of p14, p16 and hMLH1 genes is performed and methylation status is assessed by pyrosequencing. The tumor is considered CIMP High, if at least 40% of markers tested show methylation, and CIMP Low if < 40% markers show methylation.\n\nIL3 dependency Ba/F3 assay\nAn IL-3 dependent murine Ba/F3 cell reporter model was used to evaluate the functional impact of a FLT4 F131S mutation. The procedure was same as described previously [32] with few modifications. Briefly, this pro-B cell line is dependent on IL-3 for proliferation. Oncogenic transformation with a mutation results in IL-3 independent growth, thus highlighting a functionally significant mutation. Ba/F3 cells were introduced with FLT4 F131S mutant using lentivirus approach and incubated in medium with 0.5 pg/ml IL-3 which is 0.01% of regular IL-3 concentration used in cell line maintenance. Trace amount of IL-3 in medium delays IL-3 depletion-mediated cell death and gives time to the cells to adapt oncogenic mutant. Cell viability was measured after 1, 1.5, and 2 weeks.\n\nSUPPLEMENTARY MATERIALS FIGURES AND TABLES\n The authors are grateful to Dr.Kwok shing Ng, PhD for helping with the completeness of functional genomic data\n\nFUNDING\n\nThis study was funded by ROI CA 172670 (SK).\n\nCONFLICTS OF INTEREST\n\nAll authors have no conflict of interest to declare.\n\nData Deposition and Access: Genetic variant data was submitted to ClinVar (https://www.ncbi.nlm.nih.gov/clinvar) under submission ID: SUB2525808.\n\nEthic Statement: Written informed consent for publication of this case report was obtained from the patient under protocol number 2009-0091 (The Assessment of Targeted Therapies Against Colorectal Cancer-ATTACC program).\n==== Refs\nREFERENCES\n1 Grothey A Van Cutsem E Sobrero A Siena S Falcone A Ychou M Humblet Y Bouché O Mineur L Barone C Adenis A Tabernero J Yoshino T Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial Lancet 2013 381 303 312 23177514 \n2 Li J Qin S Xu R Yau TC Ma B Pan H Xu J Bai Y Chi Y Wang L Yeh KH Bi F Cheng Y Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial Lancet Oncol 2015 16 619 629 25981818 \n3 Tabernero J Lenz HJ Siena S Sobrero A Falcone A Ychou M Humblet Y Bouché O Mineur L Barone C Adenis A Yoshino T Goldberg RM Analysis of circulating DNA and protein biomarkers to predict the clinical activity of regorafenib and assess prognosis in patients with metastatic colorectal cancer: a retrospective, exploratory analysis of the CORRECT trial Lancet Oncol 2015 16 937 948 26184520 \n4 Galland F Karamysheva A Pebusque MJ Borg JP Rottapel R Dubreuil P Rosnet O Birnbaum D The FLT4 gene encodes a transmembrane tyrosine kinase related to the vascular endothelial growth factor receptor Oncogene 1993 8 1233 1240 8386825 \n5 Wilhelm SM Dumas J Adnane L Lynch M Carter CA Schütz G Thierauch KH Zopf D Regorafenib (BAY 73-4506): a new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity Int J Cancer 2011 129 245 255 21170960 \n6 Abajo A Bitarte N Zarate R Boni V Lopez I Gonzalez-Huarriz M Rodriguez J Bandres E Garcia-Foncillas J Identification of colorectal cancer metastasis markers by an angiogenesis-related cytokine-antibody array World J Gastroenterol 2012 18 637 645 22363134 \n7 Eisenhauer EA Therasse P Bogaerts J Schwartz LH Sargent D Ford R Dancey J Arbuck S Gwyther S Mooney M Rubinstein L Shankar L Dodd L New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 228 247 19097774 \n8 Mross K Frost A Steinbild S Hedbom S Büchert M Fasol U Unger C Krätzschmar J Heinig R Boix O Christensen O A phase I dose-escalation study of regorafenib (BAY 73-4506), an inhibitor of oncogenic, angiogenic, and stromal kinases, in patients with advanced solid tumors Clin Cancer Res 2012 18 2658 2667 22421192 \n9 Strumberg D Schultheis B Regorafenib for cancer Expert Opin Investig Drugs 2012 21 879 889 \n10 Eisen T Joensuu H Nathan PD Harper PG Wojtukiewicz MZ Nicholson S Bahl A Tomczak P Pyrhonen S Fife K Bono P Boxall J Wagner A Regorafenib for patients with previously untreated metastatic or unresectable renal-cell carcinoma: a single-group phase 2 trial Lancet Oncol 2012 13 1055 1062 22959186 \n11 Iseki Y Yashiro M Shibutani M Nagahara H Maeda K Matsutani S Tamura T Ohira G Yamazoe S Kimura K Toyokawa T Amano R Tanaka H [A Case of Metastatic Lung Cancer from Colon Cancer with a Long Partial Response with Regorafenib Treatment]. [Article in Japanese] Gan To Kagaku Ryoho 2016 43 2338 2340 28133314 \n12 Cerami E Gao J Dogrusoz U Gross BE Sumer SO Aksoy BA Jacobsen A Byrne CJ Heuer ML Larsson E Antipin Y Reva B Goldberg AP The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data Cancer Discov 2012 2 401 404 22588877 \n13 Gao J Aksoy BA Dogrusoz U Dresdner G Gross B Sumer SO Sun Y Jacobsen A Sinha R Larsson E Cerami E Sander C Schultz N Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal Sci Signal 2013 6 l1 \n14 Consortium U UniProt: a hub for protein information Nucleic Acids Res 2015 43 D204 212 25348405 \n15 Mirone G Perna S Shukla A Marfe G Involvement of Notch-1 in Resistance to Regorafenib in Colon Cancer Cells J Cell Physiol 2016 231 1097 1105 26419617 \n16 Corcoran RB Dias-Santagata D Bergethon K Iafrate AJ Settleman J Engelman JA BRAF gene amplification can promote acquired resistance to MEK inhibitors in cancer cells harboring the BRAF V600E mutation Sci Signal 2010 3 ra84 21098728 \n17 Yonesaka K Zejnullahu K Okamoto I Satoh T Cappuzzo F Souglakos J Ercan D Rogers A Roncalli M Takeda M Fujisaka Y Philips J Shimizu T Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab Sci Transl Med 2011 3 99ra86 \n18 Leto SM Trusolino L Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies J Mol Med (Berl) 2014 92 709 722 24811491 \n19 Dienstmann R Rodon J Prat A Perez-Garcia J Adamo B Felip E Cortes J Iafrate AJ Nuciforo P Tabernero J Genomic aberrations in the FGFR pathway: opportunities for targeted therapies in solid tumors Ann Oncol 2014 25 552 563 24265351 \n20 André F Bachelot T Commo F Campone M Arnedos M Dieras V Lacroix-Triki M Lacroix L Cohen P Gentien D Adélaide J Dalenc F Goncalves A Comparative genomic hybridisation array and DNA sequencing to direct treatment of metastatic breast cancer: a multicentre, prospective trial (SAFIR01/UNICANCER) Lancet Oncol 2014 15 267 274 24508104 \n21 Freier K Schwaenen C Sticht C Flechtenmacher C Mühling J Hofele C Radlwimmer B Lichter P Joos S Recurrent FGFR1 amplification and high FGFR1 protein expression in oral squamous cell carcinoma (OSCC) Oral Oncol 2007 43 60 66 16807070 \n22 Bandla S Pennathur A Luketich JD Beer DG Lin L Bass AJ Godfrey TE Litle VR Comparative genomics of esophageal adenocarcinoma and squamous cell carcinoma Ann Thorac Surg 2012 93 1101 1106 22450065 \n23 Jiang T Gao G Fan G Li M Zhou C FGFR1 amplification in lung squamous cell carcinoma: a systematic review with meta-analysis Lung Cancer 2015 87 1 7 25433983 \n24 Ciardiello F Tortora G EGFR antagonists in cancer treatment N Engl J Med 2008 358 1160 1174 18337605 \n25 Mok TS Wu YL Thongprasert S Yang CH Chu DT Saijo N Sunpaweravong P Han B Margono B Ichinose Y Nishiwaki Y Ohe Y Yang JJ Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma N Engl J Med 2009 361 947 957 19692680 \n26 Pawson T Regulation and targets of receptor tyrosine kinases Eur J Cancer 2002 38 S3 10 \n27 Fletcher JA Role of KIT and platelet-derived growth factor receptors as oncoproteins Semin Oncol 2004 31 4 11 \n28 Hendriks RW Drug discovery: New Btk inhibitor holds promise Nat Chem Biol 2011 7 4 5 21164510 \n29 Summy JM Gallick GE Treatment for advanced tumors: SRC reclaims center stage Clin Cancer Res 2006 12 1398 1401 16533761 \n30 Chen K Meric-Bernstam F Zhao H Zhang Q Ezzeddine N Tang LY Qi Y Mao Y Chen T Chong Z Zhou W Zheng X Johnson A Clinical actionability enhanced through deep targeted sequencing of solid tumors Clin Chem 2015 61 544 553 25626406 \n31 Lanman RB Mortimer SA Zill OA Sebisanovic D Lopez R Blau S Collisson EA Divers SG Hoon DS Kopetz ES Lee J Nikolinakos PG Baca AM Analytical and Clinical Validation of a Digital Sequencing Panel for Quantitative, Highly Accurate Evaluation of Cell-Free Circulating Tumor DNA PLoS One 2015 10 e0140712 26474073 \n32 Dogruluk T Tsang YH Espitia M Chen F Chen T Chong Z Appadurai V Dogruluk A Eterovic AK Bonnen PE Creighton CJ Chen K Mills GB Identification of Variant-Specific Functions of PIK3CA by Rapid Phenotyping of Rare Mutations Cancer Res 2015 75 5341 5354 26627007\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1949-2553",
"issue": "8(34)",
"journal": "Oncotarget",
"keywords": "biomarker; metastatic colorectal cancer; regorafenib; response; survival",
"medline_ta": "Oncotarget",
"mesh_terms": null,
"nlm_unique_id": "101532965",
"other_id": null,
"pages": "57882-57888",
"pmc": null,
"pmid": "28915719",
"pubdate": "2017-08-22",
"publication_types": "D016428:Journal Article",
"references": "22577890;23177514;24811491;16533761;16807070;22363134;26627007;22959186;25981818;26184520;22421192;21900593;8386825;22450065;12528767;25433983;23550210;26419617;19097774;21098728;18337605;25626406;24265351;22588877;24508104;28133314;21164510;19692680;15175998;25348405;26474073;21170960",
"title": "Genomic analysis of exceptional responder to regorafenib in treatment-refractory metastatic rectal cancer: a case report and review of the literature.",
"title_normalized": "genomic analysis of exceptional responder to regorafenib in treatment refractory metastatic rectal cancer a case report and review of the literature"
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"literaturereference": "KORPHAISARN K; LOREE JM; NGUYEN V; COULSON R; HOLLA V; KOPETZ S; ET AL. GENOMIC ANALYSIS OF EXCEPTIONAL RESPONDER TO REGORAFENIB IN TREATMENT-REFRACTORY METASTATIC RECTAL CANCER: A CASE REPORT AND REVIEW OF THE LITERATURE.. ONCOTARGET. 2017;XX:XX",
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"receiptdate": "20170629",
"receivedate": "20170629",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportid": 13700478,
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
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"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170830"
}
] |
{
"abstract": "A case of Cytomegalovirus (CMV) corneal endotheliitis following laser in-situ keratomileusis (LASIK) is presented. A 32-year-old man presented 3 weeks after uncomplicated myopic LASIK with unilateral LASIK flap oedema, interface fluid accumulation, keratic precipitates, anterior uveitis and raised intraocular pressure. Despite treatment with topical corticosteroids, he had 3 further recurrent episodes. Specular microscopy showed decreased endothelial cell density and aqueous humour. Polymerase chain reaction (PCR) testing was positive for CMV DNA. He was treated with topical ganciclovir and ketorolac, and the inflammation and oedema resolved. Repeat aqueous humour PCR testing was negative for CMV DNA, and he remained well at last follow-up (3 months after stopping all medications). CMV corneal endotheliitis can be reactivated after LASIK, and CMV DNA PCR of aqueous humour samples can help in definitive diagnosis. Early recognition and treatment of this condition is important to prevent permanent endothelial cell loss and corneal decompensation.",
"affiliations": "Singapore National Eye Centre, Singapore, Singapore.;Singapore National Eye Centre, Singapore, Singapore.;Singapore National Eye Centre, Singapore, Singapore.",
"authors": "Tan|Tien-En|TE|;Cheung|Chui Ming Gemmy|CM|;Mehta|Jodhbir S|JS|",
"chemical_list": "D000894:Anti-Inflammatory Agents, Non-Steroidal; D000998:Antiviral Agents; D004279:DNA, Viral; D015774:Ganciclovir; D020910:Ketorolac",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2016-216774",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2016()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000328:Adult; D000894:Anti-Inflammatory Agents, Non-Steroidal; D000998:Antiviral Agents; D001082:Aqueous Humor; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D004279:DNA, Viral; D004728:Endothelium, Corneal; D015828:Eye Infections, Viral; D015774:Ganciclovir; D006801:Humans; D020731:Keratomileusis, Laser In Situ; D020910:Ketorolac; D008297:Male; D016133:Polymerase Chain Reaction; D016896:Treatment Outcome; D014606:Uveitis, Anterior",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "27899387",
"pubdate": "2016-11-29",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21631677;12388030;25075122;16387027;23622566;18571077;21892696;25311411;19195708;17413969",
"title": "Activation of Cytomegalovirus corneal endotheliitis following laser in situ keratomileusis.",
"title_normalized": "activation of cytomegalovirus corneal endotheliitis following laser in situ keratomileusis"
} | [
{
"companynumb": "SG-ALLERGAN-1680036US",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
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{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MOXIFLOXACIN"
},
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"medicinalproduct": "MOXIFLOXACIN."
},
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE ACETATE"
},
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"drugdosageform": "EYE DROPS, SUSPENSION",
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"drugindication": "IRIDOCYCLITIS",
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"medicinalproduct": "PRED FORTE"
}
],
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"reaction": [
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Cytomegalovirus infection",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TAN T-E, CHEUNG MG, MS. ACTIVATION OF CYTOMEGALOVIRUS CORNEAL ENDOTHELIITIS FOLLOWING LASER IN SITU KERATOMILEUSIS. BMJ. 2016;VOL. 2016",
"literaturereference_normalized": "activation of cytomegalovirus corneal endotheliitis following laser in situ keratomileusis",
"qualification": "1",
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},
"primarysourcecountry": "SG",
"receiptdate": "20161223",
"receivedate": "20161214",
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20170207"
}
] |
{
"abstract": "AZD1775 (adavosertib) is an inhibitor of the Wee1 kinase. In this study, we built on our preclinical studies to evaluate the safety and efficacy of AZD1775 in combination with gemcitabine and radiation in patients with newly diagnosed locally advanced pancreatic cancer.\n\n\n\nThirty-four patients with locally advanced pancreatic cancer were enrolled with the intention to receive four 21-day cycles of gemcitabine (1,000 mg/m2 days 1 and 8) with AZD1775 (once daily on days 1, 2, 8, and 9). Cycles 2 and 3 were administered concurrently with radiation, and cycles 5 to 8 were optional. AZD1775 was dose escalated using a time-to-event continual reassessment method on the basis of the rate of dose-limiting toxicities within the first 15 weeks of therapy. The primary objective was to determine the maximum tolerated dose of AZD1775 given in conjunction with gemcitabine and radiation. Secondary objectives were to estimate overall and progression-free survival and determine pharmacodynamic activity of AZD1775 in surrogate tissues.\n\n\n\nThe recommended phase II dose of AZD1775 was 150 mg/d. Eight patients (24%) experienced a dose-limiting toxicity, most commonly anorexia, nausea, or fatigue. The median overall survival for all patients was 21.7 months (90% CI, 16.7 to 24.8 months), and the median progression-free survival was 9.4 months (90% CI, 8.0 to 9.9 months). Hair follicle biopsy samples demonstrated evidence of Wee1 inhibition with decreased phosphorylation of cyclin-dependent kinase 1 staining by immunohistochemistry after AZD1775 administration at the recommended phase II dose.\n\n\n\nAZD1775 in combination with gemcitabine and radiation therapy was well tolerated at a dose that produced target engagement in a surrogate tissue. The overall survival is substantially higher than prior results combining gemcitabine with radiation therapy and warrants additional investigation.",
"affiliations": "University of Michigan, Ann Arbor, MI.;University of Michigan, Ann Arbor, MI.;University of Michigan, Ann Arbor, MI.;University of Michigan, Ann Arbor, MI.;University of Michigan, Ann Arbor, MI.;University of Michigan, Ann Arbor, MI.;University of Michigan, Ann Arbor, MI.;University of Michigan, Ann Arbor, MI.;University of Michigan, Ann Arbor, MI.;University of Michigan, Ann Arbor, MI.;University of Michigan, Ann Arbor, MI.;University of Michigan, Ann Arbor, MI.;University of Michigan, Ann Arbor, MI.",
"authors": "Cuneo|Kyle C|KC|;Morgan|Meredith A|MA|;Sahai|Vaibhav|V|;Schipper|Matthew J|MJ|;Parsels|Leslie A|LA|;Parsels|Joshua D|JD|;Devasia|Theresa|T|;Al-Hawaray|Mahmoud|M|;Cho|Clifford S|CS|;Nathan|Hari|H|;Maybaum|Jonathan|J|;Zalupski|Mark M|MM|;Lawrence|Theodore S|TS|",
"chemical_list": "D018797:Cell Cycle Proteins; D004791:Enzyme Inhibitors; D011720:Pyrazoles; D011744:Pyrimidinones; D003841:Deoxycytidine; C056507:gemcitabine; D011505:Protein-Tyrosine Kinases; C499349:WEE1 protein, human; C549567:adavosertib",
"country": "United States",
"delete": false,
"doi": "10.1200/JCO.19.00730",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0732-183X",
"issue": "37(29)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D018797:Cell Cycle Proteins; D059248:Chemoradiotherapy; D003841:Deoxycytidine; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010190:Pancreatic Neoplasms; D011505:Protein-Tyrosine Kinases; D011720:Pyrazoles; D011744:Pyrimidinones; D015996:Survival Rate",
"nlm_unique_id": "8309333",
"other_id": null,
"pages": "2643-2650",
"pmc": null,
"pmid": "31398082",
"pubdate": "2019-10-10",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "26133775;17379445;16983110;19139112;22543215;27725641;11129476;27160474;11709563;20194642;24131140;23562156;21937510;29895190;26975930;9034337;19273710;25435281;26972648;21561347;25538019;22907750;23804422;27139057;21969502;21482692;22797065;9196156;12676583;15665856;21992793;27601554;15831461;26585231",
"title": "Dose Escalation Trial of the Wee1 Inhibitor Adavosertib (AZD1775) in Combination With Gemcitabine and Radiation for Patients With Locally Advanced Pancreatic Cancer.",
"title_normalized": "dose escalation trial of the wee1 inhibitor adavosertib azd1775 in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer"
} | [
{
"companynumb": "US-PFIZER INC-2019342307",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
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"drugdosagetext": "UNK, CYCLIC (FOURTH CYCLE OF GEMCITABINE DURING WEEKS 12 TO 14)",
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"medicinalproduct": "GEMCITABINE HYDROCHLORIDE."
},
{
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},
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"medicinalproduct": "ADAVOSERTIB."
},
{
"actiondrug": "1",
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},
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"drugindication": "ADENOCARCINOMA PANCREAS",
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"medicinalproduct": "ADAVOSERTIB."
},
{
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Decreased appetite",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CUNEO, K.. DOSE ESCALATION TRIAL OF THE WEE1 INHIBITOR ADAVOSERTIB (AZD1775) IN COMBINATION WITH GEMCITABINE AND RADIATION FOR PATIENTS WITH LOCALLY ADVANCED PANCREATIC CANCER. JOURNAL OF CLINICAL ONCOLOGY. 2019?37 (29):2643-2650",
"literaturereference_normalized": "dose escalation trial of the wee1 inhibitor adavosertib azd1775 in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20201118",
"receivedate": "20190821",
"receiver": {
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"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 16725218,
"safetyreportversion": 3,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210113"
},
{
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"medicinalproduct": "ADAVOSERTIB."
},
{
"actiondrug": "1",
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"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
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"drugdosagetext": "1000 MG/M2, CYCLIC (OVER 30 MINUTES ON DAYS 1 AND 8 OF EACH 3-WEEK CYCLE)",
"drugenddate": null,
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"drugindication": "ADENOCARCINOMA PANCREAS",
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"medicinalproduct": "GEMCITABINE HYDROCHLORIDE."
},
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},
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"medicinalproduct": "ADAVOSERTIB."
},
{
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},
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"medicinalproduct": "GEMCITABINE HYDROCHLORIDE."
}
],
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"reaction": [
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}
],
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},
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"literaturereference_normalized": "dose escalation trial of the wee1 inhibitor adavosertib azd1775 in combination with gemcitabine and radiation for patients with locally advanced pancreatic cancer",
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},
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},
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"seriousnessother": 1,
"transmissiondate": "20210113"
},
{
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"patient": {
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},
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"drugcharacterization": "1",
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"drugdosageform": "POWDER FOR INJECTION",
"drugdosagetext": "1000 MG/M2, CYCLIC (OVER 30 MINUTES ON DAYS 1 AND 8 OF EACH 3-WEEK CYCLE)",
"drugenddate": null,
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"drugindication": "ADENOCARCINOMA PANCREAS",
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"medicinalproduct": "GEMCITABINE HYDROCHLORIDE."
},
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{
"abstract": "We present a case of acute anterior myocardial infarction in a breastfeeding woman, 10 days after delivery. The presumed cause was proximal left anterior artery vasospasm, induced by a combination of smoking a first cigarette in the early morning and salbutamol inhalation, in the particular context of peripartum. We discuss briefly the epidemiology, pathophysiology, risk factors, diagnosis, treatment and prognosis of myocardial infarction related to pregnancy and the postpartum period.",
"affiliations": "Department of Cardiology, Erasme University Hospital Brussels, Belgium. Elkedv@msn.com",
"authors": "De Vuyst|Elke|E|;Preumont|Nicolas|N|;Renard|Marc|M|",
"chemical_list": "D058666:Adrenergic beta-2 Receptor Agonists; D000420:Albuterol",
"country": "England",
"delete": false,
"doi": "10.1080/ac.67.4.2170690",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5385",
"issue": "67(4)",
"journal": "Acta cardiologica",
"keywords": null,
"medline_ta": "Acta Cardiol",
"mesh_terms": "D058666:Adrenergic beta-2 Receptor Agonists; D000328:Adult; D000420:Albuterol; D056988:Anterior Wall Myocardial Infarction; D001942:Breast Feeding; D003329:Coronary Vasospasm; D005260:Female; D006801:Humans; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011644:Puerperal Disorders; D012907:Smoking",
"nlm_unique_id": "0370570",
"other_id": null,
"pages": "465-7",
"pmc": null,
"pmid": "22998003",
"pubdate": "2012-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute myocardial infarction in early postpartum.",
"title_normalized": "acute myocardial infarction in early postpartum"
} | [
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"abstract": "A late preterm infant had pulmonary hypertension caused by a variety of mechanisms leading to complex management. This child had complete atrioventricular septal defect associated with mild left ventricular hypoplasia and Down syndrome diagnosed prenatally. The mother had been treated by antiretroviral HIV treatment during pregnancy. Aortic coarctation was diagnosed and rapidly repaired. After surgery, he required noninvasive ventilation for persisting elevated PCO2. Pulmonary CT scan showed normal bronchial tree, lung parenchymal abnormalities with mosaic aspect and hyperlucent zones, and indirect signs of lung hypoplasia with peripheral microbubbles. During follow-up, severe pulmonary hypertension was diagnosed on echocardiography without recoarctation, significant intracardiac shunting or diastolic dysfunction. The patient died after four months unable to be weaned from noninvasive ventilation. Post mortem lung biopsy showed abnormally muscularized arterioles with intimal fibrosis and pulmonary immaturity. Gentetic screening identified a BMPR-2 mutation. This patient illustrates the multifactorial origin of pulmonary hypertension in the neonatal period. The respective contribution of left-to-right shunt, post-capillary obstruction, and abnormally elevated pulmonary vascular resistances led to perform right heart catheterization to exclude excessive shunting and restrictive physiology of the left heart. Subjects with Down syndrome are also highly susceptible to decreased lung vascular and alveolar growth, which may increase the risk for pulmonary hypertension and lung hypoplasia. This case highlights two issues. The first one is that right heart catheterization should be discussed in neonates with unexplained pulmonary hypertension and the second is to extend indications of genetic testing for pulmonary hypertension genes in neonates who have unusual course of neonatal pulmonary hypertension, particularly in the setting of associated congenital heart disease (CHD).",
"affiliations": "M3C-Necker, Centre de Référence Malformations Cardiaques Congénitales Complexes, Hôpital Universitaire Necker-Enfants malades, Assistance Publique - Hôpitaux de Paris, Paris, France.;M3C-Necker, Centre de Référence Malformations Cardiaques Congénitales Complexes, Hôpital Universitaire Necker-Enfants malades, Assistance Publique - Hôpitaux de Paris, Paris, France.;M3C-Necker, Centre de Référence Malformations Cardiaques Congénitales Complexes, Hôpital Universitaire Necker-Enfants malades, Assistance Publique - Hôpitaux de Paris, Paris, France.;M3C-Necker, Centre de Référence Malformations Cardiaques Congénitales Complexes, Hôpital Universitaire Necker-Enfants malades, Assistance Publique - Hôpitaux de Paris, Paris, France.",
"authors": "Bajolle|Fanny|F|https://orcid.org/0000-0002-1106-0987;Malekzadeh-Milani|S|S|;Lévy|M|M|;Bonnet|D|D|",
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"fulltext": "\n==== Front\nPulm Circ\nPulm Circ\nPUL\nsppul\nPulmonary Circulation\n2045-8932\n2045-8940\nSAGE Publications Sage UK: London, England\n\n10.1177/20458940211027433\n10.1177_20458940211027433\nCase Report\nMultifactorial origin of pulmonary hypertension in a child with congenital heart disease, Down syndrome, and BMPR-2 mutation\nhttps://orcid.org/0000-0002-1106-0987\nBajolle Fanny 1\nMalekzadeh-Milani S. 1\nLévy M. 1\nBonnet D. 12\n1 M3C-Necker, Centre de Référence Malformations Cardiaques Congénitales Complexes, Hôpital Universitaire Necker-Enfants malades, Assistance Publique – Hôpitaux de Paris, Paris, France\n2 Université de Paris, Paris, France\nFanny Bajolle, Cardiologie Congénitale et Pédiatrique, Hôpital Necker-Enfants malades, AP-HP, 149 rue de Sèvres, 75015 Paris, France. Email: fanny.bajolle@aphp.fr\n5 7 2021\nJul-Sep 2021\n11 3 204589402110274334 4 2021\n5 6 2021\n© The Author(s) 2021\n2021\nSAGE Publications Ltd, or Pulmonary Vascular Research Institute, unless otherwise noted. Manuscript content on this site is licensed under Creative Commons Licenses\nhttps://creativecommons.org/licenses/by-nc/4.0/ Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial 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).\nA late preterm infant had pulmonary hypertension caused by a variety of mechanisms leading to complex management. This child had complete atrioventricular septal defect associated with mild left ventricular hypoplasia and Down syndrome diagnosed prenatally. The mother had been treated by antiretroviral HIV treatment during pregnancy. Aortic coarctation was diagnosed and rapidly repaired. After surgery, he required noninvasive ventilation for persisting elevated PCO2. Pulmonary CT scan showed normal bronchial tree, lung parenchymal abnormalities with mosaic aspect and hyperlucent zones, and indirect signs of lung hypoplasia with peripheral microbubbles. During follow-up, severe pulmonary hypertension was diagnosed on echocardiography without recoarctation, significant intracardiac shunting or diastolic dysfunction. The patient died after four months unable to be weaned from noninvasive ventilation. Post mortem lung biopsy showed abnormally muscularized arterioles with intimal fibrosis and pulmonary immaturity. Gentetic screening identified a BMPR-2 mutation. This patient illustrates the multifactorial origin of pulmonary hypertension in the neonatal period. The respective contribution of left-to-right shunt, post-capillary obstruction, and abnormally elevated pulmonary vascular resistances led to perform right heart catheterization to exclude excessive shunting and restrictive physiology of the left heart. Subjects with Down syndrome are also highly susceptible to decreased lung vascular and alveolar growth, which may increase the risk for pulmonary hypertension and lung hypoplasia. This case highlights two issues. The first one is that right heart catheterization should be discussed in neonates with unexplained pulmonary hypertension and the second is to extend indications of genetic testing for pulmonary hypertension genes in neonates who have unusual course of neonatal pulmonary hypertension, particularly in the setting of associated congenital heart disease (CHD).\n\natrioventricular septal defect (AVSD)\ntrisomy 21\ndevelopmental lung disease\ngenetic mutation\nantiretroviral HIV\ncover-dateJuly-September 2021\ntypesetterts2\n==== Body\nIntroduction\n\nIt is not exceptional that multiple factors contribute to the development of pulmonary hypertension (PH) in children. We report a case of a late preterm infant with PH caused or aggravated by a variety of mechanisms leading to inextricable decision making.\n\nCase report\n\nA late preterm male neonate (35 weeks, birth weight 2.1 (fifth percentile)) with prenatal diagnosis of complete atrioventricular septal defect (AVSD) associated with mild left ventricular hypoplasia and Down syndrome (DS) was admitted at birth. The mother had been treated by antiretroviral HIV treatment (ritonavir, darunavir, and emtricitabine/tenofovir) during pregnancy. The child was started on zidovudine for one month. His HIV-PCR was negative. Complete AVSD with mild left heart hypoplasia and small ventricular septal defect (VSD) was confirmed. Aortic coarctation was rapidly diagnosed and was repaired through left thoracotomy. After surgery, the child required noninvasive ventilation for persisting elevated PCO2. Pulmonary CT scan showed normal bronchial tree, lung parenchymal abnormalities located in the left upper lobe and right inferior lobe with mosaic aspect of the lung and hyperlucent zones, and indirect signs of lung hypoplasia with peripheral microbubbles. During follow-up, severe PH was diagnosed on transthoracic echocardiography with an estimated systolic pulmonary arterial pressure of 100 mmHg. Right heart catheterization confirmed severe PH (with pulmonary artery pressure 72/25/44 mmHg and aortic pressure 70/39/50 mmHg) without recoarctation, significant intracardiac shunting nor diastolic dysfunction. Right atrial pressure was 10 mmHg, as well as left atrial pressure (large ostium primum). Based on the Fick Principle, indexed pulmonary vascular resistance (PVRi) was 7.6 WU × m2, QP/QS: 0.7, and cardiac index: 6 l/min/m2. He was treated by sildenafil two months after diagnosis without significant improvement. The patient died after four months unable to be weaned from noninvasive ventilation. Post mortem lung biopsy showed abnormally muscularized arterioles with intimal fibrosis (Fig. 1). The intimal lesions were highly cellularized indicating an active process. Venous vessels and lymphatic were normal as well as vessel organization. Alveoli wall were thickened as observed in pulmonary immaturity. As current practice in atypical cases with lung development anomalies, a PH genetic panel was performed in our dedicated PH lab and identified a heterozygote BMPR-2 mutation (c.1969C>T).\n\nFig. 1. Post mortem lung biopsy showing severe pulmonary arterial lesions and thickening of alveolar walls but without anomalies of pulmonary veins nor bronchial circulation. (a) and (b): HES and orcein staining showing ×10 showing few pulmonary alveoli and thick alveolar wall indicating immature lung; (c) and (d): Orcein staining ×10 and ×25 showing thick-walled intra-acinar pulmonary arteries with severe intimal proliferation and occluded lumen. Note that the surrounding parenchyma exhibits thick-walled and poor ventilated alveoli; (e) and (f): HES and orcein staining ×40 showing normal pulmonary veins without intimal fibrosis nor muscularized wall; (g) and (h): D2-40 immunostaining and actin ×25 showing that vessels surrounding occluded pulmonary arteries are lymphatics and not veins, nor bronchial arteries.\n\nDiscussion\n\nThis patient illustrates the multifactorial origin of PH in the neonatal period. Indeed, the AVSD is an obvious cause of PH but the VSD was small and should have been restrictive if pulmonary resistances had normally dropped after birth. The role of the atrial shunting aggravated by the small size of the left ventricle was a possible mechanism for severe neonatal PH. 1 The association of elevated PVR with left heart obstructive disease is also known in neonates. 1 The respective contribution of left-to-right shunt, abnormally elevated PVR, and post-capillary obstruction led to perform right heart catheterization in this infant to exclude excessive shunting and restrictive physiology of the left heart.\n\nNewborn infants with DS are at high risk of developing severe persistent PH of the newborn. 2 They also have more aggressive pulmonary vascular disease secondary to congenital heart defects compared to children without DS. 2 While the mechanisms that increase PH susceptibility of infants with DS are incompletely understood, lung hypoplasia with decreased alveolarization, peripheral lung cysts, and persistence of the double-capillary network has been described. 3 In this patient, we showed alveolar simplification (Fig. 1a and b) but we did not see double capillary network, prominent bronchial artery circulation nor intrapulmonary connections in form of bronchopulmonary anastomoses. Recent work has shown that three antiangiogenic genes are present on chromosome 21, and are each overexpressed in human fetal and infant lung tissue. 4 Experimentally, early disruption of angiogenic signaling decreases vascular growth and increases the risk for PH, and also impairs distal airspace growth. 5 Laboratory and clinical findings suggest that subjects with DS are highly susceptible to decreased lung vascular and alveolar growth, which may increase the risk for PH and lung hypoplasia as in our patient. The current WSPH Paediatric Task Force agreed that the phenotype of DS-related PH is variable and does not universally fit into a single classification group, but that children with DS will be classified as group 3 (“developmental lung disease”) in the absence of CHD. In our patient, chronic ventilation was necessary but PH did not improve while normal PCO2 and normal oxygenation were normalized.\n\nGenetic factors underlying persistent PH of newborns in a cohort of Chinese neonates had been recently described. Nine patients were identified as harboring genetic variants, including three with pathogenic/likely pathogenic variants in TBX4 and BMPR-2 and six with variants of unknown significance in BMPR-2, SMAD9, TGFB1, KCNA5 and TRPC6. 6 Three single nucleotide polymorphisms (SNPs) in CPS1 and one SNP in NOTCH3 were significantly associated with persistent PH of the newborn. CPS1 and SMAD9 were identified as risk genes for persistent PH of the newborn. 6 Currently, no BMPR-2 mutation associated to DS had been reported in this setting.\n\nIn addition, it is known that perinatally HIV-exposed but uninfected children had cardiac effect after birth. 7 Zidovudine was also suggested to affect the structural development of the human fetal lung in vitro. Disentangling these different mechanisms and identifying the most important contributor is challenging, indeed impossible. Hitherto, however, this case highlights two issues to our opinion. The first one is that right heart catheterization should be discussed in all neonatal cases when non-invasive informations cannot confirm the role of the congenital heart defect in the persistence of high PVR during the neonatal period or when these informations are ambiguous. The second issue is to extend indications of genetic testing for mutations/variants of the known PH genes in neonates who have unusual course of neonatal PH, particularly in the setting of associated congenital heart disease. Here, we were surprised to find a mutation in the BMPR-2 gene as they have rarely been observed in congenital heart diseases with PH, 8 while TBX4 and SOX17 mutations are increasingly reported. 9 Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease. 10 This unusual case is an example of multifactorial origin of neonatal PH or an illustration of the multiple hits that could lead to irreversible pulmonary vascular disease or neonatal maladaptation.\n\nAcknowledgements\n\nWe would like to thank the patient’s family for their consent to publish this report.\n\nConflict of interest: The author(s) declare that there is no conflict of interest.\n\nAuthor contributions: F.B. collected the data, drafted the manuscript, and revised the manuscript. S.M.-M., M.L., and D.B. critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.\n\nFunding: This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nORCID iD: Fanny Bajolle https://orcid.org/0000-0002-1106-0987\n==== Refs\nReferences\n\n1 Rosenzweig EB Abman SH Adatia I , et al . Paediatric pulmonary arterial hypertension: updates on definition, classification, diagnostics and management. Eur Respir J 2019; 53 : 1801916.30545978\n2 Bush D Galambos C Ivy DD , et al . Clinical characteristics and risk factors for developing pulmonary hypertension in children with Down syndrome. J Pediatr 2018; 202 : 212.e2–219.e2.30025669\n3 Bush D Abman SH Galambos C. Prominent intrapulmonary bronchopulmonary anastomoses and abnormal lung development in infants and children with Down syndrome. J Pediatr 2017; 180 : 156.e1–162.e1.27666181\n4 Galambos C Minic AD Bush D , et al . Increased lung expression of anti-angiogenic factors in Down syndrome: potential role in abnormal lung vascular growth and the risk for pulmonary hypertension. PLoS One 2016; 11 : e0159005.27487163\n5 Sanchez O Marcos E Perros F , et al . Role of endothelium-derived CC chemokine ligand 2 in idiopathic pulmonary arterial hypertension. Am J Respir Crit Care Med 2007; 176 : 1041–104–7.17823354\n6 Liu X Mei M Chen X , et al . Identification of genetic factors underlying persistent pulmonary hypertension of newborns in a cohort of Chinese neonates. Respir Res 2019; 20 : 174.31382961\n7 Lipshultz SE Miller TL Wilkinson JD , et al . Cardiac effects in perinatally HIV-infected and HIV-exposed but uninfected children and adolescents: a view from the United States of America. J Int AIDS Soc 2013; 16 : 18597.23782480\n8 Liu D Liu QQ Guan LH , et al . BMPR2 mutation is a potential predisposing genetic risk factor for congenital heart disease associated pulmonary vascular disease. Int J Cardiol 2016; 211 : 132–136.27002414\n9 Hernandez-Gonzalez I Tenorio J Palomino-Doza J , et al . Clinical heterogeneity of pulmonary arterial hypertension associated with variants in TBX4. PLoS One 2020; 15 : e0232216.32348326\n10 Zhu N Welch CL Wang J , et al . Rare variants in SOX17 are associated with pulmonary arterial hypertension with congenital heart disease. Genome Med 2018; 10 : 56.30029678\n\n",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Atrioventricular septal defect",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Bajolle F, Malekzadeh-Milani S, Levy M, Bonnet D.. Multifactorial origin of pulmonary hypertension in a child with congenital heart disease, Down syndrome, and BMPR-2 mutation.. Pulm-Circ. 2021;11(3):1-3",
"literaturereference_normalized": "multifactorial origin of pulmonary hypertension in a child with congenital heart disease down syndrome and bmpr 2 mutation",
"qualification": "3",
"reportercountry": "FR"
},
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},
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}
] |
{
"abstract": "We present the case of 60-year-old man with type 2 diabetes who developed blistering after two sequential exposures to linagliptin. Linagliptin is one of the dipeptidyl peptidase 4 (DPP-4) inhibitors, a group of oral hypoglycaemic agents used commonly for the treatment of type 2 diabetes. On the first exposure to linagliptin, he developed blisters on the hands which resolved after stopping the drug. After repeat exposure, he developed two large blisters on the left foot, which burst giving rise to secondary infection, requiring hospital admission for treatment. We discuss the latest research linking DPP-4 inhibitors with adverse skin reactions and the effect of ulcers on the morbidity and mortality of patients with diabetes. This case report highlights skin reactions as an important, rare and lesser known side effect of DPP-4 inhibitors.",
"affiliations": "Acute Medicine Department, Whittington Hospital, London, UK.;Diabetes & Endocrinology Department, Barnet Hospital, Herts, UK.;Diabetes & Endocrinology Department, Barnet Hospital, Herts, UK.",
"authors": "Psomadakis|Cristina|C|;Shahzad|Naima|N|;Katz|Jonathan|J|",
"chemical_list": "D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D000069476:Linagliptin",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-219998",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2017()",
"journal": "BMJ case reports",
"keywords": "Dermatology; Diabetes; Drugs and medicines; Endocrine system; Skin",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000284:Administration, Oral; D001768:Blister; D003924:Diabetes Mellitus, Type 2; D003937:Diagnosis, Differential; D054873:Dipeptidyl-Peptidase IV Inhibitors; D006801:Humans; D007004:Hypoglycemic Agents; D000069476:Linagliptin; D008297:Male; D008875:Middle Aged; D012872:Skin Diseases, Vesiculobullous",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28566414",
"pubdate": "2017-05-31",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16291066;16291068;20625027;21437125;21466592;23426497;24748908;26465961;7249508",
"title": "Linagliptin-associated blistering and ulceration.",
"title_normalized": "linagliptin associated blistering and ulceration"
} | [
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"companynumb": "GB-B.I. PHARMACEUTICALS,INC./RIDGEFIELD-2017-BI-032269",
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},
{
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"activesubstancename": "AMLODIPINE BESYLATE"
},
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"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"drugstructuredosageunit": "003",
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"medicinalproduct": "AMLODIPINE"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
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"drugintervaldosagedefinition": "804",
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"drugseparatedosagenumb": "1",
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"drugstructuredosagenumb": "75",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ASPIRIN."
}
],
"patientagegroup": null,
"patientonsetage": "60",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Blister",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Infected skin ulcer",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Cellulitis",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PSOMADAKIS C, SHAHZAD N, JONATHAN K. LINAGLIPTIN-ASSOCIATED BLISTERING AND ULCERATION. BMJ CASE REPORTS. 2017;.",
"literaturereference_normalized": "linagliptin associated blistering and ulceration",
"qualification": "1",
"reportercountry": "GB"
},
"primarysourcecountry": "GB",
"receiptdate": "20170615",
"receivedate": "20170615",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13654489,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170830"
}
] |
{
"abstract": "Contraception is recommended during imatinib therapy based on the teratogenicity data in rats. However, patients may become pregnant and here we describe a successful pregnancy and labor without any congenital anomaly in a patient with chronic myeloid leukemia (CML) under treatment with imatinib. The patient had received imatinib for 53 months before she became pregnant, with a complete cytogenetic response achieved after 6 months of therapy and a major molecular response (MMR) after 28 months. CML was in MMR at discovery of pregnancy and the fetus had been exposed to imatinib for 5 weeks. Treatment was discontinued, but MMR persisted during gestation.",
"affiliations": "Department of Internal Medicine, Fujita Health University, School of Medicine, Toyoake. mtsuzuki@fujita-hu.ac.jp",
"authors": "Tsuzuki|Motohiro|M|;Inaguma|Youko|Y|;Handa|Kousuke|K|;Hasegawa|Akio|A|;Yamamoto|Yukiya|Y|;Watanabe|Masato|M|;Mizuta|Syuichi|S|;Maruyama|Fumio|F|;Okamoto|Masataka|M|;Emi|Nobuhiko|N|",
"chemical_list": "D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.48.2084",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0918-2918",
"issue": "48(16)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": null,
"medline_ta": "Intern Med",
"mesh_terms": "D001549:Benzamides; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D007231:Infant, Newborn; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D010879:Piperazines; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011743:Pyrimidines; D012074:Remission Induction; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1433-5",
"pmc": null,
"pmid": "19687593",
"pubdate": "2009",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Successful pregnancy in a patient with chronic myeloid leukemia under treatment with imatinib.",
"title_normalized": "successful pregnancy in a patient with chronic myeloid leukemia under treatment with imatinib"
} | [
{
"companynumb": "PHHY2009JP35291",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": null,
"drugadministrationroute": "064",
"drugauthorizationnumb": "021588",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "MATERNAL DOSE: 200 MG, QD",
"drugenddate": "20070727",
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"medicinalproduct": "GLIVEC"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "IMATINIB MESYLATE"
},
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"drugdosagetext": "MATERNAL DOSE: 400 MG, QD",
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"drugstartdate": "20070728",
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"medicinalproduct": "GLIVEC"
},
{
"actiondrug": "6",
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"activesubstancename": "IMATINIB MESYLATE"
},
"drugadditional": null,
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"drugcumulativedosageunit": null,
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"drugdosagetext": "MATERNAL DOSE: 400 MG/DAY",
"drugenddate": "20061104",
"drugenddateformat": "102",
"drugindication": "FOETAL EXPOSURE DURING PREGNANCY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
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"drugstartdateformat": "102",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "GLIVEC"
}
],
"patientagegroup": "1",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "1",
"patientweight": "2.56",
"reaction": [
{
"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Abortion threatened",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Premature baby",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Induced labour",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 20070416"
}
},
"primarysource": {
"literaturereference": "TSUZUKI M, INAGUMA Y, HANDA K, HASEGAWA A, YAMAMOTO Y, WATANABE M ET AL.. SUCCESSFUL PREGNANCY IN A PATIENT WITH CHRONIC MYELOID LEUKEMIA UNDER TREATMENT WITH IMATINIB. INTERNAL MEDICINE. 2009?48:1433?5",
"literaturereference_normalized": "successful pregnancy in a patient with chronic myeloid leukemia under treatment with imatinib",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20180930",
"receivedate": "20090902",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 7103609,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20181010"
}
] |
{
"abstract": "Clozapine is more effective than other atypical antipsychotics for treatment resistant schizophrenia, but has serious side effects. Clozapine has an estimated cumulative seizure risk of 10% in patients treated for 3.8 years. Bupropion can also induce seizures and its estimated risk is 0.4% at recommended doses. While some risk factors for seizures are known, much remains unknown about predicting seizure risk. Cases: We present 2 cases of seizures in patients treated with clozapine and bupropion without a seizure history. In the first case, a patient with schizoaffective disorder treated with dual antipsychotic therapy had a witnessed generalized tonic-clonic seizure. With the exception of bupropion/naltrexone which was started 2.5 months prior for weight loss, she had not had any recent medication changes. In the second case, a patient with schizoaffective disorder was treated with clozapine and was prescribed bupropion SR for smoking cessation for an extended duration. He had cut back on cigarette use in the 2 months prior to reporting \"spells.\" The neurologist's assessment was probable epileptic seizures which resolved after the bupropion was stopped and divalproex was started for seizure prophylaxis.\nClozapine and bupropion are known to lower the seizure threshold, but little information is available regarding the risk when used in combination. It is unclear whether these agents, when used in combination, have additive seizure risk or possible synergistic effects. Bupropion should be used cautiously in patients treated with clozapine. Safer agents that do not lower the seizure threshold should be utilized whenever possible.",
"affiliations": "Pharmacy Department, 20057Fargo VA Health Care System, ND, USA.;Pharmacy Department, 20057Fargo VA Health Care System, ND, USA.;Mental Health Department, 20057Fargo VA Health Care System, ND, USA.",
"authors": "Schmitz|Allison|A|https://orcid.org/0000-0001-6663-7985;Botner|Brandon|B|;Hund|Morris|M|",
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"abstract": "Nocturnal hypertension (NH) is a symptom of cardiovascular dysautonomia in multiple system atrophy (MSA); however, care and medication are often insufficient. We herein report a patient with MSA who showed posterior reversible encephalopathy syndrome (PRES) caused by hypertension during sleep. He presented clinically with total blindness; T2-weighted magnetic resonance imaging showed high signal intensities in the bilateral subcortical occipital-temporal lobes. His PRES was completely reversed by blood pressure control. NH may contribute to the development of PRES. The appropriate assessment and management of hemodynamic changes in MSA, including NH, is necessary to prevent severe complications such as PRES.",
"affiliations": "Department of Neurology, Tenri Hospital, Japan.;Department of Neurology, Tenri Hospital, Japan.;Department of Neurology, Tenri Hospital, Japan.;Department of Neurology, Tenri Hospital, Japan.",
"authors": "Yagita|Kaoru|K|;Tsukita|Kazuto|K|;Shinde|Akiyo|A|;Suenaga|Toshihiko|T|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2987727810.2169/internalmedicine.0759-18Case ReportNocturnal Hypertension in Multiple System Atrophy May Cause Posterior Reversible Encephalopathy Syndrome Yagita Kaoru 1Tsukita Kazuto 1Shinde Akiyo 1Suenaga Toshihiko 1\n1 Department of Neurology, Tenri Hospital, JapanCorrespondence to Dr. Kaoru Yagita, yagita.k@gmail.com\n\n6 6 2018 1 11 2018 57 21 3187 3191 5 1 2018 3 4 2018 Copyright © 2018 by The Japanese Society of Internal Medicine2018The 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/).Nocturnal hypertension (NH) is a symptom of cardiovascular dysautonomia in multiple system atrophy (MSA); however, care and medication are often insufficient. We herein report a patient with MSA who showed posterior reversible encephalopathy syndrome (PRES) caused by hypertension during sleep. He presented clinically with total blindness; T2-weighted magnetic resonance imaging showed high signal intensities in the bilateral subcortical occipital-temporal lobes. His PRES was completely reversed by blood pressure control. NH may contribute to the development of PRES. The appropriate assessment and management of hemodynamic changes in MSA, including NH, is necessary to prevent severe complications such as PRES. \n\nmultiple system atrophy (MSA)nocturnal hypertension (NH)posterior reversible encephalopathy syndrome (PRES)\n==== Body\nIntroduction\nPosterior reversible encephalopathy syndrome (PRES) is clinically heterogeneous and characterized by vasogenic brain edema that can induce acute neurological symptoms. A primary cause of PRES is wide fluctuations in blood pressure (1).\n\nMultiple system atrophy (MSA) is a rare neurodegenerative disorder characterized by progressive autonomic failure and extrapyramidal and cerebellar features in various combinations. Variable autonomic failure is observed in MSA patients and is associated with a poor prognosis (2). Cardiovascular autonomic failures, such as orthostatic hypotension, supine hypertension, and nocturnal hypertension (NH), may cause marked fluctuations in blood pressure. However, only two studies have reported MSA cases with cardiovascular autonomic failures leading to PRES (3,4).\n\nWe herein report a case of MSA in which the patient developed PRES during sleep. He was later determined to have NH which may have caused his PRES. This is the first case in which an MSA patient developed PRES during sleep. This suggests that cardiovascular autonomic failure and NH in MSA can cause severe complications, such as PRES.\n\nCase Report\nA 63-year-old man with a 3-year history of MSA had total blindness upon waking. Approximately three years earlier, he had developed parkinsonism with bradykinesia and rigidity. His parkinsonism gradually became resistant to levodopa, and he developed cerebellar ataxia and autonomic failure, which manifested as conditions such as constipation and urinary retention. 123I-metaiodobenzylguanidine (MIBG) scintigraphy showed early and delayed heart-to-mediastinum (H/M) ratios of 2.04 and 1.79, respectively. The washout rate was 56.8%. Brain magnetic resonance imaging (MRI) showed cruciform hyperintensity in the pons and high-intensity bilateral lesions at the middle cerebellar peduncles on T2-weighted sequencing. He was diagnosed with a probable parkinsonian variant of MSA (5).\n\nThirty-two months after developing parkinsonism, he experienced frequent episodes of postural syncope and was eventually bedridden despite taking droxidopa after breakfast. The initial dosage was 200 mg/day, with an increase to 400 mg/day 1 month later. He also became more susceptible to infections and developed aspiration pneumonia and a urinary tract infection. Four days prior to the onset of total blindness, he developed aspiration pneumonia and began taking sulbactam/ampicillin. He remained primarily in a supine position, and his blood pressure increased without pain. His supine blood pressure was 130/60 mmHg 2 weeks before the onset of total blindness and increased to 170/80 mmHg a few days before the onset (Fig. 1). He awoke with total blindness despite having intact visual acuity the previous day.\n\nFigure 1. Time course showing gradual progression of supine hypertension and favorable response to nicardipine, amlodipine, and enalapril. X: day of onset, sBP: systolic blood pressure, dBP: diastolic blood pressure, mBP: mean blood pressure\n\nThe patient's medical history included gastrectomy for cancer and endoscopic submucosal dissection for esophageal cancer. His medications included taltirelin hydrate, droxidopa, and laxatives. He had not taken anticancer or immunosuppressant drugs. On an examination, he was confused and disoriented. His supine blood pressure was 200/103 mmHg, his pulse was 81 bpm and regular, and his temperature was 37.6℃. On a neurological examination, he had no light perception but did have a brisk bilateral light reflex. No other findings were remarkable compared with those on recent previous examinations. He exhibited right-dominant rigidity and a grade of 4 on the Medical Research Council scale in all muscle groups without paralysis. The levels of hemoglobin, platelets, serum protein, albumin, creatinine, and liver enzymes were all within the normal ranges, but his white blood cell count and C-reactive protein level were elevated, indicating an inflammatory response to aspiration pneumonia. These data were unchanged from two days earlier. T2-weighted brain MRI showed a high signal intensity in the bilateral cortical and subcortical occipital-temporal-parietal lobes. MR angiography did not show clear evidence of cerebral vasoconstriction. Fig. 2A-C shows a lesion with a high signal intensity on diffusion-weighted images and an apparent diffusion coefficient map.\n\nFigure 2. Brain magnetic resonance imaging (MRI) on the day of onset of posterior reversible encephalopathy syndrome. (A) T2-weighted image showing hyperintensity in the cortical and subcortical bilateral occipital-temporal lobes. (B), (C) Diffusion-weighted image and apparent diffusion coefficient map demonstrating vasogenic edema. (D) T2-weighted brain MRI after 15 days, showing remarkable reduction in high signal intensity, and (E) MRI after 92 days, showing complete resolution of abnormalities.\n\nThe patient was diagnosed with PRES, and hypertension was considered the most probable cause. Droxidopa was discontinued, and nicardipine was continuously administered for one week. His visual acuity improved markedly. He was able to count fingers two days after onset, and his visual acuity returned to normal five days after onset. Six days after he developed PRES, he was administered amlodipine at 5 mg/day and enalapril at 5 mg/day. His supine blood pressure was controlled between 100/65 and 140/80 mmHg (Fig. 1). Brain MRI showed marked improvement 15 days after the onset, but the change was completely unremarkable 92 days after the onset (Fig. 2D and E).\n\nA head-up tilt test conducted 23 days after the onset revealed severe orthostatic hypotension with a blood pressure of 142/78 mmHg in the supine position and 96/60 mmHg 5 min after the head-up test, with a heart rate increase from 70 bpm to 86 bpm and a noradrenalin value within the normal range. The 24-h ambulatory blood pressure monitoring (24-h ABPM) score 30 days after the onset revealed NH (Fig. 3). The 24-h ABPM score indicated reverse dipping NH; the daytime mean blood pressure was 108/68 mmHg, and the nighttime mean was 116/71 mmHg (6). The patient also exhibited postprandial hypotension, and his blood pressure fluctuated widely because of postural changes during rehabilitation.\n\nFigure 3. Scores for 24-hour ambulatory blood pressure monitoring over the 30-day disease course, showing higher blood pressure during the night than during the daytime (i.e., reverse dipping nocturnal hypertension). Blood pressure widely fluctuated with external stimulation, such as enteral nutrition and changes in position.\n\nThe patient discontinued taking droxidopa and spent lots of time in the head-up position throughout the day and night after the development of PRES, which was effective for his supine hypertension. In addition, we tried to change his posture and administer meals more slowly to prevent blood pressure fluctuation. These nonpharmacological interventions were effective, and his syncope was not seen despite the discontinuation of droxidopa.\n\nDiscussion\nPRES is a clinically heterogeneous neurological syndrome that occurs in many settings, including hypertensive crisis, renal failure, and preeclampsia, among others. These clinical settings induce failure in the autoregulation of cerebral blood flow and endothelial dysfunction, resulting in subcortical vasogenic brain edema (1).\n\nThe most frequent symptom of cardiovascular autonomic failure in MSA is orthostatic hypotension; a large registry of the European MSA Study Group showed a prevalence of 75% among MSA patients (7). In addition, almost half of all cases develop comorbid supine hypertension, and the loss of physiological circadian blood pressure rhythm induces NH, which was observed in 50% of MSA patients in a previous study (6).\n\nCardiovascular autonomic failure in MSA can induce severe blood pressure fluctuation. However, only two studies have reported the development of PRES in MSA patients. One report described a 51-year-old man with a 3-year history of MSA who presented with confusion, headache, dysarthria, and generalized tonic-clonic seizures caused by PRES (3). The patient had supine hypertension with a blood pressure of 180/100 mmHg at the onset, and the researchers considered the cause to be the oral administration of midodrine for 3 months. The other report described a 51-year-old man with a 7-year history of MSA who presented with visual disturbance, confusion, and generalized tonic-clonic seizures (4). He developed PRES two hours after brief syncope. His blood pressure increased to 205/115 mmHg from 88/60 mmHg for 80 min. The authors considered the cause of PRES to be severe blood pressure fluctuation.\n\nThis is the first case in which an MSA patient developed PRES during sleep, suggesting that NH influenced its pathogenesis. The two previous cases of MSA with PRES were able to walk, and their posture changes affected their blood pressure fluctuation. In our case, the individual was almost completely bedridden, suggesting that NH might be a primary reason for the severe fluctuation of his blood pressure that caused PRES.\n\nNH may be non-dipping or reverse dipping. The non-dipping form is characterized by a decrease in the blood pressure of less than 10% during the night compared to the previous day, whereas the reverse dipping form is characterized by an increase in the blood pressure during the night (8). The 24-h ABPM score showed that he had reverse dipping NH in a severe form. NH was also considered a cause of PRES in previous reports (9,10).\n\nThe 24-h ABPM score also showed that our patient's blood pressure fluctuated widely with external stimulation, such as enteral nutrition and body movement, despite appropriate medical care. His supine blood pressure increased to approximately 170/80 mmHg gradually before he developed PRES and exceeded 200/100 mmHg at onset. His blood pressure may have been higher during sleep and fluctuated more on the day he developed PRES than on the day of 24-h ABPM. In more advanced MSA cases, pathological nocturnal blood pressure appears more frequently and is associated with a pronounced blood pressure decrease after head-up tilting (6). Therefore, we considered progressive cardiovascular dysautonomia with NH as the most likely contributor to PRES in this case.\n\nThere was also one case report suggesting that NH in Parkinson's disease (PD) might be associated with the development of PRES (11). That report described a 77-year-old man with a 10-year history of PD who had supine hypertension, orthostatic hypotension, and NH, just as in our case. The authors inferred that these cardiac dysautonomias contributed to the pathogenesis. Compared with that case, the present patient developed PRES only three years after the onset of MSA, and the supine hypertension of our case progressed a few weeks before the development of PRES. Autonomic failures in MSA are generally more profound and progress more quickly than those in PD, so the course in our case indicates that early appropriate management is very important in MSA patients.\n\nFurthermore, MIBG scintigraphy in that previous PD case showed a markedly reduced uptake and high washout ratio, while our case showed mild abnormal values. Autonomic failure in PD originates from postganglionic sympathetic dysfunction, while that in MSA originates from the central nervous system, and the postganglionic sympathetic fibers are intact (12). The present case developed severe autonomic dysfunction despite mild abnormal results of MIBG scintigraphy. The MIBG uptake of PD may correlate with the cardiovascular autonomic function, but the MIBG uptake of MSA does not correlate with cardiac dysautonomia (13-15).\n\nIn the present case, the progression of clinical events accompanied by rapid improvement in radiological abnormalities strongly suggested that PRES was caused by hypertension and severe blood pressure fluctuation. The mechanisms underlying the development of PRES were complex. Our patient had pneumonia at the time, and the presence of inflammatory cytokines may have injured the cerebral endothelial cells, leading to the development of PRES (1). The continuous intake of droxidopa might also have affected his blood pressure fluctuation. However, the use of droxidopa started four months prior to PRES development, and our patient took droxidopa after his morning meals, so it was not a new risk factor of his pathogenesis, including NH.\n\nMany MSA patients with severe autonomic dysfunction take vasopressors, such as droxidopa, midodrine, and fludrocortisone. These pharmacologic therapies frequently induce supine hypertension as a side effect, and appropriate monitoring is needed. If supine hypertension is detected, patients should increase the duration of sitting upright during the daytime and should sleep in the head-up tilt position to avoid exacerbation of their NH (16). The course of the present case indicates that appropriate blood pressure management, including nonpharmacological intervention, is important for MSA patients in order to prevent severe complications such as PRES.\n\nIn conclusion, the hemodynamics of MSA change dramatically during the course of the disease, and our case suggests that NH may result in PRES. Although a causal relationship cannot be confirmed, infection and vasopressor use may have been exacerbating factors. Further studies are needed in order to determine how NH influences MSA progression, as well as to define appropriate care.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Fugate JE , Rabinstein AA \nPosterior reversible encephalopathy syndrome: clinical and radiological manifestations, pathophysiology, and outstanding questions . Lancet Neurol \n14 : 914 -925 , 2015 .26184985 \n2. Coon EA , Sletten DM , Suarez MD , et al \nClinical features and autonomic testing predict survival in multiple system atrophy . Brain \n138 : 3623 -3631 , 2015 .26369944 \n3. Kim J-S , Lee K-S , Lim S-C , et al \nReversible posterior leukoencephalopathy syndrome in a patient with multiple system atrophy: a possible association with oral midodrine treatment . Mov Disord \n22 : 1043 -1046 , 2007 .17377920 \n4. Franken TP , Demaerel P , Vandenberghe W \nPosterior reversible encephalopathy syndrome in multiple system atrophy . Parkinsonism Relat Disord \n28 : 155 -156 , 2016 .27026036 \n5. Gilman S , Wenning GK , Low PA , et al \nSecond consensus statement on the diagnosis of multiple system atrophy . Neurology \n71 : 670 -676 , 2008 .18725592 \n6. Fanciulli A , Strano S , Ndayisaba JP , et al \nDetecting nocturnal hypertension in Parkinson's disease and multiple system atrophy: proposal of a decision-support algorithm . J Neurol \n261 : 1291 -1299 , 2014 .24737171 \n7. Köllensperger M , Geser F , Ndayisaba J-P , et al \nPresentation, diagnosis, and management of multiple system atrophy in Europe: final analysis of the European multiple system atrophy registry . Mov Disord \n25 : 2604 -2612 , 2010 .20922810 \n8. Staessen JA , Asmar R , De Buyzere M , et al \nTask Force II: blood pressure measurement and cardiovascular outcome . Blood Press Monit \n6 : 355 -370 , 2001 .12055415 \n9. Casetta I , Cesnik E , Pedelini F \nPosterior reversible encephalopathy associated with nocturnal blood pressure non-dipping pattern . Blood Press \n23 : 61 -63 , 2014 .23789896 \n10. Kaut O , Kovacs A , Okulla T , et al \nReversible multifocal leukoencephalopathy associated with a nocturnal blood pressure non-dipper pattern . Blood Press \n19 : 267 -269 , 2010 .20353314 \n11. Morozumi S , Kato S , Yasui K , et al \nPosterior reversible encephalopathy syndrome in Parkinson disease probably caused by prominent supine hypertension and blood pressure fluctuation . Rinsho Shinkeigaku (Clinical Neurology) \n56 : 754 -758 , 2016 (in Japanese, Abstract in English).27773902 \n12. Orimo S , Takahashi A , Uchihara T , et al \nDegeneration of cardiac sympathetic nerve begins in the early disease process of Parkinson's disease . Brain Pathol \n17 : 24 -30 , 2007 .17493034 \n13. Katagiri A , Asahina M , Araki N , et al \nMyocardial 123I-MIBG uptake and cardiovascular autonomic function in Parkinson's disease . Parkinsons Dis \n2015 : 1 -5 , 2015 .\n14. Berganzo K , Tijero B , Somme JH , et al \nSCOPA-AUT scale in different parkinsonisms and its correlation with (123) I-MIBG cardiac scintigraphy . Parkinsonism Relat Disord \n18 : 45 -48 , 2012 .21908227 \n15. Braune S , Reinhardt M , Schnitzer R , et al \nCardiac uptake of [123I]MIBG separates Parkinson's disease from multiple system atrophy . Neurology \n53 : 1020 -1025 , 1999 .10496261 \n16. Fanciulli A , Wenning GK \nMultiple-system atrophy . N Engl J Med \n372 : 249 -263 , 2015 .25587949\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "57(21)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "multiple system atrophy (MSA); nocturnal hypertension (NH); posterior reversible encephalopathy syndrome (PRES)",
"medline_ta": "Intern Med",
"mesh_terms": "D006801:Humans; D006973:Hypertension; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D019578:Multiple System Atrophy; D054038:Posterior Leukoencephalopathy Syndrome; D012890:Sleep",
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"title": "Nocturnal Hypertension in Multiple System Atrophy May Cause Posterior Reversible Encephalopathy Syndrome.",
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}
},
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{
"abstract": "BACKGROUND\nResistance and intolerance to imatinib in patients with chronic myeloid leukemia requires alternative therapies. Nilotinib provides a choice as a second-line treatment. The objective of this report was to show the results of a group of patients with chronic myeloid leukemia who received nilotinib as a second-line treatment.\n\n\nMETHODS\nThe medical records of 16 patients of both sexes, of any age, diagnosed with chronic myeloid leukemia, who received nilotinib as a second-line treatment, were reviewed. All of them had received imatinib prior as first-line treatment; the causes to switch to nilotinib were intolerance, resistance and clinical progression of leukemia.\n\n\nRESULTS\nThe sample was of 16 patients, who achieved at least a hematologic response; 10 were males (62.5%). The age range was 24 to 75 years. Two patients received nilotinib due to intolerance to imatinib; seven due to resistance to imatinib and seven due to lack of response. There was response in the two patients who received nilotinib due to intolerance. One patient died five months after starting nilotinib due to progression of leukemia; four patients achieved major molecular response, two patients had reduced expression of BCR-ABL gene. Six patients continued with high expression of BCR-ABL gene; two of them carrying M244V mutation, and one with a complex karyotype with numerical and structural alterations.\n\n\nCONCLUSIONS\nNilotinib is an option for patients with intolerance or resistance to imatinib.",
"affiliations": "Servicio de Hematología, Hospital de Especialidades 25, Instituto Mexicano del Seguro Social, Monterrey, Nuevo León, México. ebaez@axtel.net.",
"authors": "Báez-de la Fuente|Enrique|E|;Arellano-Severiano|Baltazar|B|",
"chemical_list": "C498826:4-methyl-N-(3-(4-methylimidazol-1-yl)-5-(trifluoromethyl)phenyl)-3-((4-pyridin-3-ylpyrimidin-2-yl)amino)benzamide; D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate",
"country": "Mexico",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0443-5117",
"issue": "52(3)",
"journal": "Revista medica del Instituto Mexicano del Seguro Social",
"keywords": "Antineoplastic agents; Chronic myelogenous leukemia, BCR-ABL positive; Neoplasm drug resistance",
"medline_ta": "Rev Med Inst Mex Seguro Soc",
"mesh_terms": "D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents; D001549:Benzamides; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D008297:Male; D008875:Middle Aged; D010879:Piperazines; D011743:Pyrimidines; D017211:Treatment Failure; D055815:Young Adult",
"nlm_unique_id": "101243727",
"other_id": null,
"pages": "330-3",
"pmc": null,
"pmid": "24878095",
"pubdate": "2014",
"publication_types": "D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Nilotinib in patients with chronic myeloid leukemia without response to imatinib.",
"title_normalized": "nilotinib in patients with chronic myeloid leukemia without response to imatinib"
} | [
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{
"abstract": "BACKGROUND Antiphospholipid syndrome (APS) is an autoimmune disease characterized by antibodies directed against phospholipids on plasma membranes. Through unclear mechanisms, APS confers hypercoagulability. APS may cause recurrent thromboses in the arterial and venous vasculature. We report a case of primary APS resulting in cerebral venous thrombosis and ST-elevation myocardial infarction (STEMI) for which only antiphosphatidylserine (aPS) IgM antibody was positive after extensive investigation. CASE REPORT A 48-year-old male was admitted after a witnessed generalized seizure with subsequent confusion. Imaging demonstrated thrombosis of multiple central nervous system (CNS) sinuses, including the superior sagittal sinus and bilateral transverse sinuses. The patient was heparinized with aggressive hydration, which proved inadequate, prompting endovascular thrombectomy. Three months later, despite anticoagulation therapy, the patient developed a STEMI when International Normalized Ratio (INR) was 1.8. Echocardiogram (ECHO) and PAN CT scan were normal. Initial coagulation studies demonstrated normal anticardiolipin antibody, prothrombin time, partial thromboplastin time, and platelet count. Outpatient coagulation studies revealed normal antithrombin III, protein C/S, hemoglobin electrophoresis, homocysteine, anti-β2 glycoprotein 1 antibodies, and D-Dimer. Factor V Leiden, JAK 2 mutation, prothrombin gene mutation, and tests for paroxysmal nocturnal hemoglobinuria (PNH) were negative. A positive phosphatidylserine IgM was detected. The patient was continued on warfarin (10 mg daily) with a target INR of 3.0-3.5 and clopidogrel (75 mg daily). CONCLUSIONS Despite extensive investigation, this patient only showed evidence of elevated aPS IgM antibodies, likely contributing to his CNS venous sinus thromboses and STEMI. It is important to screen for antiphosphatidylserine antibodies in cases of unprovoked thrombosis when standard thrombophilia analysis is unrevealing. This will assist in identifying pathogenicity and help prevent recurrence of subsequent thromboses.",
"affiliations": "Physician Assistant Studies Program, Thomas Jefferson University, Philadelphia, PA, USA.;College of Medicine, Drexel University, Philadelphia, PA, USA.;Senior Attending Physician, Abington Hematology Oncology Associates, Philadelphia, PA, USA.",
"authors": "Varner|Chelsea Kathleen|CK|;Marquardt|Caillin Wyse|CW|;Pickens|Peter Vincent|PV|",
"chemical_list": "D017152:Antibodies, Antiphospholipid; D010718:Phosphatidylserines",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.909698",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3016650310.12659/AJCR.909698909698ArticlesAntiphosphatidylserine Antibody as a Cause of Multiple Dural Venous Sinus Thromboses and ST-Elevation Myocardial Infarction Varner Chelsea Kathleen BCDEFG1Marquardt Caillin Wyse BDEF2Pickens Peter Vincent ABCD3\n1 Physician Assistant Studies Program, Thomas Jefferson University, Philadelphia, PA, U.S.A.\n2 College of Medicine, Drexel University, Philadelphia, PA, U.S.A.\n3 Senior Attending Physician, Abington Hematology Oncology Associates, Philadelphia, PA, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Chelsea Kathleen Varner, e-mail: cvarner@ycp.edu2018 31 8 2018 19 1042 1046 28 2 2018 21 6 2018 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 48\n\nFinal Diagnosis: Antiphospholipid syndrome\n\nSymptoms: Chest pain • confusion • seizure-like activity\n\nMedication: —\n\nClinical Procedure: Endovascular venous suction thrombectomy\n\nSpecialty: Hematology\n\nObjective:\nRare disease\n\nBackground:\nAntiphospholipid syndrome (APS) is an autoimmune disease characterized by antibodies directed against phospholipids on plasma membranes. Through unclear mechanisms, APS confers hypercoagulability. APS may cause recurrent thromboses in the arterial and venous vasculature. We report a case of primary APS resulting in cerebral venous thrombosis and ST-elevation myocardial infarction (STEMI) for which only antiphosphatidylserine (aPS) IgM antibody was positive after extensive investigation.\n\nCase Report:\nA 48-year-old male was admitted after a witnessed generalized seizure with subsequent confusion. Imaging demonstrated thrombosis of multiple central nervous system (CNS) sinuses, including the superior sagittal sinus and bilateral transverse sinuses. The patient was heparinized with aggressive hydration, which proved inadequate, prompting endovascular thrombectomy. Three months later, despite anticoagulation therapy, the patient developed a STEMI when International Normalized Ratio (INR) was 1.8. Echocardiogram (ECHO) and PAN CT scan were normal. Initial coagulation studies demonstrated normal anticardiolipin antibody, prothrombin time, partial thromboplastin time, and platelet count. Outpatient coagulation studies revealed normal antithrombin III, protein C/S, hemoglobin electrophoresis, homocysteine, anti-β2 glycoprotein 1 antibodies, and D-Dimer. Factor V Leiden, JAK 2 mutation, prothrombin gene mutation, and tests for paroxysmal nocturnal hemoglobinuria (PNH) were negative. A positive phosphatidylserine IgM was detected. The patient was continued on warfarin (10 mg daily) with a target INR of 3.0–3.5 and clopidogrel (75 mg daily).\n\nConclusions:\nDespite extensive investigation, this patient only showed evidence of elevated aPS IgM antibodies, likely contributing to his CNS venous sinus thromboses and STEMI. It is important to screen for antiphosphatidylserine antibodies in cases of unprovoked thrombosis when standard thrombophilia analysis is unrevealing. This will assist in identifying pathogenicity and help prevent recurrence of subsequent thromboses.\n\nMeSH Keywords:\nAntiphospholipid SyndromeIntracranial ThrombosisPhosphatidylserinesThrombophilia\n==== Body\nBackground\nAntiphospholipid syndrome (APS) is an acquired autoimmune disorder that results in a hypercoagulable state characterized by recurrent venous and/or arterial thrombosis [1]. Antiphospholipid antibodies are directed against proteins that bind to anionic phospholipids on plasma membranes [2]. APS can be characterized as a primary or secondary disorder and is more frequently seen in women, particularly those who have pregnancy-related complications such as miscarriage, stillbirth, or preterm delivery [3]. APS may contribute to an increased frequency of stroke or myocardial infarction (MI), especially in younger individuals [3]. Laboratory classification of APS requires the presence of at least one of the following: lupus anticoagulant, moderate to high levels of anticardiolipin antibodies (aCL), and/or moderate to high levels of anti-β2 glycoprotein 1 antibodies (Anti-β2GP1) [3]. Anticardiolipin antibody testing should include cardiolipin and β2GP1, as well as the individual isotypes IgG, IgM, and IgA. While various risk factors can contribute to the formation of a venous thromboembolism (VTE), it is important to keep APS in the differential diagnosis, especially when thrombosis is unprovoked. Here, we report an uncommon case of primary APS resulting in cerebral venous thrombosis and STEMI, for which only aPS IgM antibody was positive after an extensive workup.\n\nCase Report\nA 48-year-old white male was taken to the emergency room after his family witnessed a generalized seizure and noted subsequent prolonged confusion and agitation in February 2017. Glasgow coma scale (GCS) was 13 upon admission. Computed tomography (CT), magnetic resonance imaging (MRI), and magnetic resonance venography (MRV) demonstrated thrombosis of multiple CNS sinuses. MRI demonstrated left temporal lobe edema and small linear hemorrhages (Figure 1). MRV and conventional angiography demonstrated cerebral venous thrombosis of multiple CNS sinuses including a vertebral artery occlusion of unknown chronicity and bilateral transverse sinus thrombosis, as well as straight sinus and superior sagittal sinus thrombosis (Figure 2). The patient was placed on levetiracetam, systemic heparin, and aggressive hydration without difficulty, but suffered progressive clinical worsening requiring endovascular mechanical venous suction thrombectomy, resulting in good angiography effect (Figure 3). The initial coagulation workup was completed and demonstrated normal aCL, prothrombin time (PT), and activated partial thromboplastin time (APTT).\n\nThe patient denied any past medical history or surgical history prior to the thrombotic event. He denied a history of tobacco and illicit drug use. He did report drinking two 12-ounce cans of beer per month.\n\nHis family history was unremarkable for familial thrombotic tendency or autoimmune disease. His maternal uncle reportedly had polycythemia vera, his paternal grandfather had prostate cancer, and his maternal grandmother had bone cancer.\n\nThe patient was discharged 6 days after admission on warfarin, enoxaparin, and levetiracetam with an appointment to follow up with hematology to begin an outpatient thrombophilia workup.\n\nWhile undergoing an outpatient workup, in May 2017, just 3 months after his initial presentation, he developed burning retrosternal chest pain with radiation to the left arm. An electrocardiogram (EKG) showed sinus rhythm with inverted T waves inferiorly, which proved to be a ST-elevation myocardial infarction (STEMI); simultaneously, International Normalized Ratio (INR) revealed a level of 1.8. Intravenous heparin was commenced. Echo showed normal left ventricular systolic function with middle inferior hypokinesis. Coronary angiography indicated evidence of obstructive coronary artery disease with 50% stenosis in the left circumflex artery, 30% stenosis in the distal left anterior descending artery, and 40% stenosis in the proximal left anterior descending artery. The patient was discharged 5 days after admission on enoxaparin 120 mg subcutaneous injection twice daily, clopidogrel 75 mg daily, atorvastatin 40 mg daily, and lisinopril 10 mg daily.\n\nAt his outpatient hematology follow-up, physical examination revealed normal vital signs. He was obese with a body mass index (BMI) of 31.4kg/m2.\n\nThe neck examination was normal, showing supple without lymphadenopathy. The skin examination was normal, with no heliotrope rash, malar rash, acrocyanosis, or livedo reticularis. Bilateral heart and lung examination results were normal. No carotid bruits were noted. The abdomen was soft, non-tender, and non-distended with no hepatosplenomegaly. The neurological examination was normal. Distal pulses were palpable and lower extremities were without edema or cyanosis.\n\nA bilateral lower-extremity venous Doppler was negative. A PAN CT scan was done to rule out underlying malignancy and was negative.\n\nLaboratory studies included a general hematology analysis, which was within normal limits with the exception of a low platelet count (120×103/uL), which recovered to 159×103/uL within 2 months. Studies showed a white blood cell count of 6.0×103/uL and a normal hemoglobin of 14.0 g/dL.\n\nHis general chemistry results were normal.\n\nBased on past thrombotic and embolic events, despite anticoagulation therapy, a full hypercoagulability workup was completed, including protein C, protein S, antithrombin III, factor V Leiden, D-dimer, fibrinogen, flow cytometry for paroxysmal nocturnal hemoglobinuria (PNH), homocysteine, hemoglobin electrophoresis, factor VIII, factor X, complement, plasminogen activator inhibitor (PAI) screen, JAK2 mutation detection, prothrombin gene mutation screen, antiphospholipid antibodies, and beta-2 glycoprotein 1 antibodies (Table 1). General coagulation tests prior to warfarin initiation showed normal prothrombin time (PT: 10.5 s), International Normalized Ratio (INR) 1.0, normal activated partial thromboplastin time (APTT: 28.5 s), and negative D-dimer of <0.20 mg/L FEU. Protein C, protein S, antithrombin III, fibrinogen, homocysteine, complement levels, and hemoglobin electrophoresis were normal. Factor VIII activity was just slightly above the normal range, while factor X was low. He lacked factor V Leiden and prothrombin gene mutation. JAK2 and PAI genotype were normal. Flow cytometry was negative for PNH. Cardiolipin antibodies were normal (IgG: <9; IgM: 13; IgA: <9). Beta-2 glycoprotein 1 antibodies were normal (IgG: <9; IgM: <9; IgA: <9). Of note, his phosphatidylserine antibodies (IgM) were significantly positive, with a value of 45. Phosphatidylserine antibodies IgG and IgA were normal (IgG: 1; IgA: 1).\n\nThe patient was continued on clopidogrel (75 mg daily) and transitioned from enoxaparin (120 mg, twice per day) to warfarin (10 mg daily) with a target INR of 3.0–3.5.\n\nDiscussion\nPhosphatidylserine is a negatively charged phospholipid that is a component of the cellular membrane. This phospholipid acts as a procoagulant when activated by collagen, thrombin, or antibodies, resulting in a hypercoagulable state [2]. While phosphatidylserine is not the most common antiphospholipid antibody (aPL), it serves as a significant antigenic target in APS [4]. Antiphospholipid syndrome is characterized by a prothrombotic state that can occur in both venous and arterial vasculature [5].\n\nThe most common aPLs include lupus anticoagulant, aCL, and anti-β2GP1 [4]. These aPLs react with phospholipids and proteins on the venous and arterial vasculature, ultimately resulting in thrombosis [4]. β2GP1 is the most common of these antibodies and is found in the vast majority of seropositive APS patients [4].\n\nThe most common sites of thrombosis consist of cerebral arterial vasculature and the lower-extremity venous system [5]. The clinical presentation of APS most commonly includes pulmonary embolism (PE), deep venous thrombosis (DVT), and/or thrombosis in the arterial system [3]. The initial presentation may or may not be associated with dermatologic manifestations such as livedo reticularis and a heliotrope rash [3].\n\nIn women of child bearing age, obstetric complications such as miscarriage and stillbirth may be the initial presentation of APS [3]. Thrombosis is the most common initial presentation and is typically diagnosed by CT, MRI, MRV, or Doppler ultrasound to confirm a thrombotic event in the brain, chest, abdomen, or deep veins of the lower extremities.\n\nThe differential diagnosis when encountering a patient with thrombophilia can be extensive. Malignancy may initially present with thrombotic tendencies and should be ruled out with imaging. Homocystinemia, antithrombin III deficiency, protein C or S deficiency, factor V Leiden mutation, and prothrombin gene mutation should be considered in patients who exhibit thrombophilia [6]. Atherosclerotic vascular disease should also be ruled out in patients presenting with prothrombotic tendencies. The workup for a hypercoagulable state should investigate both inherited and acquired conditions that may contribute to a procoagulant state [6].\n\nThe diagnosis of APS is primarily based on the detection of antiphospholipid antibodies in a patient’s serum and evidence of thrombosis [7]. Triple positivity of lupus anticoagulant, anticardiolipin antibodies, and beta-2 glycoprotein 1 antibodies create the highest risk of thromboembolic events [7]. Deficiencies in protein C, protein S, and antithrombin should be explored, as well as mutations, including factor V Leiden, prothrombin, and plasminogen inhibitor genes [6]. Antibodies directed against phosphatidylserine should also be considered when initial APS studies are negative [7]. Recent studies have demonstrated a significant association between aPS and APS, and seronegative APS patients have been found to be positive for aPS [8,9].\n\nThe mainstay of treatment for thrombotic events associated with APS primarily consists of anticoagulation [10]. In certain circumstances aspirin and heparin may be used, but warfarin is the most commonly prescribed anticoagulant for treatment of APS [10]. Recent research emphasizes the importance of indefinite anticoagulation for patients who have had a thrombotic event, due to the high recurrence risk [10].\n\nThe patient discussed in this case report is a prime example of a seronegative APS patient who tested positive only for aPS after an extensive thrombophilia workup. This patient did not have any significant risk factors that would have contributed to his thrombophilia. He denied recent hospitalization, immobilization, and smoking, showed no evidence of malignancy, and had no personal or family history of clotting disorders. The patient’s mild obesity and positive phosphatidylserine IgM were the only apparent contributing factors. Of note, a recent case report described multiple etiologies in a lower-extremity DVT, including significantly positive phosphatidylserine IgG antibodies, which demonstrates the importance of this as a risk factor for thrombosis [11]. At 1-year follow-up, the patient had not developed any autoimmune or collagen vascular diseases. This study suggests further investigation into the possibility of phosphatidylserine antibodies in individuals with clinical symptoms related to thrombosis with an exhaustive, unrevealing clinical workup.\n\nConclusions\nIt is important to consider other uncommon causes for thrombophilia, such as APS. Laboratory testing should include the common disorders that result in thrombophilia, but if results are unrevealing, further workup is necessary. Antiphosphatidylserine antibodies should be considered if there is a high index of suspicion for a hypercoagulable state in patients who have a pan-negative standard thrombophilia workup.\n\nNeuro Interventional Surgery, Larami MacKenzie, MD, Abington Neurosurgical Associates. Cardiology, Carl Reynolds, MD, FACC, Penn Medicine Heart and Vascular Institute.\n\nInstitution where work was done\n\nAbington Hematology Oncology Associates, Philadelphia, PA.\n\nFigure 1. Axial FLAIR MRI reveals hyperintensity consistent with left temporal lobe edema (arrow) and small linear hemorrhages.\n\nFigure 2. Contrast-enhanced coronal MRV demonstrating extensive superior sagittal sinus thrombosis (horizontal arrow) affecting the right transverse sinus (vertical arrow).\n\nFigure 3. Coronal MRV contrast injection revealing improved drainage through superior sagittal sinus (horizontal arrow) and transverse sinus (vertical arrow) after venous sinus aspiration thrombectomy.\n\nTable 1. Hypercoagulability profile.\n\nResult\tValue/result\tUnits\tRange\t\nProthrombin time (PT)\t10.5\tSeconds\t9.1–12.0\t\nInternational normalized ratio (INR)\t1.0\t\t0.8–1.2\t\nPartial thromboplastin time (APTT)\t28.5\tSeconds\t24.0–33.0\t\nProtein C – functional\t117\t%\t73–180\t\nProtein S, total\t120\t%\t60–150\t\nAntithrombin III activity\t94\t%\t75–135\t\nFactor V Leiden mutation\tNegative\t\tNegative\t\nD-Dimer\t<0.20\tmg/L FEU\t0.00–0.49\t\nFibrinogen\t291\tmg/dL\t193–507\t\nFlow cytometry PNH*\tNo evidence of PNH\t\tNo evidence of PNH\t\nHomocysteine\t11.7\tumol/L\t0.0–15.0\t\nHemoglobin solubility**\tNegative\t\tNegative\t\nFactor VIII activity\t168\t%\t56–163\t\nFactor X activity\t15\t%\t76–183\t\nComplement, total\t56\tU/ml\t42–60\t\nPAI-1 activity\t5G/5G***\t\t\t\nJAK2 mutation inhibitor\tNegative\t\tNegative\t\nProthrombin gene mutation\tNegative\t\tNegative\t\nAnticardiolipin Ab, IgG\t<9\tU/ml\t0–15\t\nAnticardiolipin Ab, IgM\t13\tU/ml\t0–12\t\nAnticardiolipin Ab, IgA\t<9\tU/ml\t0–11\t\nBeta-2 glycoprotein I Ab, IgG\t<9\tGPI IgG units\t0–20\t\nBeta-2 glycoprotein I Ab, IgM\t<9\tGPI IgM units\t0–32\t\nBeta-2 glycoprotein I Ab, IgA\t<9\tGPI IgA units\t0–25\t\nAntiphosphatidylserine IgG\t1\tGPS IgG\t0–11\t\nAntiphosphatidylserine IgM\t45\tMPS IgM\t0–25\t\nAntiphosphatidylserine IgA\t1\tAPS IgA\t0–20\t\n* Peripheral blood specimen;\n\n** normal adult hemoglobin present;\n\n*** homozygous for 5G insertion allele which is associated with the lowest PAI-1 activity.\n==== Refs\nReferences:\n1. Okuma H Kitagawa Y Takagi S Investigation of antiphosphatidyl-serine antibody and antiphosphatidyl-inositol antibody in ischemic stroke patients Clin Dev Immunol 2010 2010 439230 21197449 \n2. Lentz B Exposure of platelet membrane phosphatidylserine regulates blood coagulation Prog Lipid Res 2003 42 423 38 12814644 \n3. Whitaker K Antiphospholipid antibody syndrome: The difficulties of diagnosis JAAPA 2017 30 10 14 \n4. Willis R Pierangeli S Pathophysiology of the antiphospholipid antibody syndrome Auto Immun Highlights 2011 2 35 52 26000118 \n5. Giannakopoulos B Krilis S The pathogenesis of the antiphospholipid syndrome N Engl J Med 2013 368 1033 44 23484830 \n6. Montagnana M Lippi G Danese E An overview of thrombophilia and associated laboratory testing Methods Mol Biol 2017 1646 113 35 28804823 \n7. Ahluwalia J Sreedharanunni S The laboratory diagnosis of antiphospholipid syndrome Indian J Hematol Blood Transfus 2017 33 8 14 28194050 \n8. Khogeer H Alfattani A Al Kaff M Antiphosphatidylserine antibodies as diagnostic indicators of antiphospholipid syndrome Lupus 2015 24 186 90 25253571 \n9. Zohoury N Bertolaccini ML Rodriguez-Garcia JL Closing the serological gap in the antiphospholipid syndrome: The value of “non-criteria” antiphospholipid antibodies J Rheumatol 2017 44 1597 602 28864642 \n10. Chighizola CB Ubiali T Meroni PL Treatment of thrombotic antiphospholipid syndrome: The rationale of current management – an insight into future approaches J Immunol Res 2015 2015 951424 26075289 \n11. Miao J Naik G Muddana S An uncommon case of lower limb deep vein thrombosis with multiple etiological causes Am J Case Rep 2017 18 313 16 28348360\n\n",
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"mesh_terms": "D017152:Antibodies, Antiphospholipid; D016736:Antiphospholipid Syndrome; D006801:Humans; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D010718:Phosphatidylserines; D012851:Sinus Thrombosis, Intracranial",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "26000118;28348360;28864642;28804823;29120877;28194050;23484830;12814644;26075289;21197449;25253571",
"title": "Antiphosphatidylserine Antibody as a Cause of Multiple Dural Venous Sinus Thromboses and ST-Elevation Myocardial Infarction.",
"title_normalized": "antiphosphatidylserine antibody as a cause of multiple dural venous sinus thromboses and st elevation myocardial infarction"
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"literaturereference": "VARNER CK, MARQUARDT CW, PICKENS PV. ANTIPHOSPHATIDYLSERINE ANTIBODY AS A CAUSE OF MULTIPLE DURAL VENOUS SINUS THROMBOSES AND ST-ELEVATION MYOCARDIAL INFARCTION. AMERICAN JOURNAL OF CASE REPORTS. 2018?19:1042-6",
"literaturereference_normalized": "antiphosphatidylserine antibody as a cause of multiple dural venous sinus thromboses and st elevation myocardial infarction",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190120",
"receivedate": "20190120",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15846247,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190417"
},
{
"companynumb": "US-TEVA-2019-US-1004344",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
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"drugenddateformat": null,
"drugindication": "SEIZURE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
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"drugstartdate": "2017",
"drugstartdateformat": "602",
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LEVETIRACETAM."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ENOXAPARIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "076726",
"drugbatchnumb": null,
"drugcharacterization": "1",
"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": "2017",
"drugstartdateformat": "602",
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ENOXAPARIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "WARFARIN"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "40145",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
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"drugindication": "ANTICOAGULANT THERAPY",
"drugintervaldosagedefinition": null,
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"drugstartdate": "2017",
"drugstartdateformat": "602",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "WARFARIN"
}
],
"patientagegroup": null,
"patientonsetage": "48",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Acute myocardial infarction",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Antiphospholipid syndrome",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "VARNER CK, MARQUARDT CW, PICKENS PV. ANTIPHOSPHATIDYLSERINE ANTIBODY AS A CAUSE OF MULTIPLE DURAL VENOUS SINUS THROMBOSES AND ST-ELEVATION MYOCARDIAL INFARCTION. AM-J-CASE-REP 2018?19:1042-1046.",
"literaturereference_normalized": "antiphosphatidylserine antibody as a cause of multiple dural venous sinus thromboses and st elevation myocardial infarction",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190131",
"receivedate": "20190131",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15895979,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20190417"
}
] |
{
"abstract": "BACKGROUND\nDespite the availability of safe and effective direct-acting antiviral drugs (DAAs), the vast majority of patients with chronic hepatitis C (HCV) in the USA remain untreated, in part due to lack of access to specialist providers.\n\n\nOBJECTIVE\nTo determine the effectiveness of DAA-based treatment in medically underserved areas in California, in a healthcare model dependent on task-shifting--wherein a visiting hepatologist assesses patients for treatment eligibility, but subsequent routine follow-up evaluation of patients prescribed treatment is devolved to a part-time licensed vocational nurse under remote supervision of the hepatologist.\n\n\nMETHODS\nWe retrospectively determined rates of sustained virologic response 12 weeks after treatment completion (SVR-12), adverse events, and treatment discontinuations in patients who received sofosbuvir-based DAA regimens between December 2013 and November 2014.\n\n\nRESULTS\nDespite limited specialist provider involvement in medically underserved areas, all but two of 58 patients completed treatment, and 88 % of patients achieved the curative endpoint of undetectable HCV RNA 12 weeks after completing treatment (sustained virologic response, SVR-12). Almost 80 % of patients with cirrhosis and 85 % of patients with prior treatment experience achieved SVR-12.\n\n\nCONCLUSIONS\nTreatment effectiveness with sofosbuvir-based regimens in medically underserved areas utilizing task-shifting from a specialist to a mid-level provider is comparable to those achieved in pivotal clinical trials for these regimens, and to “real-world” experiences of tertiary care centers in the USA.",
"affiliations": null,
"authors": "Jayasekera|Channa R|CR|;Perumpail|Ryan B|RB|;Chao|David T|DT|;Pham|Edward A|EA|;Aggarwal|Avin|A|;Wong|Robert J|RJ|;Ahmed|Aijaz|A|",
"chemical_list": "D000998:Antiviral Agents; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir",
"country": "United States",
"delete": false,
"doi": "10.1007/s10620-015-3911-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0163-2116",
"issue": "60(12)",
"journal": "Digestive diseases and sciences",
"keywords": null,
"medline_ta": "Dig Dis Sci",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000998:Antiviral Agents; D002140:California; D005260:Female; D006297:Health Services Accessibility; D019698:Hepatitis C, Chronic; D006801:Humans; D008297:Male; D008507:Medically Underserved Area; D008875:Middle Aged; D012189:Retrospective Studies; D012254:Ribavirin; D000069616:Simeprevir; D000069474:Sofosbuvir",
"nlm_unique_id": "7902782",
"other_id": null,
"pages": "3552-7",
"pmc": null,
"pmid": "26467703",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": "21631316;24980859;26113432;24795201;23607594;19824079;24737271;25754171;25775313;25078309;25950251;23607593;24386420;25775312;24988388",
"title": "Task-Shifting: An Approach to Decentralized Hepatitis C Treatment in Medically Underserved Areas.",
"title_normalized": "task shifting an approach to decentralized hepatitis c treatment in medically underserved areas"
} | [
{
"companynumb": "US-GILEAD-2016-0199493",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "SOFOSBUVIR"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "204671",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugdosageform": "TABLET",
"drugdosagetext": "400 MG, QD",
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"drugindication": "HEPATITIS C",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "SOFOSBUVIR"
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{
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}
],
"patientagegroup": "5",
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"reaction": [
{
"reactionmeddrapt": "Jaundice",
"reactionmeddraversionpt": "19.0",
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "JAYASEKERA C.R., PERUMPAIL R.B., CHAO D.T., PHAM E.A., AGGARWAL A., WONG R.J., AHMED A.. TASK-SHIFTING: AN APPROACH TO DECENTRALIZED HEPATITIS C TREATMENT IN MEDICALLY UNDERSERVED AREAS. DIG DIS SCI. 2015?60:3552-3557",
"literaturereference_normalized": "task shifting an approach to decentralized hepatitis c treatment in medically underserved areas",
"qualification": "3",
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},
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"receivedate": "20160226",
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},
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160526"
},
{
"companynumb": "US-JNJFOC-20151126852",
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{
"actiondrug": "4",
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{
"actiondrug": "4",
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},
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}
],
"patientagegroup": "5",
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"reaction": [
{
"reactionmeddrapt": "Hepatitis C",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "JAYASEKERA CR, PERUMPAIL RB, CHAO DT, PHAM EA, AGGARWAL A, WONG RJ, ET AL. TASK-SHIFTING: AN APPROACH TO DECENTRALIZED HEPATITIS C TREATMENT IN MEDICALLY UNDERSERVED AREAS. DIG DIS SCI 14-OCT-2015?60:3552-57.",
"literaturereference_normalized": "task shifting an approach to decentralized hepatitis c treatment in medically underserved areas",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20151130",
"receivedate": "20151130",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11787058,
"safetyreportversion": 1,
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
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"seriousnesscongenitalanomali": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160305"
},
{
"companynumb": "US-JNJFOC-20151118516",
"fulfillexpeditecriteria": "1",
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{
"actiondrug": "1",
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},
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"drugdosageform": "CAPSULE",
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"drugindication": "HEPATITIS C",
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"drugstructuredosagenumb": "150",
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},
{
"actiondrug": "1",
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"activesubstancename": "SOFOSBUVIR"
},
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"drugdosagetext": null,
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"drugindication": "HEPATITIS C",
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"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "SOFOSBUVIR"
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hepatitis C",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Jaundice",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "JAYASEKERA CR, PERUMPAIL RB, CHAO DT, PHAM EA, AGGARWAL A, WONG RJ, ET AL. TASK-SHIFTING: AN APPROACH TO DECENTRALIZED HEPATITIS C TREATMENT IN MEDICALLY UNDERSERVED AREAS. DIG DIS SCI 14-OCT-2015?60:3552-57.",
"literaturereference_normalized": "task shifting an approach to decentralized hepatitis c treatment in medically underserved areas",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20151125",
"receivedate": "20151125",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11779010,
"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": "OBJECTIVE\nThe aim of this retrospective study was to evaluate bevacizumab combined with weekly paclitaxel with and without carboplatin in pre-treated patients with non-squamous non-small cell lung cancer (NSCLC).\n\n\nMETHODS\nBetween November 2009 and October 2011, 43 pre-treated patients with non-squamous NSCLC received bevacizumab (15 mg/kg, day 1) plus weekly paclitaxel (60-80 mg/m(2), days 1, 8, 15) with carboplatin (area under the curve=4-5, day 1) (n=36), or bevacizumab plus weekly paclitaxel (n=7) alone every four weeks.\n\n\nRESULTS\nThe response rate and disease control rates were 48.8% (21/43) and 86.0% (37/43), respectively. Median progression-free survival was 5.7 months, and overall survival was 14.5 months. Grade 3/4 neutropenia was observed in 37.2% of patients and peripheral neurotoxicity in 0%. No bevacizumab-related death was observed.\n\n\nCONCLUSIONS\nEven for heavily pre-treated patients, bevacizumab plus weekly paclitaxel with or without carboplatin was effective and tolerable in non-squamous NSCLC.",
"affiliations": "Division of Integrated Oncology, Institute of Biomedical Research and Innovation, 2-2, Minatojima-minamimachi, Chuo-ku, Kobe, Japan. a-hata@fbri.org.",
"authors": "Hata|Akito|A|;Katakami|Nobuyuki|N|;Tanaka|Kosuke|K|;Takeshita|Jumpei|J|;Matsumoto|Takeshi|T|;Monden|Kazuya|K|;Nagata|Kazuma|K|;Masago|Katsuhiro|K|;Kaji|Reiko|R|;Fujita|Shiro|S|;Tachikawa|Ryo|R|;Otsuka|Kyoko|K|;Otsuka|Kojiro|K|;Tomii|Keisuke|K|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D016190:Carboplatin; D017239:Paclitaxel",
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0250-7005",
"issue": "34(1)",
"journal": "Anticancer research",
"keywords": "Non-squamous non-small cell lung cancer; bevacizumab; carboplatin; weekly paclitaxel",
"medline_ta": "Anticancer Res",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000369:Aged, 80 and over; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D016190:Carboplatin; D018287:Carcinoma, Large Cell; D002289:Carcinoma, Non-Small-Cell Lung; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D017239:Paclitaxel; D011379:Prognosis; D012189:Retrospective Studies; D015996:Survival Rate",
"nlm_unique_id": "8102988",
"other_id": null,
"pages": "275-81",
"pmc": null,
"pmid": "24403474",
"pubdate": "2014-01",
"publication_types": "D002363:Case Reports; D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Bevacizumab plus weekly paclitaxel with or without carboplatin for previously-treated non-squamous non-small cell lung cancer.",
"title_normalized": "bevacizumab plus weekly paclitaxel with or without carboplatin for previously treated non squamous non small cell lung cancer"
} | [
{
"companynumb": "JP-CIPLA LTD.-2015JP00581",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CARBOPLATIN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "077383",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "INJECTION",
"drugdosagetext": "AUC 4-5 DAY 1 EVERY FOUR WEEKS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-SMALL CELL LUNG CANCER RECURRENT",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"medicinalproduct": "CARBOPLATIN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PACLITAXEL"
},
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"drugcharacterization": "1",
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"drugdosageform": "INJECTION",
"drugdosagetext": "60-80 MG/M2, DAYS 1, 8, 15 EVERY FOUR WEEKS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-SMALL CELL LUNG CANCER RECURRENT",
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"drugrecurreadministration": "3",
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"medicinalproduct": "PACLITAXEL."
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"activesubstancename": "BEVACIZUMAB"
},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Interstitial lung disease",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HATA.A, KATAKAMI.N, TANAKA.K, TAKESHITA.J, MATSUMOTO.T, MONDEN.K. BEVACIZUMAB PLUS WEEKLY PACLITAXEL WITH OR WITHOUT CARBOPLATIN FOR PREVIOUSLY-TREATED NON-SQUAMOUS NON-SMALL CELL LUNG CANCER. ANTICANCER RESEARCH. 2014;34:275-282",
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] |
{
"abstract": "Propranolol is approved for treatment of infantile hemangiomas (IH). IH proliferation coincides with the time when most women are breastfeeding, yet there are no reports describing the clinical effects on infants treated with propranolol while being nursed by mothers on oral antihypertensive medications. We describe two cases of breastfed infants, with mothers taking multiple antihypertensives of different drug classes, who were initiated on propranolol for IH treatment and discuss the theoretical risk of propranolol use in this setting.",
"affiliations": "Department of Dermatology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.;Division of Clinical Pharmacology, Children's National Hospital, Washington, DC, USA.;Division of General Pediatrics, Children's National Hospital, Washington, DC, USA.;Division of Cardiology, Children's National Hospital, Washington, DC, USA.;Division of Dermatology, Children's National Hospital, Washington, DC, USA.",
"authors": "Aizman|Leora|L|https://orcid.org/0000-0003-3280-1892;Van Den Anker|John|J|;Tender|Jennifer|J|;Krishnan|Anita|A|;Kirkorian|Anna Yasmine|AY|",
"chemical_list": "D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D011433:Propranolol",
"country": "United States",
"delete": false,
"doi": "10.1111/pde.14134",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0736-8046",
"issue": "37(3)",
"journal": "Pediatric dermatology",
"keywords": "hemangiomas/vascular tumors; neonatal; pharmacology; systemic therapy; therapysystemic; vascular malformation",
"medline_ta": "Pediatr Dermatol",
"mesh_terms": "D000319:Adrenergic beta-Antagonists; D000959:Antihypertensive Agents; D001942:Breast Feeding; D005260:Female; D006391:Hemangioma; D006801:Humans; D007223:Infant; D009035:Mothers; D011433:Propranolol; D012878:Skin Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "8406799",
"other_id": null,
"pages": "537-540",
"pmc": null,
"pmid": "32110833",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Special management considerations for propranolol use in breastfed infants of mothers taking antihypertensives.",
"title_normalized": "special management considerations for propranolol use in breastfed infants of mothers taking antihypertensives"
} | [
{
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"medicinalproduct": "HYDRALAZINE"
}
],
"patientagegroup": "2",
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"reaction": [
{
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Motor developmental delay",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Middle insomnia",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "1"
}
],
"summary": null
},
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"literaturereference": "AIZMAN L, VAN DEN ANKER J, TENDER J, KRISHNAN A, KIRKORIAN AY. SPECIAL MANAGEMENT CONSIDERATIONS FOR PROPRANOLOL USE IN BREASTFED INFANTS OF MOTHERS TAKING ANTIHYPERTENSIVES. PEDIATRIC DERMATOLOGY. 2020?00:1?4",
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},
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},
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},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20201102"
},
{
"companynumb": "US-STRIDES ARCOLAB LIMITED-2020SP008811",
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"activesubstancename": "HYDRALAZINE HYDROCHLORIDE"
},
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"medicinalproduct": "NIFEDIPINE."
},
{
"actiondrug": null,
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"activesubstancename": "HYDRALAZINE HYDROCHLORIDE"
},
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"drugdosagetext": "75 MILLIGRAM, TID (AT 6 MONTHS FOLLOW UP)",
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},
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"activesubstancename": "LISINOPRIL"
},
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"drugdosagetext": "20 MILLIGRAM, QD",
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"drugindication": "HYPERTENSION",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "LISINOPRIL."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "CHLORTHALIDONE"
},
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"drugstructuredosageunit": "003",
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"medicinalproduct": "CHLORTALIDONE"
}
],
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"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Exposure via breast milk",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "AIZMAN L, VAN DEN ANKER J, TENDER J, KRISHNAN A, KIRKORIAN AY. SPECIAL MANAGEMENT CONSIDERATIONS FOR PROPRANOLOL USE IN BREASTFED INFANTS OF MOTHERS TAKING ANTIHYPERTENSIVES.. PEDIATRIC DERMATOLOGY. 2020?37(3):537?540",
"literaturereference_normalized": "special management considerations for propranolol use in breastfed infants of mothers taking antihypertensives",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210624",
"receivedate": "20210624",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19456643,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20210717"
}
] |
{
"abstract": "OBJECTIVE\nIdentification of the offending drug is crucial and challenging in cases of severe cutaneous adverse drug reactions (CADR) like Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Poor reproducibility and varying levels of agreement have been observed among different causality assessment tools (CATs) in assessing severe CADRs. This study was conducted to examine the agreement among four different CATs in assessing cases of drug-induced SJS, TEN and SJS/TEN overlap.\n\n\nMETHODS\nAll cases of drug-induced SJS, TEN and SJS/TEN overlap, which were reported between January 2012 and January 2020 were identified from the ADR register at an ADR monitoring center. Causality assessment was done in these reported cases using the following CATs: The World Health Organization-Uppsala Monitoring Centre (WHO-UMC) scale, Naranjo algorithm, Liverpool algorithm and Algorithm of drug causality for epidermal necrolysis (ALDEN). Weighted kappa (κw) test was used to calculate the agreement among four CATs.\n\n\nRESULTS\nA total of 30 cases of drug-induced SJS, TEN and SJS/TEN overlap were included in our analyses. The most common offending group of drugs were anticonvulsants (46.7%), antimicrobials (40%) and nonsteroidal anti-inflammatory drugs (13.3%). Of the anticonvulsants, phenytoin (13.3%), carbamazepine (10%) and valproate (10%) were the commonly reported offending drugs. Poor agreement was observed among the four different causality assessment scales.\n\n\nCONCLUSIONS\nDiscrepancies were observed among four different CATs in assessing drug-induced SJS and TEN. A CAT that is more specific to drug-induced SJS and TEN, simple, user-friendly with limited subjective interpretation, incorporating new immunological and pharmacogenetic markers is necessary.",
"affiliations": "Department of Pharmacology, Sri Manakula Vinayagar Medical college and hospital, Puducherry-605017, India.;Department of Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research, Puducherry-605006, India.;Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry-605006, India.;Department of Clinical Pharmacology, Jawaharlal Institute of Postgraduate Medical Education and Research (JIPMER), Puducherry-605006, India.",
"authors": "Sivagourounadin|Kiruthika|K|;Rajendran|Priyadharsini|P|;Selvarajan|Sandhiya|S|;Ganesapandian|Mahalakshmi|M|",
"chemical_list": null,
"country": "United Arab Emirates",
"delete": false,
"doi": "10.2174/1574886316666210611160123",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1574-8863",
"issue": null,
"journal": "Current drug safety",
"keywords": "Adverse drug reactions; Drug-induced Toxic epidermal necrolysis; Liverpool algorithm; Naranjo scale; causality assessment tool; drug-induced Stevens-Johnson syndrome",
"medline_ta": "Curr Drug Saf",
"mesh_terms": null,
"nlm_unique_id": "101270895",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34126908",
"pubdate": "2021-06-11",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Agreement among different scales for causality assessment in drug-induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis.",
"title_normalized": "agreement among different scales for causality assessment in drug induced stevens johnson syndrome and toxic epidermal necrolysis"
} | [
{
"companynumb": "IN-GLAXOSMITHKLINE-IN2022GSK095901",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LAMOTRIGINE"
},
"drugadditional": "3",
"drugadministrationroute": "048",
"drugauthorizationnumb": "020241",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "200 MG, BID (TWICE DAILY)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Generalised tonic-clonic seizure",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "2",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "200",
"drugstructuredosageunit": "003",
"drugtreatmentduration": "7",
"drugtreatmentdurationunit": "804",
"medicinalproduct": "LAMOTRIGINE"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Stevens-Johnson syndrome",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "Sivagourounadin K, Rajendran P, Selvarajan S, Ganesapandian M. Agreement Among Different Scales for Causality Assessment in Drug-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Current Drug Safety. 2022;17 (1):40-46",
"literaturereference_normalized": "agreement among different scales for causality assessment in drug induced stevens johnson syndrome and toxic epidermal necrolysis",
"qualification": "1",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20220623",
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},
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"sender": {
"senderorganization": "FDA-Public Use",
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},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Stevens-Johnson syndrome",
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}
],
"summary": null
},
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"literaturereference": "Sivagourounadin K, Rajendran P, Selvarajan S, Ganesapandian M. Agreement Among Different Scales for Causality Assessment in Drug-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Current Drug Safety. 2022;17 (1):40-46",
"literaturereference_normalized": "agreement among different scales for causality assessment in drug induced stevens johnson syndrome and toxic epidermal necrolysis",
"qualification": "1",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20220623",
"receivedate": "20220623",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 20999011,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20220721"
},
{
"companynumb": "IN-GLAXOSMITHKLINE-INCH2022GSK021939",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC"
},
"drugadditional": "3",
"drugadministrationroute": "048",
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"drugdosagetext": "75 MG, BID (TWICE DAILY)",
"drugenddate": null,
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"drugindication": "Toothache",
"drugintervaldosagedefinition": "804",
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}
],
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"reaction": [
{
"reactionmeddrapt": "Stevens-Johnson syndrome",
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"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "Sivagourounadin K, Rajendran P, Selvarajan S, Ganesapandian M. Agreement Among Different Scales for Causality Assessment in Drug-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Current Drug Safety. 2022;17 (1):40-46",
"literaturereference_normalized": "agreement among different scales for causality assessment in drug induced stevens johnson syndrome and toxic epidermal necrolysis",
"qualification": "1",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20220623",
"receivedate": "20220623",
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},
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"safetyreportversion": 1,
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"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
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"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
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"seriousnessother": 1,
"transmissiondate": "20220720"
},
{
"companynumb": "IN-GLAXOSMITHKLINE-INCH2022GSK021949",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DICLOFENAC SODIUM"
},
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"medicinalproduct": "DICLOFENAC SODIUM"
}
],
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"reaction": [
{
"reactionmeddrapt": "Stevens-Johnson syndrome",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "Sivagourounadin K, Rajendran P, Selvarajan S, Ganesapandian M. Agreement Among Different Scales for Causality Assessment in Drug-Induced Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis. Current Drug Safety. 2022;17 (1):40-46",
"literaturereference_normalized": "agreement among different scales for causality assessment in drug induced stevens johnson syndrome and toxic epidermal necrolysis",
"qualification": "1",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20220623",
"receivedate": "20220623",
"receiver": {
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},
"reporttype": "1",
"safetyreportid": 20998843,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
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"seriousnessother": 1,
"transmissiondate": "20220721"
}
] |
{
"abstract": "BACKGROUND\nAcute hepatic failure (AHF) is a devastating clinical syndrome with a high mortality rate. The outcome of AHF varies with etiology, but liver transplantation (LT) can significantly improve the prognosis and survival rate of such patients. This study aimed to detect the role of LT and artificial liver support systems (ALSS) for AHF patients and to analyze the etiology and outcome of patients with this disease.\n\n\nMETHODS\nA retrospective analysis was made of 48 consecutive patients with AHF who fulfilled the Kings College Criteria for LT at our center. We analyzed and compared the etiology, outcome, prognosis, and survival rates of patients between the transplantation (LT) group and the non-transplantation (N-LT) group.\n\n\nRESULTS\nAHF was due to viral hepatitis in 25 patients (52.1%; hepatitis B virus in 22), drug or toxic reactions in 14 (29.2%; acetaminophen in 6), Wilson disease in 4 (8.3%), unknown reasons in 3 (6.3%), and miscellaneous conditions in 2 (4.2%). In the LT group, 36 patients (7 underwent living donor LT, and 29 cadaveric LT) had an average model for end-stage liver disease score (MELD) of 35.7. Twenty-eight patients survived with good graft function after a follow-up of 27.3+/-4.5 months. During the waiting time, 6 patients were treated with ALSS and 2 of them died during hospitalization. The 30-day, 12-month, and 18-month survival rates were 77.8%, 72.2%, and 66.7%, respectively. In the N-LT group, 12 patients had an average MELD score of 34.5. Four patients were treated with ALSS and all died during hospitalization. The 90-day and 1-year survival rates were only 16.7% and 8.3%, respectively.\n\n\nCONCLUSIONS\nHepatitis is the most prominent cause of AHF at our center. Most patients with AHF, who fulfill the Kings College Criteria for LT, did not survive longer without LT. ALSS did not improve the prognosis of AHF patients, but may extend the waiting time for a donor. Currently, LT is still the most effective way to improve the prognosis of AHF patients.",
"affiliations": "Department of Hepatobiliary Surgery, General Hospital of PLA, Beijing, China. shixianjie301@yahoo.com.cn",
"authors": "Shi|Xian-Jie|XJ|;Xu|Hong-Bin|HB|;Ji|Wen-Bin|WB|;Liang|Yu-Rong|YR|;Duan|Wei-Dong|WD|;He|Lei|L|;Wang|Ming-Jun|MJ|;Zhao|Zhi-Ming|ZM|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1016/s1499-3872(11)60062-3",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "10(4)",
"journal": "Hepatobiliary & pancreatic diseases international : HBPD INT",
"keywords": null,
"medline_ta": "Hepatobiliary Pancreat Dis Int",
"mesh_terms": "D000328:Adult; D002681:China; D005260:Female; D017052:Hospital Mortality; D006801:Humans; D053208:Kaplan-Meier Estimate; D017114:Liver Failure, Acute; D016031:Liver Transplantation; D019164:Liver, Artificial; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D015996:Survival Rate; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "101151457",
"other_id": null,
"pages": "369-73",
"pmc": null,
"pmid": "21813384",
"pubdate": "2011-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Efficacy of liver transplantation for acute hepatic failure: a single-center experience.",
"title_normalized": "efficacy of liver transplantation for acute hepatic failure a single center experience"
} | [
{
"companynumb": "CN-JNJFOC-20161011950",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
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"drugauthorizationnumb": "019872",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugdosageform": "UNSPECIFIED",
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "ACETAMINOPHEN."
},
{
"actiondrug": "5",
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"activesubstancename": "ACETAMINOPHEN"
},
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"drugrecurreadministration": "3",
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"medicinalproduct": "ACETAMINOPHEN."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Intracranial pressure increased",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Haemorrhage intracranial",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Acute respiratory distress syndrome",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Acute hepatic failure",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Multiple organ dysfunction syndrome",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Renal failure",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Brain oedema",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Sepsis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Gastrointestinal haemorrhage",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SHI XJ, BIN HX, JI WB, LIANG YR, DUAN WD, HE L, ET AL. EFFICACY OF LIVER TRANSPLANTATION FOR ACUTE HEPATIC FAILURE: A SINGLE-CENTER EXPERIENCE. HEPATOBILIARY AND PANCREATIC DISEASES INTERNATIONAL AUG-2011;10 (4):369-373.",
"literaturereference_normalized": "efficacy of liver transplantation for acute hepatic failure a single center experience",
"qualification": "3",
"reportercountry": "CN"
},
"primarysourcecountry": "CN",
"receiptdate": "20161027",
"receivedate": "20161018",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12855722,
"safetyreportversion": 4,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170207"
}
] |
{
"abstract": "Polymorphisms in methotrexate transporter pathways have been associated with methotrexate toxicities and clearance. Recent genome-wide association studies have revealed that the SLCO1B1 T521C variant is associated with methotrexate elimination. We present a case of a pediatric patient with acute lymphoblastic leukemia who suffered from persistently high plasma methotrexate concentrations and acute kidney injuries after the admin-istration of a medium dose of methotrexate. Subsequent genetic analysis showed that he was a carrier of dys-functional genetic variants associated with methotrexate clearance. This case highlights that polymorphisms of methotrexate transporter pathways can adversely affect methotrexate elimination in a clinically significant manner.",
"affiliations": "Department of Pharmacy, Okayama University Hospital.;Department of Pediatrics, Okayama University Hospital.;Department of Pharmacy, Okayama University Hospital.;Department of Pediatrics, Okayama University Hospital.;Department of Pediatrics, Okayama University Hospital.;Department of Pediatrics, Okayama University Hospital.;Department of Pharmacy, Okayama University Hospital.;Department of Pharmacy, Okayama University Hospital.;Department of Pediatrics, Okayama University Hospital.;Department of Pediatrics, Okayama University Hospital.",
"authors": "Tatebe|Yasuhisa|Y|;Kanamitsu|Kiichiro|K|;Kanzaki|Hirotaka|H|;Ishida|Hisashi|H|;Fujiwara|Kaori|K|;Washio|Kana|K|;Kitamura|Yoshihisa|Y|;Sendo|Toshiaki|T|;Shimada|Akira|A|;Tsukahara|Hirokazu|H|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D027381:Liver-Specific Organic Anion Transporter 1; C503999:SLCO1B1 protein, human; C573423:MTHFR protein, human; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D008727:Methotrexate",
"country": "Japan",
"delete": false,
"doi": "10.18926/AMO/61215",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0386-300X",
"issue": "74(6)",
"journal": "Acta medica Okayama",
"keywords": "acute kidney injury; acute lymphoblastic leukemia; drug elimination; methotrexate; polymorphism",
"medline_ta": "Acta Med Okayama",
"mesh_terms": "D000964:Antimetabolites, Antineoplastic; D002648:Child; D006801:Humans; D027381:Liver-Specific Organic Anion Transporter 1; D008297:Male; D008727:Methotrexate; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D020641:Polymorphism, Single Nucleotide; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma",
"nlm_unique_id": "0417611",
"other_id": null,
"pages": "545-550",
"pmc": null,
"pmid": "33361876",
"pubdate": "2020-12",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Delayed Methotrexate Elimination after Administration of a Medium Dose of Methotrexate in a Patient with Genetic Variants Associated with Methotrexate Clearance.",
"title_normalized": "delayed methotrexate elimination after administration of a medium dose of methotrexate in a patient with genetic variants associated with methotrexate clearance"
} | [
{
"companynumb": "JP-LUPIN PHARMACEUTICALS INC.-2022-05552",
"fulfillexpeditecriteria": "2",
"occurcountry": "JP",
"patient": {
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{
"actiondrug": "6",
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"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
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"medicinalproduct": "SULFAMETHOXAZOLE AND TRIMETHOPRIM"
},
{
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},
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"drugdosagetext": "3 GRAM PER SQUARE METRE TWICE",
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{
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"medicinalproduct": "METHOTREXATE"
},
{
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},
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"drugdosagetext": "250 MILLILITRE PER SQUARE METER PER 24 HR",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Prophylaxis",
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},
{
"actiondrug": null,
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"drugcharacterization": "2",
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"drugdosageform": null,
"drugdosagetext": "15 MILLIGRAM/SQ. METER, QID",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Acute lymphocytic leukaemia",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
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"medicinalproduct": "LEUCOVORIN"
},
{
"actiondrug": null,
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},
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"drugindication": "Acute lymphocytic leukaemia",
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"medicinalproduct": "DEXAMETHASONE"
},
{
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{
"abstract": "BACKGROUND\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases with high mortality rates. This study was designed to analyze the pathogenic factors, clinical manifestations, complications, treatment, and prognosis of SJS/TEN and to explore the differences between surviving and deceased patients.\n\n\nMETHODS\nSJS/TEN patients admitted to Beijing Friendship Hospital from January 2006 to December 2015 were included in the study. Patients' data were retrospectively analyzed. Comparative studies were performed on the survival group and the deceased group, and Fisher's exact probability test was used for statistical analysis.\n\n\nRESULTS\nAmong the 88 patients included, 40 (45.5%) were male with a mean age of 45 ± 18 years. Forty-eight (54.5%) had SJS, 34 (38.6%) had SJS/TEN, and 6 (6.8%) had TEN. Fifty-three (60.2%) cases were caused by medications, mainly antibiotics (n = 24) followed by traditional Chinese medicines (n = 7). Forty-two cases (47.7%) developed visceral damage. Eighty-two patients improved or recovered and were discharged from hospital, and six patients died. Comparative studies on the survival group and the deceased group showed that the presence of malignant tumor ( χ2 = 27.969,P < 0.001), connective tissue diseases ( χ2 = 9.187, P= 0.002), previous abnormal liver/kidney functions ( χ2 = 6.006, P= 0.014), heart rate >100 times/min ( χ2 = 6.347, P= 0.012), detached skin area >20% ( χ2 = 5.594, P= 0.018), concurrent mucosal involvement at the mouth, eyes, and external genitals ( χ2 = 4.945, P= 0.026), subsequent accompanying liver/kidney damage ( χ2 = 11.839, P= 0.001, and χ2 = 36.302,P < 0.001, respectively), and SCORTEN score >2 ( χ2 = 37.148,P < 0.001) increased the risk of death.\n\n\nCONCLUSIONS\nSJS/TEN is mainly caused by medications, and nearly half of patients develop visceral damage. Multiple factors increase the mortality risk.",
"affiliations": "Department of Dermatology, Allergy and Clinical Immunology Centre, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.;Department of Dermatology, Allergy and Clinical Immunology Centre, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.",
"authors": "Wang|Li|L|;Mei|Xue-Ling|XL|",
"chemical_list": "D000900:Anti-Bacterial Agents",
"country": "China",
"delete": false,
"doi": "10.4103/0366-6999.204929",
"fulltext": "\n==== Front\nChin Med J (Engl)Chin. Med. JCMJChinese Medical Journal0366-6999Medknow Publications & Media Pvt Ltd India 28469101CMJ-130-106210.4103/0366-6999.204929Original ArticleRetrospective Analysis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in 88 Chinese Patients Wang Li Mei Xue-Ling Department of Dermatology, Allergy and Clinical Immunology Centre, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, ChinaAddress for correspondence: Dr. Li Wang, Department of Dermatology, Allergy and Clinical Immunology Centre, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China E-Mail: wl8866@sohu.com05 5 2017 130 9 1062 1068 04 12 2016 Copyright: © 2017 Chinese Medical Journal2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases with high mortality rates. This study was designed to analyze the pathogenic factors, clinical manifestations, complications, treatment, and prognosis of SJS/TEN and to explore the differences between surviving and deceased patients.\n\nMethods:\nSJS/TEN patients admitted to Beijing Friendship Hospital from January 2006 to December 2015 were included in the study. Patients’ data were retrospectively analyzed. Comparative studies were performed on the survival group and the deceased group, and Fisher's exact probability test was used for statistical analysis.\n\nResults:\nAmong the 88 patients included, 40 (45.5%) were male with a mean age of 45 ± 18 years. Forty-eight (54.5%) had SJS, 34 (38.6%) had SJS/TEN, and 6 (6.8%) had TEN. Fifty-three (60.2%) cases were caused by medications, mainly antibiotics (n = 24) followed by traditional Chinese medicines (n = 7). Forty-two cases (47.7%) developed visceral damage. Eighty-two patients improved or recovered and were discharged from hospital, and six patients died. Comparative studies on the survival group and the deceased group showed that the presence of malignant tumor (χ2 = 27.969, P < 0.001), connective tissue diseases (χ2 = 9.187, P = 0.002), previous abnormal liver/kidney functions (χ2 = 6.006, P = 0.014), heart rate >100 times/min (χ2 = 6.347, P = 0.012), detached skin area >20% (χ2 = 5.594, P = 0.018), concurrent mucosal involvement at the mouth, eyes, and external genitals (χ2 = 4.945, P = 0.026), subsequent accompanying liver/kidney damage (χ2 = 11.839, P = 0.001, and χ2 = 36.302, P < 0.001, respectively), and SCORTEN score >2 (χ2 = 37.148, P < 0.001) increased the risk of death.\n\nConclusions:\nSJS/TEN is mainly caused by medications, and nearly half of patients develop visceral damage. Multiple factors increase the mortality risk.\n\nMortalityRelative RiskStevens-Johnson SyndromeStevens-Johnson Syndrome/Toxic Epidermal Necrolysis OverlapToxic Epidermal Necrolysis\n==== Body\nIntroduction\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening diseases characterized by widespread red rash, blisters, and shedding of dead skin, with mucosal involvement. They are also associated with visceral damage.[1] SJS and TEN are generally considered as different phases of the disease, and the diagnosis is based on clinical manifestations. Prodromal symptoms include fever, cough, sore throat, and other discomforts. The acute phase typically occurs during the first 8–12 days with a rapid spreading of mucous membrane death and a positive result for Nicolsky's sign.[2] Bastuji-Garin et al.[3] proposed that disease classification should be based on the percentage of the total body surface area (BSA) of the involved skin. Epidermal detachment <10% of the BSA is classed as SJS, detachment above 30% as TEN, and detachment between 10% and 30% as intermediate (SJS/TEN overlap).[3]\n\nSJS/TEN is usually caused by medications, a variety of which can cause allergic reactions including antibiotics, antituberculosis drugs, anticonvulsants, nonsteroidal anti-inflammatory drugs, and allopurinol.[2]\n\nSJS/TEN are systematic diseases. In addition to the damage to the skin, gastrointestinal tract, and respiratory tract mucosa, they can also result in visceral involvement (e.g., liver, kidneys, lungs, and hematopoietic system), leading to organ dysfunction or even failure. The reported mortality rates of SJS and TEN are 10% and 34%, respectively.[45] Bastuji-Garin et al.[3] also established the TEN-specific severity-of-illness score (SCORTEN) for predicting the mortality risk. The following seven factors were considered high-risk, with each equivalent to one point: age >40 years, presence of a malignancy, heart rate >120 times/min, serum urea level >10 mmol/L (>27 mg/dl), percentage of epidermal detachment >10% of the BSA, serum glucose level >14 mmol/L (>250 mg/dl), and serum bicarbonate level <20 mEq/L. A higher score means a higher risk of mortality: the risk is 3% for 1 point and 90% for 5 or more points.\n\nBy summarizing the clinical and laboratory findings of SJS/TEN patients who were treated in a Chinese tertiary hospital over the past 10 years, this study sought to analyze the pathogenic factors, types of causative drugs, clinical manifestations, organ damage, treatment, and prognosis of SJS/TEN and to explore the differences in these features between surviving and deceased patients.\n\nMethods\nEthical aprroval\nAs a retrospective study and data analysis was performed anonymously, this study was exempt from the ethical approval and informed consent from patients.\n\nPatient selection\nSJS/TEN patients admitted to Beijing Friendship Hospital from January 2006 to December 2015 were included.\n\nDefinition of disease\nDiagnostic criteria were based on those proposed by Bastuji-Garin et al.[3] WHO-Uppsala Monitoring Centre causality categories were used to determine whether a drug caused allergies.[6] “Incubation period” refers to the period from the first usage of the drug to the clinical onset allergy. If a drug was continuously used for more than 3 months, withdrawn for more than 14 days, or had an incubation period shorter than 3 days, it was not considered to have caused allergy.[7] Disease severity and mortality were assessed using the SCORTEN standard system.[38]\n\nStatistical analysis\nStatistical analyses were performed using SPSS version 17.0 (SPSS Inc., Chicago, IL, USA). Fisher's exact probability test was used for statistical analysis and a value of P < 0.05 was considered statistically significant.\n\nResults\nDemographic data\nData from 95 patients were included in the study, 88 of whom met the diagnostic criteria for SJS/TEN. The clinical manifestations, including raised atypical targets or skin pathology, confirmed the presence of bullous erythema multiforme (BEM) in the remaining seven cases.\n\nAmong the 88 patients diagnosed with SJS/TEN, 48 (54.5%) had SJS, 34 (38.6%) had SJS/TEN overlap, and 6 (6.8%) had TEN. There were 40 (45.5%) male patients and 48 (54.5%) females, with a male-to-female ratio of 1:1.2. The mean age of patients was 45 ± 18 years (range: 7–83 years) [Table 1]. Age distribution showed that the 31–40 age group had the highest number of patients (n = 20), followed by the 21–30 age group (n = 17). Groups of age ≤10 years or 81–90 years had the lowest number of patients: one and two cases, respectively [Figure 1]. The length of hospital stay was 3–69 days (median: 10 days; interquartile range: 7–15 days). Six (6.8%) patients had a history of drug allergy: three to sulfonamides, one to penicillin, one to amoxicillin, and one to levofloxacin. There were 29 cases with underlying disease: 10 cases of Type II diabetes, 7 cases of high blood pressure, 3 cases of coronary heart disease, 2 cases of liver disorder, 2 cases of kidney disorder, 2 cases of epilepsy, 2 cases of low white blood cell count, and 1 case each of the following diseases: nephrotic syndrome, rheumatoid arthritis, system lupus erythematosus, Sjögren's syndrome, lung cancer, hemophagocytic syndrome (primary disease for T cell lymphoma), benign cerebellar tumor, hyperthyroidism, primary biliary cirrhosis, gout, atrophic gastritis, chronic urticaria, renal transplantation, and depression. Seven patients had two types of underlying disease, and three had three types of underlying disease.\n\nTable 1 Demographic information of SJS/TEN patients\n\nVariables\tTotal (n = 88)\tSJS (n = 48)\tSJS/TEN overlap (n = 34)\tTEN (n = 6)\t\nGender, n (%)\t\t\t\t\t\n Male\t40 (45.5)\t20 (41.7)\t19 (55.9)\t1 (16.7)\t\n Female\t48 (54.5)\t28 (58.3)\t15 (44.1)\t5 (83.3)\t\nMean age (years), mean ± SD\t45 ± 18\t48 ± 19\t39 ± 15\t49 ± 13\t\nMedian hospital stay (days), median (inter quartile range)\t10 (7–15)\t10 (8–14)\t9 (7–14)\t37 (20–55)\t\nHistory of drug allergy, n (%)\t6 (6.8)\t4 (8.3)\t2 (5.9)\t0\t\nUnderlying disease, n (%)\t29 (33.0)\t16 (33.3)\t10 (29.4)\t3 (50.0)\t\nSJS: Stevens-Johnson syndrome; TEN: Toxic epidermal necrolysis; SD: Standard deviation.\n\nFigure 1 Age distribution among patients with Stevens-Johnson syndrome/toxic epidermal necrolysis (n = 88).\n\nCauses of Stevens-Johnson syndrome/toxic epidermal necrolysis and toxic epidermal necrolysis\nAmong the 88 patients, SJS/TEN was caused by infection in 13 (14.8%) patients (including upper respiratory tract infections in 11 patients, 1 case of skin infection, and 1 case of mammary gland infection) and by medications in 53 patients (60.2%). The etiologies were unclear in the remaining 22 (25.0%) patients [Figure 2].\n\nFigure 2 Pathogenic factors of Stevens-Johnson syndrome/toxic epidermal necrolysis patients (n = 88).\n\nAmong the 53 cases caused by medications, 4 had used multiple drugs before the rash occurred and therefore could not identify the specific causative agent. The remaining 49 cases had mostly used antibiotics (n = 24) or traditional Chinese medicines (TCMs, n = 7). The allergies were caused by a wide variety of medications: levofloxacin was the most common (n = 3) followed by amoxicillin, azithromycin, clindamycin, cefdinir, cefradine, carbamazepine, lamotrigine, lysine acetylsalicylate, and acetaminophen, each of which had caused 2 cases. The compound medications pseudoephedrine hydrochloride and dextromethorphan hydrobromide, and Xiaojinwan, a kind of TCM, also caused allergies in two cases each. Each of the other listed drugs caused allergy in a single case [Table 2].\n\nTable 2 Drugs that caused allergies in SJS/TEN patients\n\nResponsible drug(s)\tTotal (n = 49)\tSJS (n = 18)\tSJS/TEN overlap (n = 26)\tTEN (n = 5)\t\nAntibiotics\t24 (49.0)\t10 (55.6)\t12 (46.2)\t2 (40.0)\t\n Levofloxacin\t3 (6.1)\t2 (11.1)\t1 (3.8)\t0\t\n Amoxicillin\t2 (4.1)\t0\t1 (3.8)\t1 (20.0)\t\n Azithromycin\t2 (4.1)\t1 (5.6)\t1 (3.8)\t0\t\n Clindamycin\t2 (4.1)\t1 (5.6)\t1 (3.8)\t0\t\n Cefdinir\t2 (4.1)\t2 (11.1)\t0\t0\t\n Cefradine\t2 (4.1)\t0\t2 (7.6)\t0\t\n Amoxicillin and clavulanate potassium\t1 (2.0)\t0\t1 (3.8)\t0\t\n Cefoperazone sodium and sulbactam sodium\t1 (2.0)\t0\t1 (3.8)\t0\t\n Cefuroxime axetil\t1 (2.0)\t0\t1 (3.8)\t0\t\n Ceftizoxime\t1 (2.0)\t1 (5.6)\t0\t0\t\n Latamoxef\t1 (2.0)\t1 (5.6)\t0\t0\t\n Meropenem\t1 (2.0)\t0\t1 (3.8)\t0\t\n Roxithromycin\t1 (2.0)\t0\t1 (3.8)\t0\t\n Moxifloxacin hydrochloride\t1 (2.0)\t1 (5.6)\t0\t0\t\n Etimicin sulfate\t1 (2.0)\t1 (5.6)\t0\t0\t\n Mesylate pefloxacin\t1 (2.0)\t0\t1 (3.8)\t0\t\n Norvancomycin\t1 (2.0)\t0\t0\t1 (20.0)\t\nAnticonvulsant\t5 (10.2)\t0\t4 (15.4)\t1 (20.0)\t\n Carbamazepine\t2 (4.1)\t0\t1 (3.8)\t1 (20.0)\t\n Lamotrigine\t2 (4.1)\t0\t2 (7.6)\t0\t\n Valproate\t1 (2.0)\t0\t1 (3.8)\t0\t\nNSAID\t4 (8.2)\t1 (5.6)\t2 (7.6)\t1 (20.0)\t\n Aspisol\t2 (4.1)\t1 (5.6)\t1 (3.8)\t0\t\n Acetaminophen\t2 (4.1)\t0\t1 (3.8)\t1 (20.0)\t\nAllopurinol\t1 (2.0)\t0\t1 (3.8)\t0\t\nOmeprazole\t1 (2.0)\t1 (5.6)\t0\t0\t\nIohexol\t1 (2.0)\t1 (5.6)\t0\t0\t\nInterferon\t1 (2.0)\t0\t1 (3.8)\t0\t\nCompound medicine\t5 (10.2)\t2 (11.1)\t2 (7.6)\t1 (20.0)\t\n Pseudoephedrine hydrochloride\t2 (4.1)\t1 (5.6)\t1 (3.8)\t0\t\n Dextromethorphan hydrobromide\t2 (4.1)\t1 (5.6)\t0\t1 (20.0)\t\n Anjiahuangmin\t1 (2.0)\t0\t1 (3.8)\t0\t\nTraditional Chinese Medicine\t7 (14.3)\t3 (16.7)\t4 (15.4)\t0\t\n Xiaojinwan\t2 (4.1)\t0\t2 (7.6)\t0\t\n Wei C Yinqiao Pian\t1 (2.0)\t1 (5.6)\t0\t0\t\n Sanhuang Pian\t1 (2.0)\t1 (5.6)\t0\t0\t\n Zhengqingfengtongning\t1 (2.0)\t1 (5.6)\t0\t0\t\n Herbal medicine\t2 (4.1)\t0\t2 (7.6)\t0\t\nThe data was presented by n (%). SJS: Stevens-Johnson syndrome; TEN: Toxic epidermal necrolysis; NSAID: Nonsteroidal anti-inflammatory drug.\n\nLaboratory findings\nLaboratory tests showed that 42 cases (47.7%) developed visceral damage. Liver disorders were the most common, as demonstrated by the increased levels of liver enzymes among 32 patients (36.4%). The second most common was gastrointestinal tract damage (n = 11, 12.5%) and the symptoms included diarrhea, gastrointestinal tract hemorrhage, and appetite loss. Ten cases (11.4%) developed lung damage, as manifested by dyspnea and patchy spot-like shadows on X-ray. There were eight (9.1%) cases of kidney damage, seven (8.0%) cases of disseminated intravascular coagulation (DIC), five (5.7%) cases of myocardial damage (as manifested by increased levels of troponin T or creatine kinase-MB, possibly accompanied by ST-T changes in electrocardiography), and two cases of encephalopathy (as manifested by consciousness disorder and delirium) [Table 3].\n\nTable 3 Clinical manifestations, visceral damage, and mortalities among SJS/TEN patients\n\nVariables\tTotal (n = 88)\tSJS (n = 48)\tSJS/TEN overlap (n = 34)\tTEN (n = 6)\t\nFever, n (%)\t62 (70.5)\t30 (62.5)\t26 (76.5)\t6 (100.0)\t\nLeukocytosis, n (%)\t35 (39.8)\t16 (33.3)\t16 (47.1)\t3 (50.0)\t\n% BSA, mean ± SD\t12.5 ± 12.5\t5.2 ± 2.2\t16.6 ± 6.6\t50.0 ± 10.0\t\nOrgan involvement, n (%)\t\t\t\t\t\n Hepatitis\t32 (36.4)\t17 (35.4)\t12 (35.3)\t3 (50.0)\t\n Renal dysfunction\t8 (9.1)\t3 (6.3)\t3 (8.8)\t2 (33.3)\t\n Gastrointestinal\t11 (12.5)\t3 (6.3)\t4 (11.8)\t4 (66.7)\t\n Respiratory\t10 (11.4)\t3 (6.3)\t3 (8.8)\t4 (66.7)\t\n Encephalopathy\t2 (2.3)\t0\t1 (2.9)\t1 (16.7)\t\n Myocarditis\t5 (5.7)\t1 (2.1)\t3 (8.8)\t1 (16.7)\t\n DIC\t7 (8.0)\t3 (6.3)\t2 (5.9)\t2 (33.3)\t\nMortality, n (%)\t6 (6.8)\t2 (4.2)\t2 (5.9)\t2 (33.3)\t\nSJS: Stevens-Johnson syndrome; TEN: Toxic epidermal necrolysis; BSA: Body surface area; SD: Standard deviation; DIC: Disseminated intravenous coagulation.\n\nTreatment and clinical course\nAmong the 88 patients, 41 (46.6%) received systematic glucocorticoid treatment. Specifically, 15 of the 48 SJS patients, 20 of the 34 SJS/TEN overlap patients, and all 6 TEN patients received systematic glucocorticoid treatment. In addition, the combined application of intravenous immunoglobulin (IVIG) was administered to two SJS/TEN overlap patients and four TEN patients.\n\nAmong the 88 patients, 82 improved or recovered completely and were discharged from the hospital, and 6 died, including 2 from each of the following groups: SJS, SJS/TEN overlap, and TEN. Comparative studies on patient health history, clinical manifestations, test results, and treatment protocols were performed between the survival group and the deceased group. The results showed that death was closely correlated with the status of the systemic disease, area of detached skin, and severity of liver/kidney damage [Table 4]. Causes of death included infection, organ failure, and pulmonary embolism resulting from detached vein thrombosis in the lower limbs [Table 5].\n\nTable 4 Univariate analysis of the clinical characteristics of the survival and deceased groups (n = 88)\n\nVariables\tSurvived group (%)\tDeceased group (%)\tχ2\tP\t\nAge >70 years\t8.5\t16.7\t0.447\t0.504\t\nMale gender\t46.3\t33.3\t0.382\t0.537\t\nRecent pathological history\t\t\t\t\t\n Cancer\t0.0\t33.3\t27.969\t<0.001\t\n Renal disease\t1.2\t16.7\t6.006\t0.014\t\n Liver disease\t1.2\t16.7\t6.006\t0.014\t\n Prior infections\t41.5\t50.0\t0.167\t0.683\t\n Autoimmune diseases\t3.7\t33.3\t9.187\t0.002\t\n Diabetes\t9.8\t33.3\t3.086\t0.079\t\nEye involvement\t32.9\t66.7\t2.789\t0.095\t\nOral mucosa involvement\t36.6\t66.7\t2.134\t0.144\t\nGenital involvement\t22.0\t50.0\t2.421\t0.120\t\nInvolvement of three mucosal areas\t14.6\t50.0\t4.945\t0.026\t\nHeart rate >100 beats/min\t12.2\t50.0\t6.347\t0.012\t\nWBC >10.0×109/L\t41.5\t50.0\t0.167\t0.683\t\nBSA involvement >20%\t13.4\t50.0\t5.594\t0.018\t\nLiver involvement\t30.5\t100.0\t11.839\t0.001\t\nBUN >10 mg/dl\t2.4\t66.7\t36.302\t<0.001\t\nSerum bicarbonate <20 mEq/L\t2.4\t50.0\t23.599\t<0.001\t\nSteroid treatment\t42.7\t100.0\t7.381\t0.007\t\nAntibiotics use\t46.3\t83.3\t3.062\t0.080\t\nInfection\t46.3\t83.3\t3.062\t0.080\t\nSCORTEN >2\t8.5\t83.3\t37.148\t<0.001\t\nWBC: White blood cell; BSA: Body surface area; BUN: Blood urea nitrogen; SCORTEN: Toxic epidermal necrolysis specific severity of illness score.\n\nTable 5 Analysis of the six deceased cases among patients with SJS/TEN\n\nCase number\tDisease\tAge\tSex\tUnderlying disease\tCausative drugs\tIndication for drug therapy\tMaximum skin detachment (%)\tClinical course of the skin lesion\tSevere complications and cause of death\tMaximum doses of corticosteroids and other therapies\tSCORTEN\tTime to death\t\n1\tSJS\t62\tFemale\tHemophagocytic syndrome, T cell lymphoma\tNA\tNA\t8\tImproved\tLung infection, liver/kidney failure\tmPSL 40 mg/d\t4\t14\t\n2\tSJS\t62\tFemale\tSystemic lupus erythematosus\tImipenem, vancomycin\tLung infection\t5\tNo change\tLung infection, respiratory failure\tDXM 10 mg/d\t2\t6\t\n3\tSJS/TEN overlap\t83\tMale\tLung cancer\tMeropenem\tLung infection\t22\tImproved\tLung infection, respiratory failure, DIC\tmPSL 80 mg/d, IVIG 20 g/day\t5\t12\t\n4\tSJS/TEN overlap\t66\tMale\tMesenteric venous thrombosis with intestinal necrosis\tCefoperazone sodium and sulbactam sodium\tPeritonitis\t18\tHealed\tPeritonitis, bacterial sepsis, fungal sepsis\tmPSL 80 mg/d, IVIG 20 g/day\t3\t30\t\n5\tTEN\t45\tFemale\tSjögren’s disease, primary biliary cirrhosis\tNorvancomycin\tLung infection\t65\tImproved\tLung infection, respiratory failure\tmPSL 120 mg/d, IVIG 20 g/day\t4\t10\t\n6\tTEN\t67\tFemale\tType II diabetes\tAmoxicillin\tUpper respiratory tract infection\t70\tHealed\tPulmonary embolism resulting from the detached vein thrombosis in lower limbs\tmPSL 160 mg/d, IVIG 20 g/day\t3\t46\t\nTime to death: Time between the onset of eruption and death. SJS: Stevens–Johnson syndrome; mPSL: Methylprednisolone; DXM: Dexamethasone; IVIG: Intravenous immunoglobulin; DIC: Disseminated intravenous coagulation; TEN: Toxic epidermal necrolysis; SCORTEN: Toxic epidermal necrolysis specific severity of illness score; NA: Not available.\n\nDiscussion\nIn this study, 88 of the 95 patients met the diagnostic criteria of SJS/TEN, and 7 of them were re-diagnosed with BEM. Normally, BEM and SJS/TEN were distinguished by clinical manifestations and pathological examinations. BEM is characterized by the epidermal detachment of <10% BSA, coupled with localized typical target lesions or raised atypical targets and is typically caused by infection, of which herpes simplex virus is the most common. Skin biopsies were characterized histologically by lichenoid infiltrate.[9]\n\nSJS/TEN was mostly caused by medication use. However, vaccination, chemical exposure, and certain virus/mycoplasma infections might have also been responsible for the induction of disease. Among the 88 cases in the present study, disease severity increased along the spectrum of SJS, SJS/TEN overlap, and TEN, and cases with drug-induced diseases increased from 54% to 80%. In contrast, infection-associated cases decreased from 29% to 20%. These results suggest that TEN is more likely to be caused by drug use, which was consistent with previously reported studies.[910]\n\nAmong the seven patients who were allergic to TCMs, five were allergic to Chinese patented medicines (two cases of Xiaojin tablets; one case of Vitamin C Yinqiao tablets; one case of Sanhuang tablets; and one case of Zhengqing Fengtongning). Two patients were allergic to Chinese herbal medicines. We searched the China Knowledge Resource Integrated Database and found that allergies to the above four Chinese patent medicines had already been reported in the literature. A further literature search on each of the 23 medicinal materials contained in these 4 Chinese patented medicines showed that 14 had been described as allergy-inducing. Therefore, allergies to TCMs are not uncommon, probably because most Chinese patented medicines contain multiple medicinal materials, which contain multiple ingredients, and allergy to any of these ingredients can lead to allergic reactions. Interestingly, while some articles had reported allergic reactions to Zhengqing Fengtongning, this drug contains only one ingredient, sinomenine hydrochloride. However, most relevant studies on sinomenine hydrochloride have focused on its purification methods and therapeutic efficacies but not on the induction of clinical allergy or its underlying mechanisms. In total, there are more than 12,000 known TCMs, only 1% of which have been shown to cause an adverse reaction.[11] However, since TCMs are widely used in China and their components are relatively complex, clinicians must be particularly cautious when prescribing TCMs, especially when studies to date on the ingredients of TCMs and their pharmacological mechanisms remain inadequate.[11121314]\n\nMortalities were determined according to the SCORTEN grading system: 0–1 point, 3%; 2 points, 12%; 3 points, 35%; 4 points, 58%; and 5 points and above, >90%.[38] Among the six cases of death, one had 5 points, two had 4 points, two had 3 points, and one had 2 points. Analysis of the causes of death and statistical analyses showed that gender, age (>70 years), infection status, and diabetes status were not significantly different between patients who survived and those who did not. However, the presence or absence of malignant tumor, connective tissue disease, or liver/kidney disorder was significantly different between the survival and the deceased groups, with the presence of these diseases correlating with death. Clinically, mucosal damage to the mouth, eyes, or genitals was not individually correlated with death; however, concurrent mucosal damage to all three areas was a factor associated with death. Heart rate >100/min or skin detachment area >20% was also correlated with death. Laboratory results showed no statistically significant differences in increased levels of white blood cells, accompanying infection, and antibiotic use between the survival and deceased groups. However, liver damage, blood urea nitrogen >10 mg/dl, bicarbonate level <20 mEq/L, and SCORTEN >2 increased the risk of death. Glucocorticoid usage was also significantly different between the survival and deceased groups: the proportion of glucocorticoid usage was 100% in the deceased group but only 43% in the survival group. However, we cannot conclude that glucocorticoid usage contributed to death because patients in the deceased group had higher SCORTEN scores and more severe underlying diseases, which led to a higher rate of glucocorticoid usage. Therefore, the more likely cause of death was the diseases themselves, and the use of glucocorticoids failed to save the patients’ lives.\n\nAll six cases of death had underlying diseases, including two with the connective tissue diseases systemic lupus erythematosus, and Sjögren's disease, accompanied by primary biliary cirrhosis; two diabetes cases, with one previously admitted to hospital because of mesenteric venous thrombosis with intestinal necrosis; and two cases with malignant tumors, one of lung cancer and the other of primary T cell lymphoma with hemophagocytic syndromes. In the six deceased patients, four cases were directly caused by infection, one by liver failure, and one by pulmonary embolism caused by a detached vein thrombosis in the lower limbs. Patients who developed liver failure also had accompanying hemophagocytic syndromes, which resulted in lung infection and rapid liver/kidney deterioration in addition to their original liver/kidney damage. Five patients had accompanying infections, four of which were lung infections. Among these four cases, three developed respiratory failure and one had accompanying DIC. The infections were caused by bacteria and fungi, including Pseudomonas aeruginosa, methicillin-resistant Staphylococcus aureus, Stenotrophomonas maltophilia, Klebsiella pneumoniae, Acinetobacter baumannii, Leclercia adecarboxylata, Candida albicans, and Candida parapsilosis. Most of these pathogens are opportunistic. The infections were mainly acquired in hospital, which might correlate with the low immunity and long hospital stay of patients. Four of the five patients developed definite infection before corticoid usage, and subsequent infection control was insufficient, which directly led to death. These results indicate that infection, particularly lung infection, requires special attention when corticosteroids are used in the clinic to treat SJS/TEN.\n\nAs a retrospective study carried out in a tertiary-care setting in China, our current study was limited by its sample size, which might have caused bias in the analysis (e.g., in the types and proportions of allergy-inducing drugs). Six of the 88 patients died, yielding a mortality rate of 6.8%, which was lower than that reported in the most literature.[45] We analyzed the causes of death in terms of underlying diseases, clinical manifestations after disease onset, and laboratory findings; however, the small number of reported deaths might also have introduced bias.\n\nIn conclusions, SJS/TEN is mostly caused by medications, most commonly antibiotics, although TCMs are also considered causative factors in allergy induction. Accompanying visceral damage was common, particularly liver damage that accounted for 36% of the total cases. The following factors increased the risk of death: presence of malignant tumor, connective tissue disease, previous abnormal liver/kidney function, heart rate >100/min, detached skin area >20%, concurrent mucosal involvement in the mouth, eyes, and external genitals, consequent accompanying liver/kidney damage, and SCORTEN >2. Glucocorticoid application combined with IVIG was effective for the treatment of severe cases. During corticoid application, opportunistic, hospital-acquired infections should be prevented. Death was mostly caused by infection, followed by visceral damage.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nEdited by: Ning-Ning Wang\n==== Refs\nReferences\n1 Yamane Y Matsukura S Watanabe Y Yamaguchi Y Nakamura K Kambara T Retrospective analysis of Stevens-Johnson syndrome and toxic epidermal necrolysis in 87 Japanese patients – Treatment and outcome Allergol Int 2016 65 74 81 doi: 10.1016/j.alit. 2015.09.001 26666483 \n2 Law EH Leung M Corticosteroids in Stevens-Johnson syndrome/toxic epidermal necrolysis: Current evidence and implications for future research Ann Pharmacother 2015 49 335 42 doi: 10.1177/1060028014560012 25406459 \n3 Bastuji-Garin S Rzany B Stern RS Shear NH Naldi L Roujeau JC Clinical classification of cases of toxic epidermal necrolysis, Stevens-Johnson syndrome, and erythema multiforme Arch Dermatol 1993 129 92 6 8420497 \n4 Kim HI Kim SW Park GY Kwon EG Kim HH Jeong JY Causes and treatment outcomes of Stevens-Johnson syndrome and toxic epidermal necrolysis in 82 adult patients Korean J Intern Med 2012 27 203 10 doi: 10.3904/kjim.2012.27.2.203 22707893 \n5 Lee HY Tey HL Pang SM Thirumoorthy T Systemic lupus erythematosus presenting as Stevens-Johnson syndrome and toxic epidermal necrolysis: A report of three cases Lupus 2011 20 647 52 doi: 10.1177/0961203310385162 21148602 \n6 The Use of the WHO-UMC System for Standardised Case Causality Assessment Last accessed on 2017 Mar 29 Available from:\nhttps://www.who-umc.org/media/2768/standardised-case-causality-assessment.pdf \n7 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 80 doi: 10.1111/bjd.12501 23855313 \n8 Bastuji-Garin S Fouchard N Bertocchi M Roujeau JC Revuz J Wolkenstein P SCORTEN: A severity-of-illness score for toxic epidermal necrolysis J Invest Dermatol 2000 115 149 53 doi: 10.1046/j.1523-1747.2000.00061.x 10951229 \n9 Kohanim S Palioura S Saeed HN Akpek EK Amescua G Basu S Stevens-Johnson syndrome/toxic epidermal necrolysis – A comprehensive review and guide to therapy. I. Systemic disease Ocul Surf 2016 14 2 19 doi: 10.1016/j.jtos.2015.10.002 26549248 \n10 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 24 doi: 10.3892/etm.2015.2549 26622347 \n11 Wang X Liu Z Prevention and treatment of viral respiratory infections by traditional Chinese herbs Chin Med J 2014 127 1344 50 doi: 10.3760/cma.j.issn.0366-6999.20132029 24709192 \n12 Han L Guo S Wang Y Yang L Liu S Experimental drugs for treatment of autoimmune myocarditis Chin Med J 2014 127 2850 9 doi: 10.3760/cma.j.issn.0366-6999.20140748 25146626 \n13 Shi YL Liu WJ Zhang XF Su WJ Chen NN Lu SH Effect of Chinese herbal medicine Jinlida granule in treatment of patients with impaired glucose tolerance Chin Med J 2016 129 2281 6 doi: 10.4103/0366-6999.190676 27647185 \n14 Hua W Gao RL Zhao BC Wang J Chen XH Cai C The efficacy and safety of Wenxin Keli in patients with frequent premature ventricular contractions: A randomized, double-blind, placebo-controlled, parallel-group, multicenter trial Chin Med J 2015 128 2557 64 doi: 10.4103/0366-6999.166026 26415790\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0366-6999",
"issue": "130(9)",
"journal": "Chinese medical journal",
"keywords": null,
"medline_ta": "Chin Med J (Engl)",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D003240:Connective Tissue Diseases; D005123:Eye; D005260:Female; D005835:Genitalia; D006801:Humans; D007668:Kidney; D008099:Liver; D008297:Male; D008875:Middle Aged; D009055:Mouth; D012189:Retrospective Studies; D012867:Skin; D013262:Stevens-Johnson Syndrome",
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"other_id": null,
"pages": "1062-1068",
"pmc": null,
"pmid": "28469101",
"pubdate": "2017-05-05",
"publication_types": "D016428:Journal Article",
"references": "25406459;25146626;27647185;26415790;8420497;24709192;22707893;26666483;10951229;23855313;26622347;21148602;26549248",
"title": "Retrospective Analysis of Stevens-Johnson Syndrome and Toxic Epidermal Necrolysis in 88 Chinese Patients.",
"title_normalized": "retrospective analysis of stevens johnson syndrome and toxic epidermal necrolysis in 88 chinese patients"
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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": "Chemotherapeutic agents may induce both local and systemic cutaneous toxicity, and evaluation of these reactions in oncologic patients constitutes a real challenge. The authors describe a 78-year-old Caucasian woman, with a past medical history relevant for right radical mastectomy with axillary dissection because of stage 2 breast invasive ductal carcinoma (T2N3M0), referred to our department because of an intertriginous eruption in her groin. Two weeks before the eruption, a chemotherapy regime with cyclophosphamide, methotrexate, and 5-fluorouracil was performed. Examination revealed erythematous and dusky violaceous papules coalescing into edematous patches in the inguinal intertriginous area, including the internal surface of her thighs, groin, genital area, and intergluteal cleft. Skin cultures for bacteria and fungus were negative. Clinical and histological data were consistent with an intertriginous pattern of toxic erythema of chemotherapy (TEC). Oral prednisolone therapy (0.5 mg/kg) was started, tapered over a 1-week period, and along with general measures that included topical zinc oxide suspension, cutaneous lesions cleared completely within the first days. Although patient reassurance, she refused any kind of new chemotherapy infusions. Due to their high metabolic rate, the skin, mucous membranes, and annexes are one of the most important target organs of the toxicity associated with systemic chemotherapy. Several patterns of cutaneous eruptions to chemotherapy have been reported in the literature. Trying to resolve this issue, recently recommended was a new clinically descriptive term, TEC, in order to emphasize the overlapping features of these entities. Early recognition of this entity is critical, not just from a prognostic standpoint, but also to avoid unnecessary, potentially harmful therapeutic interventions.",
"affiliations": "Dermatology and Venereology Department, Curry Cabral Hospital, Lisbon, Portugal. rodrigoaraujocarvalho@gmail.com",
"authors": "Carvalho|Rodrigo|R|;Macias|Vasco|V|;Marques-Pinto|Gabriela|G|;Afonso|Ana|A|;Cardoso|Jorge|J|",
"chemical_list": "D005938:Glucocorticoids; D011239:Prednisolone",
"country": "England",
"delete": false,
"doi": "10.3109/15569527.2011.572572",
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"issn_linking": "1556-9527",
"issue": "30(4)",
"journal": "Cutaneous and ocular toxicology",
"keywords": null,
"medline_ta": "Cutan Ocul Toxicol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D004890:Erythema; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007402:Intertrigo; D011239:Prednisolone; D016896:Treatment Outcome",
"nlm_unique_id": "101266892",
"other_id": null,
"pages": "309-11",
"pmc": null,
"pmid": "21501039",
"pubdate": "2011-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Intertriginous pattern of toxic erythema of chemotherapy.",
"title_normalized": "intertriginous pattern of toxic erythema of chemotherapy"
} | [
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"transmissiondate": "20190417"
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},
{
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"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
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"literaturereference_normalized": "intertriginous pattern of toxic erythema of chemotherapy",
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},
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}
] |
{
"abstract": "Burns injuries during pregnancy are rarely reported in developed countries, but an increasing in mortality and morbidity has been observed. The authors describe their experience in the treatment of pregnant women in a burn unit. A 12-year retrospective study of burns in pregnant women hospitalized was conducted. Since 2008, two pregnant women were admitted in their unit. Patient 1, a 32-year-old pregnant woman on second trimester (27s6d), suffered a second-degree burn injury, 16% total body surface area (TBSA), caused by fire. She was admitted in their burn unit and submitted to medical treatment, wound dressing, and surgical treatment. Cerium nitrate and silver sulfadiazine were used in burn lesions and the patient was submitted to debridement and skin graft surgery. No uneventful events occurred with the fetus. Patient 2 was a 32-year-old pregnant woman on second trimester (26s), HVC positive, admitted with a second-degree flash burn, 8% TBSA. She was submitted to endotracheal intubation before arriving to the hospital due to risk of airway burn. Dexamethasone was administered for fetus lung maturation. No uneventful events were observed. The incidence of thermal injury in pregnancy in Portugal is low. Active medical treatment together with conservative wound care should be the standard in each trimester of pregnancy. Although there is limited safety information on cerium nitrate or silver sulfadiazine during pregnancy, those were used with no adverse effects on one of their patients. Obstetrical management should be individualized.",
"affiliations": "Department of Plastic and Reconstructive Surgery, Centro Hospitalar S. João, Porto, Portugal.;Department of Plastic and Reconstructive Surgery, Centro Hospitalar S. João, Porto, Portugal.;Department of Plastic and Reconstructive Surgery, Centro Hospitalar S. João, Porto, Portugal.;Department of Plastic and Reconstructive Surgery, Centro Hospitalar S. João, Porto, Portugal.;Department of Plastic and Reconstructive Surgery, Centro Hospitalar S. João, Porto, Portugal.;Department of Plastic and Reconstructive Surgery, Centro Hospitalar S. João, Porto, Portugal.;Department of Plastic and Reconstructive Surgery, Centro Hospitalar S. João, Porto, Portugal.",
"authors": "Correia-Sá|Inês|I|;Marques|Marisa|M|;Horta|Ricardo|R|;Costa-Ferreira|António|A|;Rodrigues|Acácio G|AG|;Silva|Álvaro|Á|;Egipto|Paula|P|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1093/jbcr/iraa141",
"fulltext": null,
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"issn_linking": "1559-047X",
"issue": "42(2)",
"journal": "Journal of burn care & research : official publication of the American Burn Association",
"keywords": null,
"medline_ta": "J Burn Care Res",
"mesh_terms": null,
"nlm_unique_id": "101262774",
"other_id": null,
"pages": "232-235",
"pmc": null,
"pmid": "32844994",
"pubdate": "2021-03-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Experience in Management of Burn Injury During Pregnancy in a Burn Unit.",
"title_normalized": "experience in management of burn injury during pregnancy in a burn unit"
} | [
{
"companynumb": "PT-ALKEM LABORATORIES LIMITED-PT-ALKEM-2020-05789",
"fulfillexpeditecriteria": "1",
"occurcountry": "PT",
"patient": {
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "SILVER SULFADIAZINE"
},
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"abstract": "A 13-year-old healthy girl presented with dizziness and palpitations, found to have a left atrial mass. An 8-cm tumor was removed en bloc. Pathology confirmed grade 3 leiomyosarcoma with multifocal positive margins. She received adjuvant ifosfamide and doxorubicin, followed by concurrent proton radiotherapy and ifosfamide. Radiotherapy included 66 Gy (RBE) in 33 fractions to the operative bed. Prospectively graded toxicities included Grade 2 esophagitis and Grade 1 anorexia, dermatitis, and fatigue. She completed six cycles of ifosfamide. Two years post operation, she had no evidence of disease, intermittent palpitations with normal cardiac function, and no other cardiopulmonary or esophageal symptoms.",
"affiliations": "Department of Radiation Oncology, Winship Cancer Institute at Emory University, Atlanta, Georgia, USA.;Pediatric Cardiac Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia, USA.;Department of Radiation Oncology, Winship Cancer Institute at Emory University, Atlanta, Georgia, USA.;Department of Radiation Oncology, Winship Cancer Institute at Emory University, Atlanta, Georgia, USA.;Department of Pediatric Hematology and Oncology, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.;Department of Radiation Oncology, Winship Cancer Institute at Emory University, Atlanta, Georgia, USA.",
"authors": "Janopaul-Naylor|James|J|https://orcid.org/0000-0002-3612-4852;Kanter|Kirk R|KR|;Flampouri|Stella|S|;Nguyen|Vivi|V|;Olson|Thomas A|TA|https://orcid.org/0000-0002-6691-5380;Eaton|Bree R|BR|https://orcid.org/0000-0003-2431-2933",
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"doi": "10.1002/pbc.29241",
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"issn_linking": "1545-5009",
"issue": "68(10)",
"journal": "Pediatric blood & cancer",
"keywords": "cardiac sarcoma; cardiac toxicity; doxorubicin; pediatric oncology; proton therapy; radiotherapy; soft tissue sarcoma",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": null,
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e29241",
"pmc": null,
"pmid": "34260156",
"pubdate": "2021-10",
"publication_types": "D016428:Journal Article",
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"title": "Adjuvant chemoradiation for high-grade cardiac leiomyosarcoma in a child: Case report and review of literature.",
"title_normalized": "adjuvant chemoradiation for high grade cardiac leiomyosarcoma in a child case report and review of literature"
} | [
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"literaturereference": "JANOPAUL?NAYLOR J, KANTER K, FLAMPOURI S, NGUYEN V, OLSON T, EATON B. ADJUVANT CHEMORADIATION FOR HIGH?GRADE CARDIAC LEIOMYOSARCOMA IN A CHILD: CASE REPORT AND REVIEW OF LITERATURE. PEDIATRIC BLOOD AND CANCER. 2021?. DOI:10.1002/PBC.29241",
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{
"abstract": "OBJECTIVE\nTo compare overall survival (OS) for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for advanced breast cancer.\n\n\nMETHODS\nThe Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST) was a phase II, randomized, open-label, multicenter trial. Postmenopausal women with estrogen receptor-positive, locally advanced/metastatic breast cancer who had no previous therapy for advanced disease received either fulvestrant 500 mg (days 0, 14, 28, and every 28 days thereafter) or anastrozole 1 mg (daily). The primary end point (clinical benefit rate [72.5% and 67.0%]) and a follow-up analysis (median time to progression [23.4 months and 13.1 months]) have been reported previously for fulvestrant 500 mg and anastrozole, respectively. Subsequently, the protocol was amended to assess OS by unadjusted log-rank test after approximately 65% of patients had died. Treatment effect on OS across several subgroups was examined. Tolerability was evaluated by adverse event monitoring.\n\n\nRESULTS\nIn total, 205 patients were randomly assigned (fulvestrant 500 mg, n = 102; anastrozole, n = 103). At data cutoff, 61.8% (fulvestrant 500 mg, n = 63) and 71.8% (anastrozole, n = 74) had died. The hazard ratio (95% CI) for OS with fulvestrant 500 mg versus anastrozole was 0.70 (0.50 to 0.98; P = .04; median OS, 54.1 months v 48.4 months). Treatment effects seemed generally consistent across the subgroups analyzed. No new safety issues were observed.\n\n\nCONCLUSIONS\nThere are several limitations of this OS analysis, including that it was not planned in the original protocol but instead was added after time-to-progression results were analyzed, and that not all patients participated in additional OS follow-up. However, the present results suggest fulvestrant 500 mg extends OS versus anastrozole. This finding now awaits prospective confirmation in the larger phase III FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy Naïve Advanced Breast Cancer) trial (ClinicalTrials.gov identifier: NCT01602380).",
"affiliations": "Matthew J. Ellis, Baylor College of Medicine, Houston, TX; Antonio Llombart-Cussac, Hospital Arnau de Vilanova, Lérida, Spain; David Feltl, FNsP Ostrava, Ostrava-Poruba, Czech Republic; John A. Dewar, Ninewells Hospital and Medical School, Dundee; Nicola Hewson and Yuri Rukazenkov, AstraZeneca Pharmaceuticals, Macclesfield; John F.R. Robertson, University of Nottingham, Derby, United Kingdom; and Marek Jasiówka, Instytut im Marii Skłodowskiej-Curie, Kraków, Poland. Matthew.Ellis@bcm.edu.;Matthew J. Ellis, Baylor College of Medicine, Houston, TX; Antonio Llombart-Cussac, Hospital Arnau de Vilanova, Lérida, Spain; David Feltl, FNsP Ostrava, Ostrava-Poruba, Czech Republic; John A. Dewar, Ninewells Hospital and Medical School, Dundee; Nicola Hewson and Yuri Rukazenkov, AstraZeneca Pharmaceuticals, Macclesfield; John F.R. Robertson, University of Nottingham, Derby, United Kingdom; and Marek Jasiówka, Instytut im Marii Skłodowskiej-Curie, Kraków, Poland.;Matthew J. Ellis, Baylor College of Medicine, Houston, TX; Antonio Llombart-Cussac, Hospital Arnau de Vilanova, Lérida, Spain; David Feltl, FNsP Ostrava, Ostrava-Poruba, Czech Republic; John A. Dewar, Ninewells Hospital and Medical School, Dundee; Nicola Hewson and Yuri Rukazenkov, AstraZeneca Pharmaceuticals, Macclesfield; John F.R. Robertson, University of Nottingham, Derby, United Kingdom; and Marek Jasiówka, Instytut im Marii Skłodowskiej-Curie, Kraków, Poland.;Matthew J. Ellis, Baylor College of Medicine, Houston, TX; Antonio Llombart-Cussac, Hospital Arnau de Vilanova, Lérida, Spain; David Feltl, FNsP Ostrava, Ostrava-Poruba, Czech Republic; John A. Dewar, Ninewells Hospital and Medical School, Dundee; Nicola Hewson and Yuri Rukazenkov, AstraZeneca Pharmaceuticals, Macclesfield; John F.R. Robertson, University of Nottingham, Derby, United Kingdom; and Marek Jasiówka, Instytut im Marii Skłodowskiej-Curie, Kraków, Poland.;Matthew J. Ellis, Baylor College of Medicine, Houston, TX; Antonio Llombart-Cussac, Hospital Arnau de Vilanova, Lérida, Spain; David Feltl, FNsP Ostrava, Ostrava-Poruba, Czech Republic; John A. Dewar, Ninewells Hospital and Medical School, Dundee; Nicola Hewson and Yuri Rukazenkov, AstraZeneca Pharmaceuticals, Macclesfield; John F.R. Robertson, University of Nottingham, Derby, United Kingdom; and Marek Jasiówka, Instytut im Marii Skłodowskiej-Curie, Kraków, Poland.;Matthew J. Ellis, Baylor College of Medicine, Houston, TX; Antonio Llombart-Cussac, Hospital Arnau de Vilanova, Lérida, Spain; David Feltl, FNsP Ostrava, Ostrava-Poruba, Czech Republic; John A. Dewar, Ninewells Hospital and Medical School, Dundee; Nicola Hewson and Yuri Rukazenkov, AstraZeneca Pharmaceuticals, Macclesfield; John F.R. Robertson, University of Nottingham, Derby, United Kingdom; and Marek Jasiówka, Instytut im Marii Skłodowskiej-Curie, Kraków, Poland.;Matthew J. Ellis, Baylor College of Medicine, Houston, TX; Antonio Llombart-Cussac, Hospital Arnau de Vilanova, Lérida, Spain; David Feltl, FNsP Ostrava, Ostrava-Poruba, Czech Republic; John A. Dewar, Ninewells Hospital and Medical School, Dundee; Nicola Hewson and Yuri Rukazenkov, AstraZeneca Pharmaceuticals, Macclesfield; John F.R. Robertson, University of Nottingham, Derby, United Kingdom; and Marek Jasiówka, Instytut im Marii Skłodowskiej-Curie, Kraków, Poland.;Matthew J. Ellis, Baylor College of Medicine, Houston, TX; Antonio Llombart-Cussac, Hospital Arnau de Vilanova, Lérida, Spain; David Feltl, FNsP Ostrava, Ostrava-Poruba, Czech Republic; John A. Dewar, Ninewells Hospital and Medical School, Dundee; Nicola Hewson and Yuri Rukazenkov, AstraZeneca Pharmaceuticals, Macclesfield; John F.R. Robertson, University of Nottingham, Derby, United Kingdom; and Marek Jasiówka, Instytut im Marii Skłodowskiej-Curie, Kraków, Poland.",
"authors": "Ellis|Matthew J|MJ|;Llombart-Cussac|Antonio|A|;Feltl|David|D|;Dewar|John A|JA|;Jasiówka|Marek|M|;Hewson|Nicola|N|;Rukazenkov|Yuri|Y|;Robertson|John F R|JF|",
"chemical_list": "D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D065171:Estrogen Receptor Antagonists; D009570:Nitriles; D014230:Triazoles; D000077267:Fulvestrant; D000077384:Anastrozole; D004958:Estradiol",
"country": "United States",
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"doi": "10.1200/JCO.2015.61.5831",
"fulltext": "\n==== Front\nJ Clin OncolJ. Clin. OncoljcojcoJCOJournal of Clinical Oncology0732-183X1527-7755American Society of Clinical Oncology 263711341583110.1200/JCO.2015.61.5831Bc7ORIGINAL REPORTSBreast CancerFulvestrant 500 mg Versus Anastrozole 1 mg for the First-Line Treatment of Advanced Breast Cancer: Overall Survival Analysis From the Phase II FIRST Study Fulvestrant 500 mg: Overall Survival Versus AnastrozoleEllis Matthew J. Llombart-Cussac Antonio Feltl David Dewar John A. Jasiówka Marek Hewson Nicola Rukazenkov Yuri Robertson John F.R. Matthew J. Ellis, Baylor College of Medicine, Houston, TX; Antonio Llombart-Cussac, Hospital Arnau de Vilanova, Lérida, Spain; David Feltl, FNsP Ostrava, Ostrava-Poruba, Czech Republic; John A. Dewar, Ninewells Hospital and Medical School, Dundee; Nicola Hewson and Yuri Rukazenkov, AstraZeneca Pharmaceuticals, Macclesfield; John F.R. Robertson, University of Nottingham, Derby, United Kingdom; and Marek Jasiówka, Instytut im Marii Skłodowskiej-Curie, Kraków, Poland.Corresponding author: Matthew J. Ellis, MD, Lester and Sue Smith Breast Center, One Baylor Plaza, Baylor College of Medicine, Houston, TX 77030; e-mail: Matthew.Ellis@bcm.edu.10 11 2015 14 9 2015 14 9 2015 33 32 3781 3787 © 2015 by American Society of Clinical Oncology2015American Society of Clinical OncologyLicensed under the Creative Commons Attribution 3.0 License: http://creativecommons.org/licenses/by/3.0/.Purpose\nTo compare overall survival (OS) for fulvestrant 500 mg versus anastrozole as first-line endocrine therapy for advanced breast cancer.\n\nPatients and Methods\nThe Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST) was a phase II, randomized, open-label, multicenter trial. Postmenopausal women with estrogen receptor–positive, locally advanced/metastatic breast cancer who had no previous therapy for advanced disease received either fulvestrant 500 mg (days 0, 14, 28, and every 28 days thereafter) or anastrozole 1 mg (daily). The primary end point (clinical benefit rate [72.5% and 67.0%]) and a follow-up analysis (median time to progression [23.4 months and 13.1 months]) have been reported previously for fulvestrant 500 mg and anastrozole, respectively. Subsequently, the protocol was amended to assess OS by unadjusted log-rank test after approximately 65% of patients had died. Treatment effect on OS across several subgroups was examined. Tolerability was evaluated by adverse event monitoring.\n\nResults\nIn total, 205 patients were randomly assigned (fulvestrant 500 mg, n = 102; anastrozole, n = 103). At data cutoff, 61.8% (fulvestrant 500 mg, n = 63) and 71.8% (anastrozole, n = 74) had died. The hazard ratio (95% CI) for OS with fulvestrant 500 mg versus anastrozole was 0.70 (0.50 to 0.98; P = .04; median OS, 54.1 months v 48.4 months). Treatment effects seemed generally consistent across the subgroups analyzed. No new safety issues were observed.\n\nConclusion\nThere are several limitations of this OS analysis, including that it was not planned in the original protocol but instead was added after time-to-progression results were analyzed, and that not all patients participated in additional OS follow-up. However, the present results suggest fulvestrant 500 mg extends OS versus anastrozole. This finding now awaits prospective confirmation in the larger phase III FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy Naïve Advanced Breast Cancer) trial (ClinicalTrials.gov identifier: NCT01602380).\n==== Body\nINTRODUCTION\nTamoxifen and third-generation aromatase inhibitors (AIs), such as anastrozole, exemestane, and letrozole are established first-line endocrine therapies for the treatment of postmenopausal women with estrogen receptor (ER) –positive, advanced breast cancer.1–3 Given the high prevalence of resistance to AI therapy, multiple treatment options with distinct mechanisms of action are desirable.4\n\nFulvestrant, a 17β-estradiol analog, is a selective ER antagonist that suppresses estrogen signaling by binding to ER and inducing a conformational change.5,6 Dimerization is subsequently blocked, triggering accelerated degradation and downregulation of the ER protein.5 Fulvestrant exhibits lack of cross-reactivity with tamoxifen. Consequently, patients whose disease progresses on fulvestrant may retain sensitivity to treatment with further endocrine therapies.7,8 The clinical efficacy of fulvestrant was initially demonstrated in two phase III trials that compared fulvestrant 250 mg per month with anastrozole 1 mg daily as a second-line therapy for advanced breast cancer.9,10 A combined analysis of these trials demonstrated that time to progression (TTP) with fulvestrant 250 mg was noninferior to anastrozole.11\n\nFulvestrant 250 mg was not proven to be superior to tamoxifen in a double-blind, randomized trial.12 This finding was unexpected given the superiority of anastrozole over tamoxifen13 and the comparable efficacy of anastrozole and fulvestrant 250 mg as second-line therapy.11 Pharmacokinetic modeling, as well as observations made during early clinical studies,11 suggested the efficacy of fulvestrant could be improved with use of a higher dose, which led to the development of a dosage regimen of fulvestrant 500 mg, including a loading dose component to reduce the time to reach steady-state plasma levels. Subsequently, the phase III Comparison of Faslodex in Recurrent or Metastatic Breast Cancer (CONFIRM) trial found that fulvestrant 500 mg was associated with improved progression-free survival (PFS) and overall survival (OS) compared with the 250-mg dose in patients who experienced disease recurrence or progression after previous endocrine therapy.14,15\n\nThe Fulvestrant First-Line Study Comparing Endocrine Treatments (FIRST) was a phase II, randomized, open-label, multicenter trial that also used the fulvestrant 500-mg dose regimen, comparing efficacy and safety with anastrozole in the first-line setting. The primary end point of clinical benefit rate was noninferior for fulvestrant 500 mg compared with anastrozole,16 with both treatments demonstrating similar, well-tolerated safety profiles. A follow-up analysis, performed because only 35.6% of patients experienced disease progression at the time of the primary analysis, reported a hazard ratio (HR) of TTP for fulvestrant 500 mg versus anastrozole of 0.66 with a 95% CI of 0.47 to 0.92 (P = .01; median TTP, 23.4 months v 13.1 months). No additional safety issues were reported.17 Given the improvement in TTP observed during fulvestrant 500 mg treatment compared with anastrozole in this phase II trial, a subsequent protocol amendment was made to address whether this apparent extension in disease control would translate into an improvement in OS.\n\nPATIENTS AND METHODS\nStudy Design and Participants\nFIRST was a phase II, randomized, open-label, multicenter, parallel-group trial comparing fulvestrant 500 mg with anastrozole 1 mg. Postmenopausal women with ER-positive locally advanced or metastatic breast cancer who had not received any previous systemic therapy for locally advanced or metastatic disease were included. Patients were permitted to have received previous endocrine therapy for early disease, providing this had been completed more than 12 months before random assignment. This trial was conducted in accordance with the Declaration of Helsinki, was consistent with the International Conference on Harmonisation–Good Clinical Practice guidelines, and is registered with Clinicaltrials.gov. All patients provided written, informed consent. Full details of this trial have been reported previously.16,17\n\nRandom Assignment and Procedures\nEligible patients were randomly assigned sequentially 1:1 to either fulvestrant 500 mg (administered intramuscularly on days 0, 14, 28, and every 28 days thereafter) or anastrozole 1 mg (administered orally once per day). The data cutoff for the primary analysis was 6 months after the last patient was randomly assigned. On disease progression or after data cutoff for the primary analysis, all patients entered a follow-up phase after a protocol amendment for an analysis of TTP. The TTP follow-up required a questionnaire to be completed for each patient 12 months after the patient entered the follow-up phase and every 12 months thereafter for patients continuing to receive randomized treatment. After the TTP analysis was performed, a further protocol amendment was developed to enter patients into an optional follow-up phase to establish OS. To ensure sufficient maturity, the OS analysis was planned for when approximately 65% of patients had died. Patients who did not contribute additional data to the follow-up extension were right-censored at the last known date they were alive, and their data until this point were included in the analysis. Sites were invited to request written consent from patients for the collection of additional data. Patients were contacted every 3 months until the first of the following events: death, patient withdrawal, data cutoff was reached, or the patient was lost to follow-up. Patients with a last known survival status of alive were contacted within 2 weeks of data cutoff to ensure they were still alive.\n\nOutcomes\nThe primary study end point was clinical benefit rate; secondary end points included objective response rate, TTP, duration of clinical benefit, and duration of response. These primary and secondary end points have been reported previously.16,17\n\nThe follow-up analysis assessed OS, defined as the time from being randomly assigned to death from any cause. A log-rank test (unadjusted model with treatment factor only) was performed for the primary analysis of OS. HRs with 95% CIs were used to compare fulvestrant 500 mg with anastrozole; no adjustments were made for multiplicity. A statistical significance level of .05 was used to indicate a difference in OS between the treatment groups. For patients for whom follow-up responses could not be obtained, data were censored at the date the patient was last known to be alive.\n\nExploratory subgroup analyses were conducted using the log-rank test to compare OS for the following prespecified patient subgroups: less than 65 years of age versus 65 years of age or greater; not positive for both ER and progesterone receptor versus positive for both ER and progesterone receptor; no visceral involvement versus visceral involvement; no previous chemotherapy versus previous adjuvant chemotherapy; no measurable disease versus measurable disease; and no previous endocrine therapy versus previous endocrine therapy.\n\nTwo sensitivity analyses were performed to examine any potential impact of nonparticipation on OS results: a Kaplan-Meier OS analysis was performed in which the censoring indicator was reversed; and baseline covariates were assessed for patients censored greater than 3 months before data cutoff and for those censored 3 months or less before data cutoff, which corresponds to patients who did not participate in the OS follow-up and to those who did, respectively.\n\nTolerability was assessed by serious adverse event (SAE) monitoring. All SAEs were coded in compliance with the Medical Dictionary for Regulatory Activities and recorded in an internal AstraZeneca database for evaluation. SAEs were monitored for up to 8 weeks after the last dose of fulvestrant 500 mg or for 30 days after the last dose of anastrozole.\n\nRESULTS\nIn total, 205 patients were randomly assigned to receive fulvestrant 500 mg (n = 102) or anastrozole 1 mg (n = 103) at 62 centers in nine countries (Brazil, Bulgaria, the Czech Republic, France, Italy, Poland, Spain, the United Kingdom, and the United States).\n\nBaseline characteristics and patient demographics were similar between the treatment groups as reported previously.16 The proportion of patients who had not received previous endocrine treatment for early disease was similar for the fulvestrant 500 mg and anastrozole treatment groups (71.6% and 77.7% of patients at baseline, respectively). Of those that did, almost all had received tamoxifen exclusively. Of the 205 randomly assigned patients, 35 (16 in the fulvestrant 500 mg group and 19 in the anastrozole group) did not participate in the OS follow-up phase and were censored at the date they were last known to be alive; for these patients, data until this time are included in the OS analysis, and thus all patients contributed data to the analysis. The majority of the nonparticipating patients (n = 20) did not contribute additional data because they attended centers that declined to contribute to the OS follow-up phase. An additional 15 individual patients from nine participating centers did not consent to follow-up. No patients participating in the OS phase were lost to follow-up, and the survival status at data cutoff was known for all patients consenting to the OS follow-up.\n\nEfficacy\nAt the time of the follow-up analysis for OS, 63 of 102 patients in the fulvestrant 500 mg group (61.8%) and 74 of 103 patients in the anastrozole group (71.8%) were known to have died (Fig 1). The primary analysis of OS was improved in the fulvestrant 500 mg group compared with anastrozole 1 mg; the HR was 0.70 (95% CI, 0.50 to 0.98; log-rank test P = .04; median OS, 54.1 months v 48.4 months; Fig 2). The HR for fulvestrant 500 mg versus anastrozole was found to be generally consistent across all subgroup analyses (Fig 3). At 3 years, 64% (fulvestrant 500 mg) and 58% (anastrozole) of patients were event free; at 5 years, the equivalent values were 47% and 38%.\n\nFig 1. Study overview. (*) These patients were right censored at the time of their last known date alive, and data until this point were used in the overall survival (OS) analysis.\n\nFig 2. Kaplan-Meier plot of overall survival.\n\nFig 3. Overall survival subgroup analysis. ER+, estrogen receptor positive; NC, not calculable; PgR+, progesterone receptor positive.\n\nSensitivity Analyses\nThere were no important differences between the treatment groups in time to censoring (data not shown). Furthermore, when key baseline covariates for patients censored within the last 3 months before data cutoff and for those censored more than 3 months before data cutoff were summarized, there were no important differences between treatment groups, indicating that the results were not caused by differences between patients who did and did not consent to OS follow-up (Table 1).\n\nTable 1. Baseline Covariates and Subgroups by Patients Censored ≥ 3 Months and ≤ 3 Months Before DCO\n\nSubgroup\tNo. of Patients (%)\t\nCensored > 3 Months Before DCO\tCensored ≤ 3 Months Before DCO\t\nFulvestrant 500 mg (n = 16)\tAnastrozole 1 mg (n = 19)\tFulvestrant 500 mg (n = 23)\tAnastrozole 1 mg (n = 10)\t\nAge, years\t\t\t\t\t\n < 65\t5 (31.3)\t7 (36.8)\t11 (47.8)\t4 (40.0)\t\n ≥ 65\t11 (68.8)\t12 (63.2)\t12 (52.2)\t6 (60.0)\t\nReceptor status at diagnosis\t\t\t\t\t\n Not both ER+ and PgR+\t6 (37.5)\t5 (26.3)\t4 (17.4)\t2 (20.0)\t\n Both ER+ and PgR+\t10 (62.5)\t14 (73.7)\t19 (82.6)\t8 (80.0)\t\nVisceral involvement\t\t\t\t\t\n No\t9 (56.3)\t11 (57.9)\t16 (69.6)\t8 (80.0)\t\n Yes\t7 (43.8)\t8 (42.1)\t7 (30.4)\t2 (20.0)\t\nPrevious chemotherapy\t\t\t\t\t\n No\t11 (68.8)\t13 (68.4)\t19 (82.6)\t8 (80.0)\t\n Yes\t5 (31.3)\t6 (31.6)\t4 (17.4)\t2 (20.0)\t\nMeasurable disease at diagnosis\t\t\t\t\t\n No\t1 (6.3)\t3 (15.8)\t1 (4.3)\t0\t\n Yes\t15 (93.8)\t16 (84.2)\t22 (95.7)\t10 (100.0)\t\nPrevious endocrine therapy\t\t\t\t\t\n No\t11 (68.8)\t13 (68.4)\t18 (78.3)\t8 (80.0)\t\n Yes\t5 (31.3)\t6 (31.6)\t5 (21.7)\t2 (20.0)\t\nAbbreviations: DCO, data cutoff; ER+, estrogen receptor–positive; PgR+, progesterone receptor–positive.\n\nSafety\nThe occurrence of SAEs during the main study period and the follow-up period combined is detailed in Table 2. The majority of SAEs were considered by the investigator to be unrelated to the treatment. Two SAEs considered to be treatment related were documented (one case of hypertension and one case of pulmonary embolism, both in the fulvestrant 500 mg treatment group).\n\nTable 2. Incidence of SAEs and Deaths\n\nSAE\tNo. of Patients (%)\t\nFulvestrant 500 mg (n = 101)\tAnastrozole 1 mg (n = 103)\t\nAny SAE\t24 (23.8)\t22 (21.4)\t\nAny SAE related to death\t3 (3.0)\t5 (4.9)\t\nAny SAE with outcome other than death\t21 (20.8)\t18 (17.5)\t\nAny causally related SAE\t2 (2.0)\t0\t\nMost commonly reported (≥ two patients) SAEs\t\t\t\n Atrial fibrillation\t1 (1.0)\t1 (1.0)\t\n Cardiac failure\t2 (2.0)\t0\t\n Death\t0\t2 (1.9)\t\n Decreased appetite\t2 (2.0)\t0\t\n Dehydration\t2 (2.0)\t0\t\n Dyspnea\t2 (2.0)\t0\t\n Femur fracture\t1 (1.0)\t2 (1.9)\t\n Neuralgia\t1 (1.0)\t1 (1.0)\t\n Transient ischemic attack\t0\t2 (1.9)\t\nAbbreviation: SAE, serious adverse event.\n\nDISCUSSION\nThis study reports improved OS with fulvestrant 500 mg treatment compared with anastrozole in the first-line setting for ER-positive advanced breast cancer, with an approximately 30% reduction in mortality risk. The previously reported improvements in TTP have translated into an improvement in OS of approximately 6 months with fulvestrant 500 mg (54.1 months) compared with anastrozole (48.4 months). This OS advantage is consistent with the OS benefit for fulvestrant 500 mg versus 250 mg in the second-line setting in the CONFIRM trial.15 The effect of fulvestrant 500 mg on OS was generally consistent across all prespecified subgroups (Fig 3). Furthermore, no new safety or tolerability issues were reported from the OS follow-up phase of this study, consistent with previously reported safety data.16,17\n\nThe improved OS with fulvestrant 500 mg (54.1 months) relative to anastrozole (48.4 months) was observed although the median OS for the anastrozole group in this study was higher than has previously been reported. For example, OS of 39.2 months was reported for anastrozole as first-line endocrine therapy for advanced breast cancer in a combined analysis of two phase III studies,18 and OS of 41.3 months was reported for the anastrozole monotherapy arm of a phase III combination study.19 In addition, corresponding median OS values of 34.0 months (letrozole)20 and 37.2 months (exemestane)21 have been reported for other AIs. It is therefore unlikely that the present analysis overestimates the margin of improvement with fulvestrant 500 mg over anastrozole, which might have been possible had the control arm underperformed.\n\nThe role of fulvestrant 500 mg as first-line therapy will be further defined by the ongoing phase III, double-blind FALCON (Fulvestrant and Anastrozole Compared in Hormonal Therapy Naïve Advanced Breast Cancer) trial (ClinicalTrials.gov identifier: NCT01602380). The FALCON trial will assess the efficacy of fulvestrant 500 mg versus anastrozole in women with locally advanced or metastatic breast cancer with strict definitions of endocrine therapy–naïve disease, including restrictions on exposure to hormone replacement therapy.\n\nEndocrine therapy–naïve advanced breast cancer is relatively uncommon in countries with advanced health care, but represents a numerically substantial patient population, given the high disease prevalence. Furthermore, in unscreened populations and in developing countries, metastatic disease at presentation is a significant problem. Recent clinical trials reporting on first-line endocrine therapy in patients with ER-positive breast cancer have contained a substantial proportion, and often a majority, of endocrine therapy–naïve patients.19,22–24 In FIRST, previous endocrine therapy had been received by 29 (28.4%) of the patients treated with fulvestrant 500 mg and 23 (22.3%) of the anastrozole-treated patients. Of these 52 patients, only 3 had received AI previously (2 in the anastrozole group and 1 in the fulvestrant 500 mg group); the remainder had received adjuvant tamoxifen. Therefore, AI resistance resulting from previous AI exposure cannot account for the observed OS difference. Indeed, hypothetically, previous exposure to tamoxifen may bias against fulvestrant as both agents are in the same therapeutic class. Upon disease progression, patients were treated according to the standard of care, and therefore, there could potentially be imbalances between the two treatment groups that could have affected the OS analysis. However, response to subsequent therapies (systemic chemotherapy or endocrine therapy) has previously been shown to be similar between the treatment groups, demonstrating that patients with disease progression on fulvestrant retain sensitivity to subsequent treatments.17 Differential second-line response, therefore, is also an unlikely explanation for the observed OS effect.\n\nThere are significant limitations to this report. The sample size was relatively small, and the OS analysis was not specified in the original protocol but was added as a hypothesis in a protocol amendment after TTP results were known. Furthermore, 35 patients did not contribute additional data to the OS follow-up; the decision not to participate in the extended follow-up for OS was made solely by the patient or participating center and was known at the start of the OS follow-up and before the data were collected and analyzed. Data from these patients until the time of censoring were included in the OS analysis, and similar censoring patterns were seen in the two treatment groups. The sensitivity analyses support the main findings, that is, the differences in OS between treatment arms were unrelated to differences in censoring patterns. All-cause mortality was used to determine OS in this analysis because it is regarded as the most unbiased and objective end point used in oncology.25 This point is particularly relevant to an open-label study like FIRST. A final limitation was that the number of patients within subgroups was relatively small. Therefore, care should be taken when interpreting results.\n\nRecent results from several trials with the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib are also pertinent to the discussion. PALOMA-1 (Palbociclib Ongoing Trials in the Management of Breast Cancer), a phase II trial of letrozole plus palbociclib versus letrozole alone, provided provisional US Food and Drug Administration approval for palbociclib in the first-line setting on the basis of PFS.23 No positive OS data have been reported to date; the results of a phase III trial of this comparison are pending (PALOMA-2, NCT01740427). Data from the phase III PALOMA-3 trial, comparing fulvestrant 500 mg plus palbociclib versus fulvestrant 500 mg alone in the second-line or subsequent setting in postmenopausal women (or pre- or perimenopausal women receiving goserelin), reported a marked PFS advantage for the combination, but OS data were also pending at the time of publication.26 The median PFS for fulvestrant 500 mg alone was shorter in PALOMA-3 than in previous studies, indicative of the younger, higher-risk, and more heavily pretreated population recruited into the PALOMA-3 trial.\n\nThe treatment algorithm for ER-positive advanced breast cancer, therefore, is in a state of flux. Currently, it is rational to consider fulvestrant 500 mg as a first-line treatment option given the potential for survival benefits, particularly in settings where palbociclib is not available or palbociclib cost or adverse effects are a significant concern, and especially if these results are confirmed in FALCON. These data also suggest that a first-line study of fulvestrant 500 mg with a CDK4/6 inhibitor versus fulvestrant 500 mg alone is a logical proposition that could lead to further prolonged TTP. Recent preclinical data on the efficacy of an ER degrading agent with a CDK4/6 inhibitor in ESR1-mutant breast cancer provides further rationale for this population, because improvements in TTP or OS could be caused by suppression of ESR1-mutant AI-resistant clones.27\n\nIn conclusion, we report that fulvestrant 500 mg may be associated with improved OS versus anastrozole in the first-line setting for ER-positive advanced breast cancer. To our knowledge, this represents the first time an endocrine monotherapy has demonstrated improved efficacy compared with a third-generation AI. The phase III FALCON trial may provide confirmation for these OS results; until then, the findings reported here should be regarded as preliminary, but clinically relevant.\n\nSupplementary Material\nProtocol\n Supported by AstraZeneca.\n\nTerms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.\n\nPresented at the 2014 San Antonio Breast Cancer Symposium, San Antonio, TX, December 9-13, 2014.\n\nAuthors' disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.\n\nClinical trial information: NCT00274469.\n\nAcknowledgment\nWe thank Martin Bell, PhD, from Complete Medical Communications, who provided medical writing support, funded by AstraZeneca.\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\nDisclosures provided by the authors are available with this article at www.jco.org.\n\nAUTHOR CONTRIBUTIONS\nConception and design: Matthew J. Ellis, John F.R. Robertson\n\nProvision of study materials or patients: Matthew J. Ellis, John F.R. Robertson\n\nCollection and assembly of data: Matthew J. Ellis, David Feltl, John F.R. Robertson\n\nData analysis and interpretation: Matthew J. Ellis, Antonio Llombart-Cussac, John A. Dewar, Marek Jasiówka, Nicola Hewson, Yuri Rukazenkov, John F.R. Robertson\n\nManuscript writing: All authors\n\nFinal approval of manuscript: All authors\n\nGlossary Terms\nAnastrozole:a third-generation nonsteroidal aromatase inhibitor that prevents the conversion of androgen to estrogen in the peripheral tissues in postmenopausal women. Because hormone-dependent breast cancer progresses with estrogen, anastrozole has been used in the treatment of breast cancer in postmenopausal women. See aromatase inhibitors.\n\nAromatase inhibitors:inhibitors used in treating breast cancer in postmenopausal women. Aromatase inhibitors inhibit the conversion of androgens to estrogens by the enzyme aromatase, thus depriving the tumor of estrogenic signals. Because of decreased production of estrogen, estrogen receptors, which are important in the progression of breast cancer, cannot be activated.\n\nEstrogen receptor (ER):ligand-activated nuclear proteins, belonging to the class of nuclear receptors, present in many breast cancer cells that are important in the progression of hormone-dependent cancers. After binding, the receptor-ligand complex activates gene transcription. There are two types of estrogen receptors (ERα and ERβ). ERα is one of the most important proteins controlling breast cancer function. ERβ is present in much lower levels in breast cancer, and its function is uncertain. Estrogen receptor status guides therapeutic decisions in breast cancer.\n\nOverall survival:the duration between random assignment and death.\n\nAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST\nFulvestrant 500 mg Versus Anastrozole 1 mg for the First-Line Treatment of Advanced Breast Cancer: Overall Survival Analysis From the Phase II FIRST Study\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 jco.ascopubs.org/site/ifc.\n\nMatthew J. Ellis\nEmployment: Bioclassifier\n\nLeadership: Bioclassifier\n\nStock or Other Ownership: Bioclassifier\n\nConsulting or Advisory Role: AstraZeneca, Pfizer, Novartis, Celgene\n\nPatents, Royalties, Other Intellectual Property: Bioclassifier\n\nAntonio Llombart-Cussac\nHonoraria: Roche, Eli Lilly, Pfizer, Novartis, AstraZeneca\n\nConsulting or Advisory Role: Roche, AstraZeneca, Pfizer\n\nResearch Funding: MedSIR\n\nDavid Feltl\nNo relationship to disclose\n\nJohn A. Dewar\nNo relationship to disclose\n\nMarek Jasiówka\nHonoraria: Roche, Amgen\n\nResearch Funding: AstraZeneca, Roche\n\nTravel, Accommodations, Expenses: AstraZeneca, Roche, Janssen-Cilag\n\nNicola Hewson\nEmployment: AstraZeneca\n\nYuri Rukazenkov\nEmployment: AstraZeneca\n\nStock or Other Ownership: AstraZeneca\n\nJohn F.R. Robertson\nLeadership: Oncimmune\n\nStock or Other Ownership: Oncimmune\n\nHonoraria: AstraZeneca, Bayer AG\n\nConsulting or Advisory Role: AstraZeneca, Bayer AG, Oncimmune\n\nResearch Funding: AstraZeneca (Inst), Bayer AG (Inst), Oncimmune (Inst), Novartis (Inst)\n\nPatents, Royalties, Other Intellectual Property: Oncimmune\n\nTravel, Accommodations, Expenses: AstraZeneca, Bayer AG, Oncimmune, Novartis\n==== Refs\nREFERENCES\n1. Cardoso F Costa A Norton L ESO-ESMO 2nd International Consensus Guidelines for advanced breast cancer (ABC2) Ann Oncol 2014 25 1871 1888 25234545 \n2. Cardoso F Costa A Norton L ESO-ESMO 2nd International Consensus Guidelines for advanced breast cancer (ABC2) Breast J 2014 23 489 502 \n3. Burstein HJ Temin S Anderson H Adjuvant endocrine therapy for women with hormone receptor–positive breast cancer: American Society of Clinical Oncology Clinical Practice Guideline Focused Update J Clin Oncol 2014 32 2255 2269 24868023 \n4. Ma CX Reinert T Chmielewska I Mechanisms of aromatase inhibitor resistance Nat Rev Cancer 2015 15 261 275 25907219 \n5. Wakeling AE Dukes M Bowler J A potent specific pure antiestrogen with clinical potential Cancer Res 1991 51 3867 3873 1855205 \n6. Wakeling AE Similarities and distinctions in the mode of action of different classes of antioestrogens Endocr Relat Cancer 2000 7 17 28 10808193 \n7. Osborne CK Wakeling A Nicholson RI Fulvestrant: An oestrogen receptor antagonist with a novel mechanism of action Br J Cancer 2004 90 suppl 1 S2 S6 15094757 \n8. Robertson JFR Howell A Gorbunova VA Sensitivity to further endocrine therapy is retained following progression on first-line fulvestrant Breast Cancer Res Treat 2005 92 169 174 15986127 \n9. Osborne CK Pippen J Jones SE Double-blind, randomized trial comparing the efficacy and tolerability of fulvestrant versus anastrozole in postmenopausal women with advanced breast cancer progressing on prior endocrine therapy: Results of a North American trial J Clin Oncol 2002 20 3386 3395 12177098 \n10. Howell A Robertson JFR Quaresma Albano J Fulvestrant, formerly ICI 182,780, is as effective as anastrozole in postmenopausal women with advanced breast cancer progressing after prior endocrine treatment J Clin Oncol 2002 20 3396 3403 12177099 \n11. Robertson JFR Osborne CK Howell A Fulvestrant versus anastrozole for the treatment of advanced breast carcinoma in postmenopausal women: A prospective combined analysis of two multicenter trials Cancer 2003 98 229 238 12872340 \n12. Howell A Robertson JFR Abram P Comparison of fulvestrant versus tamoxifen for the treatment of advanced breast cancer in postmenopausal women previously untreated with endocrine therapy: A multinational, double-blind, randomized trial J Clin Oncol 2004 22 1605 1613 15117982 \n13. Howell A Cuzick J Baum M Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer Lancet 2005 365 60 62 15639680 \n14. Di Leo A Jerusalem G Petruzelka L Results of the CONFIRM Phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor–positive advanced breast cancer J Clin Oncol 2010 28 4594 4600 20855825 \n15. Di Leo A Jerusalem G Petruzelka L Final overall survival: Fulvestrant 500mg vs 250mg in the randomized CONFIRM trial J Natl Cancer Inst 2014 106 djt337 24317176 \n16. Robertson JF Llombart-Cussac A Rolski J Activity of fulvestrant 500 mg versus anastrozole 1 mg as first-line treatment for advanced breast cancer: Results from the FIRST study J Clin Oncol 2009 27 4530 4535 19704066 \n17. Robertson JF Lindemann J Llombart-Cussac A Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of advanced breast cancer: Follow-up analysis from the randomized ‘FIRST’ study Breast Cancer Res Treat 2012 136 503 511 23065000 \n18. Nabholtz JM Bonneterre J Buzdar A Anastrozole (Arimidex) versus tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: Survival analysis and updated safety results Eur J Cancer 2003 39 1684 1689 12888362 \n19. Mehta RS Barlow WE Albain KS Combination anastrozole and fulvestrant in metastatic breast cancer N Engl J Med 2012 367 435 444 22853014 \n20. Mouridsen H Gershanovich M Sun Y Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: Analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group J Clin Oncol 2003 21 2101 2109 12775735 \n21. Paridaens RJ Dirix LY Beex LV Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: The European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group J Clin Oncol 2008 26 4883 4890 18794551 \n22. Bergh J Jönsson PE Lidbrink EK FACT: An open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer J Clin Oncol 2012 30 1919 1925 22370325 \n23. Finn RS Crown JP Lang I The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor–positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): A randomised phase 2 study Lancet Oncol 2015 16 25 35 25524798 \n24. Martin M Loibl S Von Minckwitz G Phase III trial evaluating the addition of bevacizumab to endocrine therapy as first-line treatment for advanced breast cancer: The Letrozole/Fulvestrant and Avastin (LEA) study J Clin Oncol 2015 33 1045 1052 25691671 \n25. Saad ED Buyse M Overall survival: Patient outcome, therapeutic objective, clinical trial end point, or public health measure? J Clin Oncol 2012 30 1750 1754 22393092 \n26. Turner NC Ro J Andre F Palbociclib in hormone receptor–positive advanced breast cancer N Engl J Med 2015 \n27. Wardell SE Ellis MJ Alley HM Efficacy of SERD/SERM hybrid-CDK4/6 inhibitor combinations in models of endocrine therapy resistant breast cancer Clin Cancer Res 10.1158/1078-0432.CCR-15-0360 [epub ahead of print May 19, 2015]\n\n",
"fulltext_license": "CC BY",
"issn_linking": "0732-183X",
"issue": "33(32)",
"journal": "Journal of clinical oncology : official journal of the American Society of Clinical Oncology",
"keywords": null,
"medline_ta": "J Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000077384:Anastrozole; D018931:Antineoplastic Agents, Hormonal; D047072:Aromatase Inhibitors; D001943:Breast Neoplasms; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D004958:Estradiol; D065171:Estrogen Receptor Antagonists; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D009570:Nitriles; D016896:Treatment Outcome; D014230:Triazoles",
"nlm_unique_id": "8309333",
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"pages": "3781-7",
"pmc": null,
"pmid": "26371134",
"pubdate": "2015-11-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D013485:Research Support, Non-U.S. Gov't",
"references": "25524798;12177099;25907219;10808193;12177098;25991817;25234545;25244983;26030518;24868023;24317176;23065000;22853014;22370325;22393092;20855825;19704066;18794551;15986127;15639680;1855205;15117982;15094757;12888362;12872340;12775735;25691671",
"title": "Fulvestrant 500 mg Versus Anastrozole 1 mg for the First-Line Treatment of Advanced Breast Cancer: Overall Survival Analysis From the Phase II FIRST Study.",
"title_normalized": "fulvestrant 500 mg versus anastrozole 1 mg for the first line treatment of advanced breast cancer overall survival analysis from the phase ii first study"
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"abstract": "In this article, we present a case of a young female patient with previously diagnosed lupus pneumonitis, now with a flare and new superimposed COVID-19 infection that was treated with intravenous steroids. On computed tomography scans, she had extensive interstitial lung fibrosis in addition to a positive COVID-19 polymerase chain reaction test requiring 6 L of oxygen via nasal cannula on admission. After administration of methylprednisolone, the patient improved and was weaned off her oxygen requirements and was discharged home.",
"affiliations": "St. Mary's of Saginaw Hospital, Saginaw, MI, USA.;Central Michigan University, Saginaw, MI, USA.;Central Michigan University, Saginaw, MI, USA.;St. Mary's of Saginaw Hospital, Saginaw, MI, USA.;Geisinger Commonwealth School of Medicine, Scranton, PA, USA.;Geisinger Commonwealth School of Medicine, Scranton, PA, USA.",
"authors": "Kichloo|Asim|A|0000-0003-4788-8572;Aljadah|Michael|M|;Albosta|Michael|M|;Wani|Farah|F|;Singh|Jagmeet|J|;Solanki|Shantanu|S|",
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"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620933438\n10.1177_2324709620933438\nCase Report\nCOVID-19 and Acute Lupus Pneumonitis: Diagnostic and Treatment Dilemma\nhttps://orcid.org/0000-0003-4788-8572Kichloo Asim MD12 Aljadah Michael MD2 Albosta Michael MD2 Wani Farah MD1 Singh Jagmeet MD3 Solanki Shantanu MD, MPH3 1 St. Mary’s of Saginaw Hospital, Saginaw, MI, USA\n2 Central Michigan University, Saginaw, MI, USA\n3 Geisinger Commonwealth School of Medicine, Scranton, PA, USA\nAsim Kichloo, MD, Central Michigan University College of Medicine, 1000 Houghton Avenue, Saginaw, MI 48602, USA. Email: kichlooasim@gmail.comAll authors have contributed equally to the article.\n\n\n5 6 2020 \nJan-Dec 2020 \n8 232470962093343823 4 2020 18 5 2020 20 5 2020 © 2020 American Federation for Medical Research2020American Federation for Medical ResearchThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial 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).In this article, we present a case of a young female patient with previously diagnosed lupus pneumonitis, now with a flare and new superimposed COVID-19 infection that was treated with intravenous steroids. On computed tomography scans, she had extensive interstitial lung fibrosis in addition to a positive COVID-19 polymerase chain reaction test requiring 6 L of oxygen via nasal cannula on admission. After administration of methylprednisolone, the patient improved and was weaned off her oxygen requirements and was discharged home.\n\nCOVID-19lupuspneumonitispneumoniacover-dateJanuary-December 2020typesetterts1\n==== Body\nCase Report\nA 22-year-old female with a past medical history of systemic lupus erythematosus (SLE), which included fibrotic lupus pneumonitis, grade IV lupus nephritis, and pericardial tamponade, presented to the hospital due to fevers and progressive shortness of breath. Initial oxygen saturations on room air were in the low 80s. A computed tomography (CT) scan of the lungs showed granular and interstitial ground glass opacities with chronic interstitial lung fibrosis (Figure 1). At presentation, the differential diagnosis included an acute exacerbation of chronic lupus pneumonitis and COVID-19 interstitial pneumonia. As a result, the first test performed was a COVID-19 polymerase chain reaction (PCR) test. To evaluate for an acute lupus flare, anti-dsDNA and C3/C4 serum complement levels were ordered, which showed anti-dsDNA at 19 IU/mL (reference interval: <10 IU/mL). Serum complement levels C3/C4 were mildly decreased at 84 mg/dL and 9 mg/dL, respectively (reference interval: C3 [88-201 mg/dL]; C4 [10-40 mg/dL]). Additionally, proteinuria was not detected on urinalysis. Other initial laboratory findings showed lymphopenia, elevated D-dimer levels, elevated lactate dehydrogenase (LDH) levels, and a negative upper respiratory PCR viral panel. Atypical pneumonia sputum culture was also negative. The patient’s home medications including hydroxychloroquine and mycophenolic acid as a part of her outpatient management of SLE were continued. Due to the diagnostic dilemma between acute lupus pneumonitis and COVID-19 interstitial pneumonia, the patient was not given any steroids initially. The patient required up to 6 L of oxygen via nasal cannula, maintaining an oxygen saturation of 94%. After 24 hours of admission with no improvement, the patient was started on 60 mg of intravenous methylprednisolone 3 times daily, which resulted in improved respiratory status and decreased oxygen requirements to 2 L via nasal cannula to maintain oxygen saturation of 94%. Eventually, results of the COVID-19 PCR test returned as positive. On day 5 of her hospital admission, the steroids were tapered down to a total 60 mg of oral prednisone daily, and a repeat CT scan showed significant improvement (Figure 2). The patient was subsequently removed from the nasal cannula with an oxygen saturation of 95% on room air and was discharged home.\n\nFigure 1. Computed tomography scan showing granular and interstitial ground glass opacities.\n\nFigure 2. Computed tomography scan on day 5 of admission showing significant improvement of interstitial opacities bilaterally.\n\nDiscussion\nLupus Pneumonitis\nPulmonary manifestations are very common in patients with SLE, with 50% to 70% of patients suffering from some form of pulmonary complication during the disease process.1 These pulmonary manifestations may include pleural disease such as pleurisy or pleural effusions, parenchymal disease, vascular involvement including pulmonary arterial hypertension, diffuse alveolar hemorrhage, and venous thromboembolism, as well as superimposed infections.1 Acute lupus pneumonitis is a relatively rare pulmonary complication, only occurring in 1% to 4% of patients with SLE.1,2 The presenting symptoms of patients with acute lupus pneumonitis are relatively nonspecific, and therefore are difficult to distinguish from infectious etiologies or acute respiratory distress syndrome (ARDS).3 In one case series, the most common presenting symptoms of lupus pneumonitis included fever, cough, dyspnea, hypoxia, and lung crepitations.3 This is consistent with our patient, as she presented with fevers and progressive dyspnea. Mortality of patients with acute lupus pneumonitis is notoriously poor with rates up to 50%.1,4 A large percentage of patients who survive acute episodes of lupus pneumonitis will progress to chronic interstitial pneumonitis1,4 as in our patient. Because of the nonspecific symptoms at presentation and the relatively high mortality rate, one can appreciate the necessity of prompt initiation of treatment in patients whom this condition is suspected.\n\nLaboratory abnormalities are common in patients with lupus, and in fact hematologic abnormalities including hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia are included in the 2019 classification criteria for SLE by the European League Against Rheumatism/American College of Rheumatology.5 Additional abnormalities often include antibodies against double-stranded DNA, Smith antigen, RO/SS-A, La/SS-B, and nuclear ribonucleoprotein.2 Findings on radiography and histology in patients with lupus pneumonitis tend to be nonspecific as well. Chest radiography often demonstrates unilateral or bilateral infiltrates, while findings on histology can include damage to the alveolar wall, inflammatory cell infiltrates, edema, hemorrhage, and necrosis.1,2 Because of this, there can be a lot of confusion when attempting to establish a diagnosis of lupus pneumonitis, especially during the current epidemic of COVID-19.\n\nTreatment for lupus pneumonitis is largely empirical due to a lack of controlled studies. The mainstay of treatment is prednisone, given at 1 to 1.5 mg/kg/day.4 If patients fail to respond to prednisone in the first 72 hours, intravenous methylprednisolone is added at 1 g/day for 3 additional days.4 In patients whom steroids fail, immunosuppressive or cytotoxic agents may be used.2 As mentioned before, the initiation of steroids early in the disease course is of extreme importance due to the high mortality rate of lupus pneumonitis. This is in contrast with the current treatment recommendations for COVID-19, which will be discussed below.\n\nCOVID-19\nCOVID-19 is a disease caused by the 2019 novel coronavirus, named severe acute respiratory syndrome coronavirus 2 (SARS-CoV2).6 On March 11, 2020, COVID-19 was declared a pandemic by the World Health Organization. The most common symptoms on presentation of COVID-19 include fever, dry cough, and dyspnea.7,8 Other symptoms that have been noted include fatigue/myalgias, sputum production, rhinorrhea, sore throat, headache, and diarrhea.7,8 The primary clinical features of COVID-19 are very similar to that of an acute presentation of lupus pneumonitis, which may contribute to the diagnostic uncertainty in patients presenting with these symptoms during the current pandemic.\n\nCommon laboratory values in patients presenting with COVID-19 include lymphocytopenia and elevated C-reactive protein.6 A lesser number of patients were found to have elevations in aspartate aminotransferase, alanine aminotransferase, creatine kinase, and D-dimer.6 In addition, some of the most common findings on chest imaging include ground glass opacities and bilateral patchy shadowing.7,8 COVID-19 has been found to have a rapidly progressive course in some patients, with one study showing the time between hospital admission and the development of ARDS to be as quickly as 2 days.8 The findings of lymphocytopenia and nonspecific findings on imaging prove significant overlap between lupus pneumonitis and COVID-19, as seen in this case.\n\nCurrently, there is no medical therapy known to be effective for the treatment of COVID-19; therefore, the mainstay of treatment remains supportive care.9 However, there are several medications in clinical trials. These include chloroquine and hydroxychloroquine, which have been used in the treatment of malaria as well as SLE and rheumatoid arthritis; lopinavir/ritonavir, which has been used in the treatment of HIV; and the antiviral medications ribavirin, remdesivir, and favipiravir.9 Glucocorticoids have been considered as an adjunctive therapy for COVID-19, with the rationale for their use being reduction of the inflammatory response in the lungs.9 However, previous studies in patients with SARS and MERS (Middle East Respiratory Syndrome) coronaviruses showed that glucocorticoids had no association with improved survival, and even delayed viral clearance and had high rates of complications.7-9\n\nSLE and COVID-19\nThere is current controversy regarding whether patients with rheumatologic diseases such as SLE are protected from COVID-19. This controversy is primarily due to the fact that patients with SLE may be taking hydroxychloroquine at baseline. The rationale for using hydroxychloroquine in patients with COVID-19 is due to antiviral effects of the drug, including inhibiting the glycosylation of host receptors, proteolytic processing, and acidification of the endosome, all of which contribute to blocking viral entry into cells.9 While the drug has shown this potent antiviral activity in vitro, there have been mixed results regarding the efficacy of hydroxychloroquine for the treatment of COVID-19 in human trials.9-11 In addition to this, the COVID-19 Global Rheumatology Alliance recently launched a registry to evaluate data regarding patients with rheumatologic disease who have been diagnosed with COVID-19. Initial data collected showed that of 110 patients with rheumatologic disease who had been diagnosed with COVID-19, 19 of those patients had history of SLE.12 Last, Romão et al13 report 2 cases of patients with SLE who were being treated with hydroxychloroquine that subsequently developed COVID-19. In our case, we present a patient with known history of SLE who tested positive for COVID-19 despite home treatment with hydroxychloroquine. While these cases alone are not enough to disprove claims that patients with SLE on hydroxychloroquine may have protection from COVID-19, they provide evidence that this particular patient population is certainly being affected by the novel coronavirus.\n\nConclusion\nThis case highlights a difficult clinical scenario that led to a promising improvement for the use of steroids in the treatment of our patient. Our patient presented with a possible flare up of lupus pneumonitis during the COVID-19 outbreak. The presenting symptoms between these 2 disease processes comprise significant overlap, including cough, fever, and dyspnea.3,7,8 In addition, lymphocytopenia has been shown to be a common laboratory finding in both pathologies.5,6 Due to the relatively nonspecific findings on imaging in both pathologies, we were poised with a dilemma in the face of 2 potential disease processes with the ability to rapidly progress. Due to the patient’s existing condition of lupus pneumonitis, a literature search was performed to help guide management. Based on the promising cases described by Mok and Ying14 during the 2003 SARS outbreak, we decided to initiate therapy with methylprednisolone, which resulted in rapid improvement of her respiratory symptoms including a decrease in her required O2 from 6 L to 2 L. The patient was found to be positive for COVID-19; however, she continued to improve clinically, including a significant improvement in her CT scan. She was eventually transitioned to oral prednisone, discontinued O2, and was discharged home. Despite a lack of recommendation for the use of steroids in patients with COVID-19, our case shows promise for the use of steroids in the management of the novel coronavirus if underlying lupus pneumonitis is present.6-8\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\nEthics Approval: Our institution does not require ethical approval for reporting individual cases or case series.\n\nInformed Consent: Verbal informed consent was obtained from the patient(s) for their anonymized information.\n\nORCID iD: Asim Kichloo \nhttps://orcid.org/0000-0003-4788-8572\n==== Refs\nReferences\n1 \nHannah JR D’Cruz DP \nPulmonary complications of systemic lupus erythematosus\n. Semin Respir Crit Care Med . 2019 ;40 :227 -234\n.31137062 \n2 \nKeane MP Lynch JP 3rd \nPleuropulmonary manifestations of systemic lupus erythematosus\n. Thorax . 2000 ;55 :159 -166\n.10639536 \n3 \nWan SA Teh CL Jobli AT \nLupus pneumonitis as the initial presentation of systemic lupus erythematosus: case series from a single institution\n. Lupus . 2016 ;25 :1485 -1490\n.27125293 \n4 \nAguilera-Pickens G Abud-Mendoza C \nPulmonary manifestations in systemic lupus erythematosus: pleural involvement, acute pneumonitis, chronic interstitial lung disease and diffuse alveolar hemorrhage\n. Reumatol Clin . 2018 ;14 :294 -300\n.29773465 \n5 \nAringer M Costenbader K Daikh D , et al\n2019 European League Against Rheumatism/American College of Rheumatology classification criteria for systemic lupus erythematosus\n. Arthritis Rheumatol . 2019 ;71 :1400 -1412\n.31385462 \n6 \nGuan WJ Ni ZY Hu Y , et al\nClinical characteristics of coronavirus disease 2019 in China\n. N Engl J Med . 2020 ;382 :1708 -1720\n.32109013 \n7 \nBhatraju PK Ghassemieh BJ Nichols M , et al\nCovid-19 in critically ill patients in the Seattle region—case series\n. N Engl J Med . 2020 ;382 :2012 -2022\n.32227758 \n8 \nHuang C Wang Y Li X , et al\nClinical features of patients infected with 2019 novel coronavirus in Wuhan, China\n. Lancet . 2020 ;395 :497 -506\n.31986264 \n9 \nSanders JM Monogue ML Jodlowski TZ Cutrell JB \nPharmacologic treatments for coronavirus disease 2019 (COVID-19): a review\n. JAMA . Published online April 13, 2020. doi:10.1001/jama.2020.6019 \n10 \nYao X Ye F Zhang M , et al\nIn vitro antiviral activity and projection of optimized dosing design of hydroxychloroquine for the treatment of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)\n. Clin Infect Dis . Published online March 9, 2020. doi:10.1093/cid/ciaa237 \n11 \nTang W Cao Z Han M , et al\nHydroxychloroquine in patients with mainly mild to moderate coronavirus disease 2019: open label, randomised controlled trial\n. BMJ . 2020 ;369 :m1849 .32409561 \n12 \nRobinson PC Yazdany J \nThe COVID-19 Global Rheumatology Alliance: collecting data in a pandemic\n. Nat Rev Rheumatol . Published online April 2, 2020. doi:10.1038/s41584-020-0418-0 \n13 \nRomão VC Cruz-Machado AR Fonseca JE \nNo evidence so far on the protective effect of hydroxychloroquine to prevent COVID-19: response to the comment by Joob and Wiwanitkit\n. Ann Rheum Dis . Published online May 13, 2020. doi:10.1136/annrheumdis-2020-217665 \n14 \nMok CC Ying KY \nLupus pneumonitis or severe acute respiratory syndrome?\n\nLupus . 2004 ;13 :549 -553\n.15352429\n\n",
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},
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnessother": 1,
"transmissiondate": "20201103"
}
] |
{
"abstract": "Pulmonary aspergillosis is a very serious complication in cystic fibrosis (CF) patients due to the great variety of its clinical presentations and the fact that it worsens the prognosis. We can distinguish the following: Aspergillus colonization (AC), Aspergillus infection (AI) and allergic bronchopulmonary aspergillosis (ABPA). Aspergillus colonization (AC) is defined as isolation of Aspergillus spp. from 50% ormore sputum samples over six months to one year without observing deterioration in lung function and an increase in such respiratory symptoms as cough. Aspergillus infection (AI) is diagnosed in subjects with Aspergillus colonization and a decline in lung function, respiratory exacerbation with and without cough or with an incomplete response to a 2-4 week course of appropriate broad-spectrum antibiotics. Aspergillus can also cause allergic bronchopulmonary aspergillosis (ABPA). The classic diagnostic criteria of allergic bronchopulmonary aspergillosis in cystic fibrosis have been established during the Cystic Fibrosis Foundation Conference in 2001.\n\n\nOBJECTIVE\nTo establish the prevalence of pulmonary aspergillosis in children with cystic fibrosis under the care of our centre and to investigate the potential predisposing factors to Aspergillus infection (AI) and allergic bronchopulmonary aspergillosis (ABPA).\n\n\nMETHODS\nAn analysis was conducted of the medical documentation of 374 children aged 0-18 years monitored regularly in the Cystic Fibrosis Centre of the Institute of Mother and Child in Warsaw from 01.01.2010 to 31.08.2014. We selected 13 patients who presented an evidently worsening clinical status and course of the bronchopulmonary disease (decline in lung function parameters, respiratory exacerbations with increased cough, new or recent abnormalities in chest imaging) despite standard treatment with a high calorie diet, supplementation of pancreatic enzymes and vitamins, dornase alpha, inhaled and/or oral antibiotics, inhaled or oral corticosteroids, bronchodilators, physiotherapy. In this group of 13 CF children Aspergillus fumigatus was isolated from sputum. They represented 3.5% of the patients treated in our centre. Pulmonary aspergillosis was analyzed in relation to the age, sex, genotype, exocrine pancreatic insufficiency, body mass index, pulmonary function, microbiological examination of sputum, pulmonary complications and therapies. The mean age was 10.7 years (range 4.5-16.3). Only one child was under the age of six years. Patients were divided into 3 groups: patients with Aspergillus infection (AI), patients with allergic bronchopulmonary aspergillosis (ABPA), and a patient with Aspergillus infection and bronchopulmonary aspergillosis.\n\n\nRESULTS\nAspergillus infection (AI) was diagnosed in 9 cases (2.4%) and allergic bronchopulmonary aspergillosis (ABPA) in 3 (0.8%). One patient was treated with corticosteroids, because of allergic bronchopulmonary aspergillosis (ABPA) and after 8 months he developed Aspergillus infection (AI).n Most of the children were homo- or heterozygous for mutation F508del. Pancreatic insufficiency was recognized in all the children with ABPA, most of those with AI (8/9) and in one boy with ABPA and AI. Most of the patients had chronic respiratory colonization of Staphylococcus aureus and Pseudomonas aeruginosa. Children with AI were older (mean age:12.4), had a worse nutritional status (three of them had aBMI 3rd percentile), poorer lung function (five had severe lung disease *FEV1 40%*, complications occurred in one of the underlying diseases *haemoptysis, CFRD - Cystic Fibrosis Related Diabetes*, two of them had vascuport inserted due to the need for frequent intravenous antibiotic therapy. All the patients received inhaled antibiotics. A long-term oral azithromycin regime was applied in all the children with allergic bronchopulmonary aspergillosis, in most of those with Aspergillus infection *6,9* and in one boy with ABPA and AI. In three patients diagnosed with Aspergillus infection, antifungal treatment did not give any clinical or radiological improvement. They underwent surgical resection in the Department of Thoracic Surgery in Rabka (Poland). One patient had pneumonectomy and two underwent lobectomies. One boy had lung transplantation in Rigshospitalet in Copenhagen nine months after being diagnosed with Aspergillus infection.\n\n\nCONCLUSIONS\nSince pulmonary aspergillosis is a very serious complication in CF children, it seems reasonable to include screening for early detection of Aspergillus colonization in the annual assessment of CF patients who are over 6 years old. Due to the small sample size and retrospective design of our analysis, the identification of risk factors of pulmonary aspergillosis in CF children require further prospective studies. .",
"affiliations": "Cystic Fibrosis Centre, Institute of Mother and Child, Kasprzaka Street 17A, 01-211 Warsaw, Poland, tel. (+48 22)-32-77-455, e-mail: katarzyna.walicka@wp.pl.",
"authors": "Walicka-Serzysko|Katarzyna|K|;Sands|Dorota|D|",
"chemical_list": "D000935:Antifungal Agents; D017963:Azithromycin",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1428-345X",
"issue": "19(1)",
"journal": "Developmental period medicine",
"keywords": null,
"medline_ta": "Dev Period Med",
"mesh_terms": "D000293:Adolescent; D000935:Antifungal Agents; D001232:Aspergillus fumigatus; D017963:Azithromycin; D002648:Child; D002675:Child, Preschool; D015897:Comorbidity; D003550:Cystic Fibrosis; D010188:Exocrine Pancreatic Insufficiency; D005260:Female; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D016040:Lung Transplantation; D008297:Male; D009752:Nutritional Status; D011013:Pneumonectomy; D015995:Prevalence; D055732:Pulmonary Aspergillosis; D012189:Retrospective Studies; D012307:Risk Factors; D013183:Sputum",
"nlm_unique_id": "101636421",
"other_id": null,
"pages": "66-79",
"pmc": null,
"pmid": "26003072",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "The clinical presentations of pulmonary aspergillosis in children with cystic fibrosis - preliminary report.",
"title_normalized": "the clinical presentations of pulmonary aspergillosis in children with cystic fibrosis preliminary report"
} | [
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"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
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"reactionmeddrapt": "Haemoptysis",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
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{
"abstract": "OBJECTIVE\nDetermine whether preoperative oral acetaminophen increases gastric residual volume and lowers gastric pH.\n\n\nMETHODS\nProspective, randomized.\n\n\nMETHODS\nHealthy children, 1 to 14 years, having elective magnetic resonance imaging (MRI) were randomized to oral acetaminophen within 1 hour of induction versus fasting. Gastric volume and pH were measured immediately after intubation. Adverse events were documented from induction through 72 hours post MRI.\n\n\nRESULTS\nThirty-seven children completed the study (16 treatment, 21 control). Gastric residual volume between groups was not significantly different. The acetaminophen group had significantly higher pH than control group (1.86 ± 0.42 vs 1.56 ± 0.34; P ≤ .044). Three children in the control and 6 in the treatment group experienced minor adverse events.\n\n\nCONCLUSIONS\nFindings suggest administering oral acetaminophen prior to induction of anesthesia is not associated with increased gastric residual volume and increases the gastric pH. Further study is needed to examine outcomes such as aspiration pneumonitis risk.",
"affiliations": null,
"authors": "Burke|Constance N|CN|;D'Agostino|Rebecca|R|;Tait|Alan R|AR|;Malviya|Shobha|S|;Voepel-Lewis|Terri|T|",
"chemical_list": "D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": "10.1016/j.jopan.2018.05.015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1089-9472",
"issue": "34(2)",
"journal": "Journal of perianesthesia nursing : official journal of the American Society of PeriAnesthesia Nurses",
"keywords": "acetaminophen; aspiration; gastric pH; gastric volume",
"medline_ta": "J Perianesth Nurs",
"mesh_terms": "D000082:Acetaminophen; D000284:Administration, Oral; D000293:Adolescent; D000768:Anesthesia, General; D002648:Child; D002675:Child, Preschool; D005215:Fasting; D005260:Female; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D011446:Prospective Studies",
"nlm_unique_id": "9610507",
"other_id": null,
"pages": "297-302",
"pmc": null,
"pmid": "30270047",
"pubdate": "2019-04",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Effect of Preemptive Acetaminophen Administered Within 1 Hour of General Anesthesia on Gastric Residual Volume and pH in Children.",
"title_normalized": "effect of preemptive acetaminophen administered within 1 hour of general anesthesia on gastric residual volume and ph in children"
} | [
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"reaction": [
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"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Vomiting",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
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"reactionmeddrapt": "Airway complication of anaesthesia",
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},
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"literaturereference": "VOEPEL-LEWIS T, D^AGOSTINO R, TAIT A, MALVIYA S, BURKE C. EFFECT OF PREEMPTIVE ACETAMINOPHEN ADMINISTERED WITHIN 1 HOUR OF GENERAL ANESTHESIA ON GASTRIC RESIDUAL VOLUME AND PH IN CHILDREN. JOURNAL OF PERIANESTHESIA NURSING. 2019 APR?34/2:297-302.",
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},
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] |
{
"abstract": "Envenomation by Centruroides sculpturatus can manifest with cranial nerve dysfunction and neuromuscular hyperactivity. While these symptoms are most commonly seen in young children, they may also be seen in adults.\n\n\n\nThree cases of adult patients are presented with grades III & IV scorpion envenomation. They reported symptoms including disconjugate, roving eye movements, and motor involvement. Also reported were hyposmia, difficulty with fine motor movements, and dysgeusia. All were first treated with benzodiazepines with little to no effect. They then received a three vial antivenom bolus with resolution of severe symptoms within 30-60 min.\n\n\n\nSevere Centruroides envenomation can occur in adults as well as children. These three cases demonstrate the usefulness, safety, and effectiveness of antivenom therapy to quickly relieve symptoms in adult patients with grades III & IV envenomations.",
"affiliations": "a Arizona Poison & Drug Information Center , The University of Arizona College of Pharmacy , Tucson , AZ , USA.;b Department of Emergency Medicine , Martin Army Community Hospital , Fort Benning , GA , USA.;a Arizona Poison & Drug Information Center , The University of Arizona College of Pharmacy , Tucson , AZ , USA.;c The University of Arizona College of Pharmacy , Tucson , AZ , USA.;d Center for Health Outcomes and Pharmacoeconomic Research, College of Pharmacy , The University of Arizona , Tucson , AZ , USA.;e Arizona Poison & Drug Information Center, The University of Arizona College of Pharmacy, Center for Toxicology Pharmacology Education and Research , University of Arizona College of Medicine Phoenix , Tucson , AZ , USA.;e Arizona Poison & Drug Information Center, The University of Arizona College of Pharmacy, Center for Toxicology Pharmacology Education and Research , University of Arizona College of Medicine Phoenix , Tucson , AZ , USA.",
"authors": "Hurst|Nicholas B|NB|0000-0001-7298-7105;Lipe|Demis N|DN|;Karpen|Stephen R|SR|;Patanwala|Asad E|AE|;Taylor|Ann M|AM|;Boesen|Keith J|KJ|;Shirazi|F Mazda|FM|",
"chemical_list": "D000997:Antivenins; C035413:Centruroides toxin; D012604:Scorpion Venoms",
"country": "England",
"delete": false,
"doi": "10.1080/15563650.2017.1371310",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "56(4)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": "Anascorp; Scorpion; adult; antivenom; envenomation",
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D000328:Adult; D000997:Antivenins; D001130:Arizona; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D011247:Pregnancy; D011248:Pregnancy Complications; D065008:Scorpion Stings; D012604:Scorpion Venoms; D055815:Young Adult",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "294-296",
"pmc": null,
"pmid": "28871821",
"pubdate": "2018-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Centruroides sculpturatus envenomation in three adult patients requiring treatment with antivenom.",
"title_normalized": "centruroides sculpturatus envenomation in three adult patients requiring treatment with antivenom"
} | [
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dysphagia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Abnormal sensation in eye",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypoacusis",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Muscle twitching",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Pain",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Paraesthesia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hyposmia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Sensory disturbance",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Eye movement disorder",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Venom poisoning",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Nausea",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Vision blurred",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Myalgia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Condition aggravated",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Taste disorder",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Muscle contractions involuntary",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Movement disorder",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Tremor",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Erythema",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HURST NB, LIPE DN, KARPEN SR, PATANWALA AE, TAYLOR AM, BOESEN KJ ET AL. CENTRUROIDES SCULPTURATUS ENVENOMATION IN THREE ADULT PATIENTS REQUIRING TREATMENT WITH ANTIVENOM. CLINICAL TOXICOLOGY. 2018?56 (4):294-6",
"literaturereference_normalized": "centruroides sculpturatus envenomation in three adult patients requiring treatment with antivenom",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190730",
"receivedate": "20190730",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16646967,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20191004"
}
] |
{
"abstract": "Gemcitabine considered is to be a well-tolerated cytostatic drug with little known side effects. Cutaneous reactions are well known but still rarely reported. We report the case of a 75-year-old man with stage IV non-small-cell lung carcinoma treated with combination of gemcitabine 1000 mg/m2 and cisplatin 75 mg/m2 repeated every 28 days, who developed bilateral cutaneous bullous lesions of lower limbs following gemcitabine administration. Histopathologic examination did not show any toxidermy aspect and there was not any sign of immunoglobulin deposit in direct immunofluorescence test. Chemotherapy was stopped and lesions disappeared without any treatment. Even delayed with regard to gemcitabine administration, the causal relationship of gemcitabine treatment with skin reaction is possible according to the Naranjo probability scale. Pathologists should be aware of this kind of side effect in managing chemotherapy drugs and report any dermatologic reactions in order to identify the cause of toxicity and avoid a misdiagnosis.",
"affiliations": "Respiratory Diseases Department, III, Abderrahman-Mami Hospital, 2080 Ariana, Tunisia. imen.aissa@rns.tn",
"authors": "Imen|Aissa|A|;Amal|Khattab|K|;Ines|Zendah|Z|;Sameh|El Farhati|el F|;Fethi|El Mekki|el M|;Habib|Ghedira|G|",
"chemical_list": "D000964:Antimetabolites, Antineoplastic; D003841:Deoxycytidine; C056507:gemcitabine",
"country": "England",
"delete": false,
"doi": "10.1016/j.rmed.2005.11.027",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0954-6111",
"issue": "100(8)",
"journal": "Respiratory medicine",
"keywords": null,
"medline_ta": "Respir Med",
"mesh_terms": "D000368:Aged; D000964:Antimetabolites, Antineoplastic; D001768:Blister; D002289:Carcinoma, Non-Small-Cell Lung; D003841:Deoxycytidine; D003875:Drug Eruptions; D006801:Humans; D008175:Lung Neoplasms; D008297:Male",
"nlm_unique_id": "8908438",
"other_id": null,
"pages": "1463-5",
"pmc": null,
"pmid": "16434173",
"pubdate": "2006-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Bullous dermatosis associated with gemcitabine therapy for non-small-cell lung carcinoma.",
"title_normalized": "bullous dermatosis associated with gemcitabine therapy for non small cell lung carcinoma"
} | [
{
"companynumb": "TN-PFIZER INC-2019261249",
"fulfillexpeditecriteria": "1",
"occurcountry": "TN",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
},
"drugadditional": "1",
"drugadministrationroute": "042",
"drugauthorizationnumb": "078339",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1000 MG/M2, CYCLIC (ON DAYS 1, 8 AND 15, REPEATED EVERY 28 DAYS)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-SMALL CELL LUNG CANCER STAGE IV",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
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"drugstartdate": "200309",
"drugstartdateformat": "610",
"drugstructuredosagenumb": "1000",
"drugstructuredosageunit": "009",
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"medicinalproduct": "GEMCITABINE HYDROCHLORIDE."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
"drugadditional": "1",
"drugadministrationroute": "042",
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "75 MG/M2, CYCLIC (ON DAY 15, REPEATED EVERY 28 DAYS)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-SMALL CELL LUNG CANCER STAGE IV",
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"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": "200309",
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"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CISPLATIN."
}
],
"patientagegroup": null,
"patientonsetage": "75",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Dermatitis bullous",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "IMEN, A.. BULLOUS DERMATOSIS ASSOCIATED WITH GEMCITABINE THERAPY FOR NON-SMALL-CELL LUNG CARCINOMA. RESPIRATORY MEDICINE. 2006?100 (8):1463-1465",
"literaturereference_normalized": "bullous dermatosis associated with gemcitabine therapy for non small cell lung carcinoma",
"qualification": "3",
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},
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"receivedate": "20190619",
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},
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
}
] |
{
"abstract": "Peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS) is a relatively rare condition in Australia. Here, we report a case of PTCL, NOS in a patient who presented with persistent fever and progressive pancytopenia on a background of mediastinal lymphadenopathy, initially presumed reactive and hepatosplenomegaly with deranged liver function tests. The diagnosis was challenging, with multiple negative blood cultures and inconclusive bone marrow studies, and it required extensive investigations that ultimately revealed the characteristic clinical, histopathological and immunophenotypic features of PTCL, NOS. The patient underwent multiple rounds of multiagent chemotherapy after the diagnosis. This case highlights the difficulty in diagnosing PTCL, NOS and the importance of including it as a differential diagnosis in younger patients who present with constitutional symptoms and hepatosplenomegaly.",
"affiliations": "Medicine, Central Gippsland Health Service, Sale, Victoria, Australia.;Medicine Department, Central Gippsland Health Service, Sale, Victoria, Australia.;Monash Lung & Sleep, Central Gippsland Health Service, Sale, Victoria, Australia akmnizam@gmail.com.",
"authors": "McKay|Catharine|C|http://orcid.org/0000-0002-0548-4935;Hong|Lin-Tse|LT|;Uddin|A K M Nizam|AKMN|http://orcid.org/0000-0002-9836-4093",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2020-237806",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "14(3)",
"journal": "BMJ case reports",
"keywords": "haematology (incl blood transfusion); medical education; pathology; screening (oncology)",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D001315:Australia; D005335:Fever of Unknown Origin; D006801:Humans; D008111:Liver Function Tests; D016411:Lymphoma, T-Cell, Peripheral; D008297:Male; D010198:Pancytopenia",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33692045",
"pubdate": "2021-03-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Peripheral T-cell lymphoma presenting as fever of unknown origin in a man with deranged liver function tests and pancytopenia.",
"title_normalized": "peripheral t cell lymphoma presenting as fever of unknown origin in a man with deranged liver function tests and pancytopenia"
} | [
{
"companynumb": "AU-BAXTER-2021BAX028408",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "050718",
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"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
"drugdosageform": "Infusion",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Peripheral T-cell lymphoma unspecified",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "DOXIL"
},
{
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"activesubstancename": "CYCLOPHOSPHAMIDE"
},
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"drugcumulativedosageunit": null,
"drugdosageform": "Powder for solution for injection",
"drugdosagetext": null,
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"drugenddateformat": null,
"drugindication": "Peripheral T-cell lymphoma unspecified",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "CYCLOPHOSPHAMIDE"
},
{
"actiondrug": "5",
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"activesubstancename": "ETOPOSIDE"
},
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"drugindication": "Peripheral T-cell lymphoma unspecified",
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},
{
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"activesubstancename": "VINCRISTINE"
},
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"drugcharacterization": "1",
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"drugindication": "Peripheral T-cell lymphoma unspecified",
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"medicinalproduct": "VINCRISTINE"
},
{
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},
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"drugenddate": null,
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"drugindication": "Peripheral T-cell lymphoma unspecified",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE"
}
],
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"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Febrile neutropenia",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Clostridium difficile colitis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Oral candidiasis",
"reactionmeddraversionpt": "24.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "McKay C, Hong L, Uddin A. PERIPHERAL T-CELL LYMPHOMA PRESENTING AS FEVER OF UNKNOWN ORIGIN IN A MAN WITH DERANGED LIVER FUNCTION TESTS AND PANCYTOPENIA. BMJ CASE REP. 2021;14:1-5.",
"literaturereference_normalized": "peripheral t cell lymphoma presenting as fever of unknown origin in a man with deranged liver function tests and pancytopenia",
"qualification": "3",
"reportercountry": "AU"
},
"primarysourcecountry": "AU",
"receiptdate": "20211005",
"receivedate": "20210910",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 19818002,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": 2,
"seriousnessdeath": 2,
"seriousnessdisabling": 2,
"seriousnesshospitalization": 2,
"seriousnesslifethreatening": 2,
"seriousnessother": 1,
"transmissiondate": "20220303"
}
] |
{
"abstract": "Reactivation of Chagas disease has been described in immunosuppressed patients, but there is a paucity of literature describing reactivation in patients on immunosuppressive therapies for the treatment of autoimmune rheumatic diseases. We describe a case of Chagas disease reactivation in a woman taking azathioprine and prednisone for limited cutaneous systemic sclerosis (lcSSc). Reactivation manifested as indurated and erythematous cutaneous nodules. Sequencing of a skin biopsy specimen confirmed the diagnosis of Chagas disease. She was treated with benznidazole with clinical improvement in the cutaneous lesions. However, her clinical course was complicated and included disseminated CMV disease and subsequent septic shock due to bacteremia. Our case and review of the literature highlight that screening for Chagas disease should be strongly considered for patients who will undergo immunosuppression for treatment of autoimmune disease if epidemiologically indicated.",
"affiliations": "Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California, USA.;Department of Internal Medicine, Stanford University School of Medicine, Stanford, California, USA.;Department of Internal Medicine, Stanford University School of Medicine, Stanford, California, USA.;Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California, USA.;Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California, USA.;Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California, USA.;Division of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.;Harvard Medical School, Boston, Massachusetts, USA.;Department of Dermatology, Stanford University School of Medicine, Redwood City, California, USA.;Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.;Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.;Department of Internal Medicine, Stanford University School of Medicine, Stanford, California, USA.;Clinical Microbiology Laboratory, Stanford Health Care, Stanford, California, USA.;Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA.;Clinical Microbiology Laboratory, Stanford Health Care, Stanford, California, USA.;Department of Dermatology, Stanford University School of Medicine, Redwood City, California, USA.;Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California, USA.;Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California, USA.;Division of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California, USA.",
"authors": "Czech|Mary M|MM|;Nayak|Ashwin K|AK|;Subramanian|Kavitha|K|;Suarez|Jose F|JF|;Ferguson|Jessica|J|;Jacobson|Karen Blake|KB|;Montgomery|Susan P|SP|;Chang|Michael|M|;Bae|Gordon H|GH|;Raghavan|Shyam S|SS|;Wang|Hannah|H|0000-0002-3712-9188;Miranti|Eugenia|E|;Budvytiene|Indre|I|;Shoor|Stanford Mervyn|SM|;Banaei|Niaz|N|;Rieger|Kerri|K|;Deresinski|Stan|S|;Holubar|Marisa|M|0000-0002-7585-1809;Blackburn|Brian G|BG|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1093/ofid/ofaa642",
"fulltext": "\n==== Front\nOpen Forum Infect Dis\nOpen Forum Infect Dis\nofid\nOpen Forum Infectious Diseases\n2328-8957 Oxford University Press US \n\n10.1093/ofid/ofaa642\nofaa642\nNovel ID Cases\nAcademicSubjects/MED00290\nReactivation of Chagas Disease in a Patient With an Autoimmune Rheumatic Disease: Case Report and Review of the Literature\nCzech Mary M 1 Nayak Ashwin K 2 Subramanian Kavitha 2 Suarez Jose F 1 Ferguson Jessica 1 Jacobson Karen Blake 1 Montgomery Susan P 3 Chang Michael 4 Bae Gordon H 5 Raghavan Shyam S 6 http://orcid.org/0000-0002-3712-9188Wang Hannah 6 Miranti Eugenia 2 Budvytiene Indre 7 Shoor Stanford Mervyn 8 Banaei Niaz 7 Rieger Kerri 56 Deresinski Stan 1 http://orcid.org/0000-0002-7585-1809Holubar Marisa 1 Blackburn Brian G 1 1 \nDivision of Infectious Diseases and Geographic Medicine, Stanford University School of Medicine, Stanford, California, USA\n2 \nDepartment of Internal Medicine, Stanford University School of Medicine, Stanford, California, USA\n3 \nDivision of Parasitic Diseases and Malaria, Centers for Disease Control and Prevention, Atlanta, Georgia, USA\n4 \nHarvard Medical School, Boston, Massachusetts, USA\n5 \nDepartment of Dermatology, Stanford University School of Medicine, Redwood City, California, USA\n6 \nDepartment of Pathology, Stanford University School of Medicine, Stanford, California, USA\n7 \nClinical Microbiology Laboratory, Stanford Health Care, Stanford, California, USA\n8 \nDivision of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, California, USA\nCorrespondence: M. M. Czech, MD, MS, 300 Pasteur Drive, Lane Building, L134 MC:5107, Stanford, CA 94305–5107 (mmc16@stanford.edu).\n2 2021 \n05 2 2021 \n05 2 2021 \n8 2 ofaa64221 10 2020 16 12 2020 08 1 2021 05 2 2021 © The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.2021This 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\nReactivation of Chagas disease has been described in immunosuppressed patients, but there is a paucity of literature describing reactivation in patients on immunosuppressive therapies for the treatment of autoimmune rheumatic diseases. We describe a case of Chagas disease reactivation in a woman taking azathioprine and prednisone for limited cutaneous systemic sclerosis (lcSSc). Reactivation manifested as indurated and erythematous cutaneous nodules. Sequencing of a skin biopsy specimen confirmed the diagnosis of Chagas disease. She was treated with benznidazole with clinical improvement in the cutaneous lesions. However, her clinical course was complicated and included disseminated CMV disease and subsequent septic shock due to bacteremia. Our case and review of the literature highlight that screening for Chagas disease should be strongly considered for patients who will undergo immunosuppression for treatment of autoimmune disease if epidemiologically indicated.\n\nChagas diseaseautoimmune rheumatic disease\n==== Body\nPATIENT CASE\nAn 86-year-old woman developed painful subcutaneous nodules on her medial thighs and left upper extremity (Figure 1A, B). Over the ensuing 2 months, the nodules enlarged and became more indurated, erythematous, and painful. She also developed night sweats, fatigue, diarrhea, anorexia, and weight loss.\n\nFigure 1. A, Skin lesions on left medial thigh. B, Skin lesions on right medial thigh.\n\nThe patient had a history of poorly controlled diabetes mellitus and limited cutaneous systemic sclerosis (lcSSc; a multisystem autoimmune rheumatic disease), manifested as pulmonary hypertension and Reynaud’s syndrome. Eight months before admission, she was diagnosed with tachy-brady syndrome, requiring a pacemaker. Echocardiogram at that time showed a dilated right ventricle with elevated pressures, preservation of left ventricle ejection fraction, and no wall motion abnormalities or apical aneurysms. For management of lcSSc, she had been on long-standing azathioprine (100 mg/d). Prednisone (15 mg/d) was added 3 months before the current presentation for management of a diagnosis of retinal vasculitis.\n\nThe patient was born and raised in a rural mountain village near Trujillo, Venezuela. As a child, she lived in a mud hut and cared for many animals including chickens, dogs, and cats. At 20 years of age, she emigrated to the United States. She traveled back to Venezuela only once at 70 years of age, and otherwise denied international travel.\n\nShe was admitted to the hospital, where she was initially afebrile and hemodynamically stable. Physical exam showed no mucosal abnormalities or regional lymphadenopathy. White blood cell count was 4.4 K/μL with profound lymphopenia (absolute lymphocytes 0.2 K/μL), hemoglobin 11.5 g/dL, and platelets 126 K/μL. Kidney and liver function were normal. An HIV antigen/antibody test was negative. Strongyloides serology was negative. Computed tomography scan showed scattered bilateral pulmonary nodules; normal caliber esophagus, small bowel, and large bowel; and inflammation in the ascending colon. Contrast-enhanced brain magnetic resonance imaging was normal.\n\nBiopsy of the skin nodules (Figure 2A, B) showed a lymphohistiocytic infiltrate in the superficial and deep dermis with round intracellular organisms noted on hematoxylin/eosin stain. Periodic acid-Schiff-diastase, Gomori methenamine silver (GMS), Fite, and gram stains did not highlight the organisms. However, structures resembling kinetoplasts were minimally accentuated on GMS stain. Bacterial, fungal, and acid-fast bacillus cultures were ultimately negative. Serology for Trypanosoma cruzi (performed at Mayo Clinic Laboratories) was positive by both enzyme-linked immunosorbent assay and a lateral flow assay. A Giemsa-stained smear of peripheral blood (buffy coat) was negative, and real-time polymerase chain reaction (PCR) testing of a whole-blood sample for T. cruzi was also negative (performed at ARUP Laboratories). Tissue obtained from the cutaneous biopsy specimen identified T. cruzi by sequencing of the internal transcribed spacer 2 and D2 region of the 28S rRNA gene (performed at Stanford Health Care [1–3]).\n\nFigure 2. A, Biopsy of skin nodules, 200× magnification, hematoxylin and eosin (H&E) stain. Histologic sections show an epidermis with mild spongiosis and an underlying lymphohistiocytic infiltrate. B, Biopsy of skin nodules, 400× magnification, H&E stain. Histologic sections show numerous parasitized histiocytes (demonstrated by arrows). The organisms are circular without a well-defined capsule.\n\nGiven the patient’s remote exposure to an area endemic for T. cruzi, she was diagnosed with reactivation of Chagas disease (CD). Immunosuppression was weaned, and oral benznidazole 150 mg twice daily (~5 mg/kg/d) was initiated.\n\nConcurrent with the finding of CD, the patient was also found to have disseminated cytomegalovirus (CMV) disease. Plasma CMV viral load was >1.2 million copies/mL. Lung, colon, and skin biopsies all contained cells demonstrating cytopathic changes, which were positive by CMV immunostaining. Intravenous ganciclovir was started.\n\nWith treatment, the patient’s constitutional symptoms improved, and the skin lesions became less tender and erythematous. However, 1 month after the initiation of benznidazole, the patient developed Enterobacter cloacae bacteremia and septic shock. Shortly thereafter, she died.\n\nChagas Disease Epidemiology and Natural History\n\nT. cruzi is primarily transmitted to humans via inoculation of wounds or mucosal membranes with infected feces of blood-sucking triatomine insects. CD is endemic throughout much of Latin America. However, as people have migrated from endemic areas, CD has become increasingly prevalent in traditionally nonendemic regions. In the United States, it is estimated that 1.3% of Latin American immigrants are infected with T. cruzi [4].\n\nIn acute CD, nearly all infected individuals have an effective host immune response that controls the parasitemia within 1–2 months of initial infection. However, in the absence of effective antiparasitic treatment, tissue infection persists for the life of the host. Chronic indeterminate CD occurs in persons without signs or symptoms of infection, with normal electrocardiogram, and normal radiographic appearance of the chest, esophagus, and colon. Indeterminate CD may persist for life or progress to determinate CD in 20%–30% of patients. Determinate CD results from tissue destruction related to persistent parasite replication and the immune response. It manifests with cardiac disease (conduction abnormalities, arrhythmias, dilated cardiomyopathy) and, less frequently, gastrointestinal disease (esophageal/colonic dysmotility and dilatation) [5, 6]. In some immunocompromised persons, chronic (indeterminate or determinate) CD can reactivate.\n\nIn conjunction with clinical symptoms, diagnosis of CD reactivation can be aided by laboratory testing. Serologic tests will be positive in most patients infected with T. cruzi. In chronic CD, patients can have transient parasitemia detected on microscopic examination of whole blood (or, preferably, buffy coat) smears [7]. With CD reactivation, patients often have more persistent parasitemia [8]. Positive T. cruzi blood PCR assays are suggestive but not diagnostic of reactivation. However, positive blood PCR results can herald the development of subsequent invasive Chagas disease reactivation in immunocompromised patients. Furthermore, rising parasite numbers demonstrated by quantitative PCR in serial specimens are highly suggestive of reactivated disease [8].\n\nReactivation of Chagas Disease\nCD reactivation is best described in patients with advanced Chagas cardiomyopathy who undergo orthotopic heart transplantation [9–11]. The immunosuppressive drugs used to prevent transplant rejection predispose to CD reactivation. In these patients, reactivation most commonly manifests first as asymptomatic parasitemia or acute myocarditis [12]. Reactivation can also present as subcutaneous lesions [13], panniculitis [14], or, less commonly, meningoencephalitis [15]. Case series involving other solid organ transplant recipients (mostly renal transplant recipients) describe similar manifestations of CD reactivation [16–19]. CD reactivation is also known to occur in people with HIV/AIDS, most commonly presenting as meningoencephalitis [20] and/or brain abscesses (chagomas) [3, 21]. CD reactivation has also been described in patients receiving chemotherapy for hematologic and solid malignancies [22–25] and hematopoietic cell transplant (HCT) recipients [26–29].\n\nReactivation of Chagas Disease in Patients With Autoimmune Rheumatic Disease\nThere is a paucity of data regarding CD reactivation in patients receiving immunosuppressive therapy for autoimmune rheumatic diseases (ARDs; includes conditions such as systemic lupus erythematosus [SLE], rheumatoid arthritis, dermatomyositis, mixed connective tissue disease, and scleroderma). Compared with transplant recipients, patients with AIDS, and those receiving chemotherapy, patients undergoing treatment for ARD are often less immunosuppressed. However, it is unclear whether the dearth of literature in this cohort reflects infrequent reactivation or simply a lack of published case reports.\n\nAmong published English-language case reports that describe CD reactivation in patients with ARD on immunosuppressive regimens, the minority describe symptomatic CD reactivation (Table 1). Two patients developed brain chagomas—1 patient was successfully treated [30], and the other expired shortly after diagnosis [31]. Two other patients presented with Chagas skin lesions [30, 32], 1 of whom suffered recurrent disease after a course of benznidazole [30]. Other cases describe asymptomatic reactivation detected by T. cruzi PCR [33, 34], for which 1 patient was treated with off-label posaconazole after failing therapy with benznidazole [33]. The remaining patient reports describe possible reactivation detected through T. cruzi blood PCR positivity on a single test [30, 35]; given the absence of symptoms and serial testing, it is unclear if these patients had true CD reactivation or merely intermittently detectable parasites associated with chronic CD.\n\nTable 1. Published Studies Describing Chagas Disease Reactivation (or Possible Reactivation) in Patients With Autoimmune Disease who Were Receiving Immunosuppressive Therapy\n\nStudy\tPatient\tAutoimmune Disease\tImmunosuppression\tCountry of Origin\tChagas Diagnosis Known Before Evaluation for Reactivation\tEvidence of Chagas Reactivation (or Possible Reactivation)\tTreatment\tOutcome\t\nCurrent case\t86 yo F\tLimited cutaneous systemic sclerosis\tPrednisone 15 mg/d, azathioprine 100 mg/d\tVenezuela\tNo\tSkin lesions—erythematous, indurated, painful nodules on medial thighs and upper extremity\tBenznidazole\tPatient died 1 mo after initiation of benznidazole\t\nKaushal et al., 2019 [31]\t88 yo F\tRA\tMTX\tUnknown \tNo\tBrain chagoma \tBenznidazole\tPatient died shortly after diagnosis\t\nGerman Sanchez et al., 2019 [30]\t53 yo F\tSLE\tPrednisone 5 mg/d, MMF, CP\tAll patients in study from Argentina\tNo\tBrain chagoma and T. cruzi blood PCR pos\tBenznidazole\tPCR neg \t\n\t68 yo F\tPsoriatic arthritis\tPrednisone 20 mg/d, HCQ, MTX\t\tYes\tPanniculitis and T. cruzi blood PCR pos\tBenznidazole\tRelapse with recurrent skin lesions 1 y s/p treatment\t\n7 of 13 patients with ARDs who had Chagas reactivation (or possible reactivation)\t48 yo F\tRA\tMTX, adalimumab\t\tYes\tSingle T. Cruz blood PCR pos\tBenznidazole\tPCR neg \t\n\t66 yo M\tRA\tPrednisone 5 mg/d, MTX, etanercept\t\tYes\tSingle T. Cruzi blood PCR pos\tBenznidazole\tPCR neg \t\nTreatment durations for all patients were 1–2 mo\t81 yo F\tRA\tPrednisone 5 mg/d, HCQ, MTX, leflunomide\t\tYes\tSingle T. Cruzi blood PCR pos\tNifurtimox\tPCR neg \t\n\t66 yo F\tSjogren syndrome\tPrednisone 5 mg/d, HCQ\t\tYes\tSingle T. Cruzi blood PCR pos\tBenznidazole \tPCR neg \t\n\t57 yo F\tVasculitis\tPrednisone 5 mg/d, CP\t\tNo\tSingle T. cruzi blood PCR pos\tBenznidazole\tPCR neg \t\nVacas et al., 2017 [35]\t57 yo M\tPsoriatic erythroderma\tInfliximab\tArgentina \tYes \tSingle T. cruzi blood PCR pos\tBenznidazole × 45 d \tPCR neg \t\nNavarrete-Dechent et al., 2015 [34]\t52 yo M\tPsoriasis\tAdalimumab \tChile\tYes—Chagas megacolon, received preemptive treatment with nifurtimox \t\nT. cruzi blood PCR pos 8 months following preemptive nifurtimox\tRepeat course nifurtimox × 2 mo\tPCR neg \t\nBurgos et al., 2012 [32]\t44 yo F\tSLE\tPrednisone 50 mg/d, azathioprine 50 mg/d\tParaguay\tNo \tParasitemia, skin lesions—erythematous, painful nodules that progressed to ulcer and eschar\tBenznidazole × 2 mo\tClinically improved \t\nPinazo et al., 2010 [33]\t44 yo F\tSLE\tSteroids, CP\tArgentina \tYes—chronic indeterminate Chagas\t\nT. cruzi blood PCR pos, treated with benznidazole with recurrent PCR pos\tBenznidazole × 2 mo, and then posaconazole × 3 mo for relapse \tSerial PCR neg after posaconazole\t\nAbbreviations: CP, cyclophosphamide; HCQ, hydroxychloroquine; MMF, mycophenolate mofetil; MTX, methotrexate; NA, not applicable; neg, negative; PCR, polymerase chain reaction; pos, positive; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus.\n\nAlthough limited by small sample size and abbreviated longitudinal follow-up, other studies have attempted to investigate the risk for patients with ARD developing CD reactivation while on immunosuppression. One such study described 2 of 13 patients with ARD who developed symptomatic reactivation on immunosuppressive therapies over a 2-year period, and another 5 patients who developed possible CD reactivation detected by a single positive T. cruzi blood PCR test (Table 1) [30]. In other case series, the majority of immunosuppressed patients with ARD and CD were treated for chronic CD before the development of any evidence of CD reactivation, and only a small minority of these patients subsequently developed CD reactivation while receiving immunosuppression [25, 36, 37]. In 1 such study, 6 of 8 patients with ARD and CD were treated in this manner with varying regimens of benznidazole and nifurtimox. Three patients were treated for CD before a diagnosis of an ARD was made. Only 1 of the patients who received such treatment subsequently developed CD reactivation while receiving immunosuppression (further patient details not specified) [36]. In another study, 11 of 14 patients with chronic CD and ARD were treated for chronic CD with benznidazole for 60 days at the time of study enrollment, and none of the 14 patients experienced CD reactivation while receiving immunosuppression during follow-up [25]. Lastly, 3 patients with ARD and chronic CD were all treated at the time of CD diagnosis with benznidazole for 60 days; none of these patients developed subsequent CD reactivation during a 36-month follow-up period [37]. Though these preliminary data are intriguing, larger population studies, conducted over longer durations, are needed in order to draw more substantial conclusions about factors predisposing to CD reactivation in this cohort and the outcomes of prophylactic therapy.\n\nDISCUSSION\nOur patient is among the few in whom symptomatic CD reactivation was documented in the setting of immunosuppressive therapy for an ARD. Our patient likely had unrecognized determinate CD, clinically manifested by tachy-brady syndrome requiring a pacemaker [38]. CD reactivated after intensification of her immunosuppression regimen, ultimately manifesting as disseminated skin nodules, with sequencing of the skin biopsy revealing T. cruzi.\n\nOur patient’s case was unique in that symptomatic CD reactivation occurred in the setting of a negative T. cruzi blood PCR. Typically, T. cruzi blood PCR positivity develops before symptomatic reactivation [11]. Though it is unclear why our patient’s PCR was negative, it is possibly related to blood volume collected or PCR test characteristics. Importantly, this demonstrates that PCR positivity should not be the sole diagnostic measure in the evaluation for CD reactivation; assessment must also include careful clinical evaluation.\n\nCD reactivation in patients being treated for ARD additionally involves a different degree of immunosuppression compared with other better-studied cohorts. An effective host response against T. cruzi requires both cellular and humoral immunity [39]. Our patient was taking low-dose prednisone and azathioprine. Corticosteroids are nonspecific immune function inhibitors [40]. However, there are no reports that describe an increased incidence of CD reactivation in patients receiving corticosteroids as their sole form of immunosuppression. Azathioprine is an antimetabolite that decreases both T and B lymphocyte production [40]. However, some heart transplant recipients with a history of Chagas cardiomyopathy preferentially receive azathioprine over mycophenolate due to a 6-fold lower incidence of CD reactivation with azathioprine compared with mycophenolate [41]. Taken together, prednisone in doses <20 mg/d and azathioprine still seem to convey a relatively low risk for CD reactivation.\n\nIn our patient’s case, it is possible that more multifaceted immunosuppression led to her disease. Specifically, the synergistic effect of prednisone and azathioprine, in conjunction with her profound lymphopenia, advanced age, and uncontrolled diabetes, may have contributed to CD reactivation. However, these immunosuppressing factors still do not clearly explain our patient’s profound functional immunosuppression, further exhibited by concurrent disseminated CMV disease. Based on prior data [42–45], patients with rheumatoid arthritis and SLE may have an increased risk of infection independent of immunomodulatory therapy. Further research might better delineate the relationship between CD and immune function.\n\nScreening for Chagas Disease in Patients With ARD\nCurrently, consensus guidelines recommend serologic screening for CD in transplant donors and recipients with epidemiologic risk factors. A positive serologic result should be confirmed by at least 2 distinct serologic methods. In the United States, CD treatment based solely on a positive serology result in either the donor or the recipient is generally not recommended given the toxicity of the therapeutic options [46, 47]. Alternatively, transplant recipients who are seropositive should be monitored for reactivation, especially during the times of most intense immunosuppression. Laboratory monitoring employs microscopy of blood/buffy coats and blood PCR. If monitoring reveals parasitemia and/or PCR positivity (especially increasing the parasite load on serial quantitative PCRs), patients are typically given preemptive CD treatment, as the development of detectable T. cruzi in this cohort often heralds the development of symptomatic reactivation [46–49].\n\nGiven that data regarding CD reactivation in patients with ARD are so scant, it is uncertain if similar screening and treatment guidelines should be applied to ARD patients in the face of immunosuppression. However, in light of our patient’s case and our review of the literature, our opinion is that strong consideration should be given to serologic screening for T. cruzi before immunosuppression for ARD in patients who have CD risk factors. (Note that serologic screening following immunosuppression may be falsely negative due to a blunted immune response.) Data are insufficient to comment on the risks versus benefits of CD treatment based solely on a positive serologic result in this cohort. However, similar to transplant recipients, for those who are seropositive, clinical assessment and serial blood microscopy/PCR monitoring should be employed during immunosuppressive therapy. There should be strong consideration of preemptive treatment of patients with parasitemia and/or PCR blood positivity (especially increasing parasite load on serial quantitative PCRs) even in the absence of symptoms; of course, evaluation/treatment for those with symptoms/signs concerning for CD reactivation. More research is needed to refine the screening and subsequent treatment approach for CD in patients with ARD.\n\nCONCLUSIONS\nThis report describes CD reactivation in a patient with an ARD receiving immunosuppressive therapy. It highlights the need for more research regarding CD and reactivation in this patient population. It additionally suggests the need for broader serologic screening of patients with risk factors for CD before starting immunosuppression, and subsequent monitoring of at-risk patients while they receive such therapy.\n\nAcknowledgments\n\nFinancial support. None\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. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.\n\n\nDisclaimer. The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.\n\n\nPatient consent. Our study does not include factors necessitating patient consent.\n==== Refs\nReferences\n1. \n\nMoncada PA , Budvytiene I , Ho DY , et al. Utility of DNA sequencing for direct identification of invasive fungi from fresh and formalin-fixed specimens\n. 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"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2328-8957",
"issue": "8(2)",
"journal": "Open forum infectious diseases",
"keywords": "Chagas disease; autoimmune rheumatic disease",
"medline_ta": "Open Forum Infect Dis",
"mesh_terms": null,
"nlm_unique_id": "101637045",
"other_id": null,
"pages": "ofaa642",
"pmc": null,
"pmid": "33575423",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": "21401868;26312707;19640226;21530219;18337139;18000201;26180822;29381572;26055418;18260176;30204269;29162358;22795242;29412344;29364464;23349998;28673423;23897255;27504862;7929693;24891470;31176839;28500812;12355475;22814327;29020284;23192911;21335192;11428981;15996254;25734103;12533185;16236550;22802973;26170177;16226286;30484538;31211674;22790268;1750119;32981047;28284779;31295157;22715827;31145496;30496249;10530448;20348503;24147999",
"title": "Reactivation of Chagas Disease in a Patient With an Autoimmune Rheumatic Disease: Case Report and Review of the Literature.",
"title_normalized": "reactivation of chagas disease in a patient with an autoimmune rheumatic disease case report and review of the literature"
} | [
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{
"abstract": "Clonal haemopoiesis of indeterminate potential (CHIP) is an age-associated genetic event linked to increased risk of primary haematological malignancies and increased all-cause mortality, but the prevalence of CHIP in patients who develop therapy-related myeloid neoplasms is unknown. We did this study to investigate whether chemotherapy-treated patients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms.\n\n\n\nWe did a nested, case-control, proof-of-concept study to compare the prevalence of CHIP between patients with cancer who later developed therapy-related myeloid neoplasms (cases) and patients who did not develop these neoplasms (controls). We identified cases from our internal biorepository of 123 357 patients who consented to participate in the Total Cancer Care biobanking protocol at Moffitt Cancer Center (Tampa, FL, USA) between Jan 1, 2006, and June 1, 2016. We included all individuals who were diagnosed with a primary malignancy, were treated with chemotherapy, subsequently developed a therapy-related myeloid neoplasm, and were 70 years or older at either diagnosis. For inclusion in this study, individuals must have had a peripheral blood or mononuclear cell sample collected before the diagnosis of therapy-related myeloid neoplasm. Controls were individuals who were diagnosed with a primary malignancy at age 70 years or older and were treated with chemotherapy but did not develop therapy-related myeloid neoplasms. Controls were matched to cases in at least a 4:1 ratio on the basis of sex, primary tumour type, age at diagnosis, smoking status, chemotherapy drug class, and duration of follow-up. We used sequential targeted and whole-exome sequencing and described clonal evolution in cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available. The primary endpoint of this study was the development of therapy-related myeloid neoplasm and the primary exposure was CHIP.\n\n\n\nWe identified 13 cases and 56 case-matched controls. The prevalence of CHIP in all patients (23 [33%] of 69 patients) was higher than has previously been reported in elderly individuals without cancer (about 10%). Cases had a significantly higher prevalence of CHIP than did matched controls (eight [62%] of 13 cases vs 15 [27%] of 56 controls, p=0·024; odds ratio 5·75, 95% CI 1·52-25·09, p=0·013). The most commonly mutated genes in cases with CHIP were TET2 (three [38%] of eight patients) and TP53(three [38%] of eight patients), whereas controls most often had TET2 mutations (six [40%] of 15 patients). In most (four [67%] of six patients) cases for whom paired CHIP and therapy-related myeloid neoplasm samples were available, the mean allele frequency of CHIP mutations had expanded by the time of the therapy-related myeloid neoplasm diagnosis. However, a subset of paired samples (two [33%] of six patients) had CHIP mutations that decreased in allele frequency, giving way to expansion of a distinct mutant clone.\n\n\n\nPatients with cancer who have CHIP are at increased risk of developing therapy-related myeloid neoplasms. The distribution of CHIP-related gene mutations differs between individuals with therapy-related myeloid neoplasm and those without, suggesting that mutation-specific differences might exist in therapy-related myeloid neoplasm risk.\n\n\n\nMoffitt Cancer Center.",
"affiliations": "DeBartolo Family Personalised Medicine Institute, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Cancer Epidemiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Center for Pharmacogenomics and Individualised Therapy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, USA.;Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Biostatistics and Bioinformatics, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Molecular Genomics Core, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Molecular Genomics Core, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;DeBartolo Family Personalised Medicine Institute, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Cancer Epidemiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;DeBartolo Family Personalised Medicine Institute, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA; Department of Cancer Epidemiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA.;Department of Malignant Hematology, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA. Electronic address: Eric.Padron@moffitt.org.",
"authors": "Gillis|Nancy K|NK|;Ball|Markus|M|;Zhang|Qing|Q|;Ma|Zhenjun|Z|;Zhao|YuLong|Y|;Yoder|Sean J|SJ|;Balasis|Maria E|ME|;Mesa|Tania E|TE|;Sallman|David A|DA|;Lancet|Jeffrey E|JE|;Komrokji|Rami S|RS|;List|Alan F|AF|;McLeod|Howard L|HL|;Alsina|Melissa|M|;Baz|Rachid|R|;Shain|Kenneth H|KH|;Rollison|Dana E|DE|;Padron|Eric|E|",
"chemical_list": "D014408:Biomarkers, Tumor",
"country": "England",
"delete": false,
"doi": "10.1016/S1470-2045(16)30627-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1470-2045",
"issue": "18(1)",
"journal": "The Lancet. Oncology",
"keywords": null,
"medline_ta": "Lancet Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D014408:Biomarkers, Tumor; D016022:Case-Control Studies; D002999:Clone Cells; D005260:Female; D005431:Florida; D005500:Follow-Up Studies; D006410:Hematopoiesis; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D015994:Incidence; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009190:Myelodysplastic Syndromes; D009367:Neoplasm Staging; D009369:Neoplasms; D016609:Neoplasms, Second Primary; D011379:Prognosis; D012307:Risk Factors; D015996:Survival Rate",
"nlm_unique_id": "100957246",
"other_id": null,
"pages": "112-121",
"pmc": null,
"pmid": "27927582",
"pubdate": "2017-01",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D052061:Research Support, N.I.H., Extramural",
"references": "25426838;25918287;27546487;25487151;27414978;20601685;23349305;17510973;21653522;23412096;19299336;12712466;26140431;16782915;25931582;23242139;21127174;8943866;25939896;22157297;25102416;18692692;27923552;24030381;19124806;19505943;25426837;22581179",
"title": "Clonal haemopoiesis and therapy-related myeloid malignancies in elderly patients: a proof-of-concept, case-control study.",
"title_normalized": "clonal haemopoiesis and therapy related myeloid malignancies in elderly patients a proof of concept case control study"
} | [
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{
"abstract": "To evaluate the feasibility and clinical efficacy of the combination of alemtuzumab with dose-adjusted etoposide/cyclophosphamide/doxorubicin/vincristine/prednisone (DA-EPOCH) as upfront therapy for untreated aggressive T and NK cell lymphomas, a phase 1/2 trial was conducted. Thirty patients were treated with the study regimen, consisting of alemtuzumab on day 1 of a 21 day cycle with standard dosing of DA-EPOCH for 6-8 cycles. Alemtuzumab 30 mg IV was used for the phase 2 component. Of 30 treated patients, 17 had a complete response (CR) and eight had a partial response (83.3% overall response rate). The median overall survival and progression-free survival were 20.2 and 6.6 months, respectively. There were five treatment-related deaths on study mainly due to infectious complications, including one case each of disseminated toxoplasmosis and pneumonia and two cases of sepsis. Alemtuzumab with DA-EPOCH is of limited clinical utility due to unacceptable toxicity, despite the high rate of CR.",
"affiliations": "a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA.;a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA.;a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA.;c Laboratory of Pathology , National Cancer Institute , Bethesda , MD , USA.;a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA.;a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA.;c Laboratory of Pathology , National Cancer Institute , Bethesda , MD , USA.;a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA.;a Center for Cancer Research, National Cancer Institute , Bethesda , MD , USA.",
"authors": "Roswarski|Joseph|J|0000-0002-1470-8814;Roschewski|Mark|M|;Melani|Christopher|C|;Pittaluga|Stefania|S|;Lucas|Andrea|A|;Steinberg|Seth M|SM|;Jaffe|Elaine S|ES|;Waldmann|Thomas A|TA|0000-0003-4500-6660;Wilson|Wyndham H|WH|",
"chemical_list": "D000074323:Alemtuzumab; D014750:Vincristine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "United States",
"delete": false,
"doi": "10.1080/10428194.2018.1562184",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1026-8022",
"issue": "60(8)",
"journal": "Leukemia & lymphoma",
"keywords": "EPOCH; PTCL; alemtuzumab; lymphoma",
"medline_ta": "Leuk Lymphoma",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D000074323:Alemtuzumab; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D004317:Doxorubicin; D005047:Etoposide; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D054391:Lymphoma, Extranodal NK-T-Cell; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D011241:Prednisone; D016896:Treatment Outcome; D014750:Vincristine; D055815:Young Adult",
"nlm_unique_id": "9007422",
"other_id": null,
"pages": "2062-2066",
"pmc": null,
"pmid": "30626252",
"pubdate": "2019-08",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article",
"references": "17581918;20660290;29507077;17145843;10561185;20548096;28971899;21940214;12171721;25193992;17406867;11929754;21212158;1706610;19236377",
"title": "Phase 1/2 study of alemtuzumab with dose-adjusted EPOCH in untreated aggressive T and NK cell lymphomas.",
"title_normalized": "phase 1 2 study of alemtuzumab with dose adjusted epoch in untreated aggressive t and nk cell lymphomas"
} | [
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"literaturereference": "ROSWARSKI J, WILSON W, ROSCHEWSKI M, MELANI C, PITTALUGA S, LUCAS A, STEINBERG S, JAFFE E, WALDMANN T. PHASE 1/2 STUDY OF ALEMTUZUMAB WITH DOSE-ADJUSTED EPOCH IN UNTREATED AGGRESSIVE T AND NK CELL LYMPHOMAS. LEUKEMIA AND LYMPHOMA. 2019?60(8):2062-2066.",
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"reporttype": "2",
"safetyreportid": 15844253,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20191004"
},
{
"companynumb": "US-PFIZER INC-2019024001",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOPHOSPHAMIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK UNK, CYCLIC(ON DAYS 1-5 OF A 21-DAY CYCLE)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-HODGKIN^S LYMPHOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugseparatedosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CYCLOPHOSPHAMIDE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "VINCRISTINE SULFATE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "071484",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK UNK, CYCLIC(ON DAYS 1-5 OF A 21-DAY CYCLE )",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-HODGKIN^S LYMPHOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "VINCRISTINE SULFATE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DOXORUBICIN HYDROCHLORIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": "050467",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK UNK, CYCLIC (ON DAYS 1-5 OF A 21-DAY CYCLE)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-HODGKIN^S LYMPHOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugseparatedosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "DOXORUBICIN HCL"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK UNK, CYCLIC(ON DAYS 1-5 OF A 21-DAY CYCLE)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-HODGKIN^S LYMPHOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ETOPOSIDE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK UNK, CYCLIC(ON DAYS 1-5 OF A 21-DAY CYCLE )",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-HODGKIN^S LYMPHOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ALEMTUZUMAB"
},
"drugadditional": "3",
"drugadministrationroute": "042",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK UNK, CYCLIC (DAY 1 OF EACH 21-DAY CYCLE)",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NON-HODGKIN^S LYMPHOMA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ALEMTUZUMAB"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pneumonia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ROSWARSKI, J.. PHASE 1/2 STUDY OF ALEMTUZUMAB WITH DOSE-ADJUSTED EPOCH IN UNTREATED AGGRESSIVE T AND NK CELL LYMPHOMAS.. LEUKEMIA + LYMPHOMA. 2019?60 (8):2062-2066",
"literaturereference_normalized": "phase 1 2 study of alemtuzumab with dose adjusted epoch in untreated aggressive t and nk cell lymphomas",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190722",
"receivedate": "20190118",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 15843913,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20191004"
}
] |
{
"abstract": "OBJECTIVE\nTo describe 2 cases of Nocardia keratitis resistant to topical compounded amikacin therapy.\n\n\nMETHODS\nA 24-year-old woman presented with a corneal infiltrate. Cultures were taken, and topical moxifloxacin was administered. Corneal biopsy was performed when clinical status deteriorated, which confirmed infection with Nocardia. The patient was administered topical compounded amikacin. When clinical status further deteriorated, she was switched to compounded trimethoprim-sulfamethoxazole, which resulted in rapid resolution. Separately, a 22-year-old woman presented with contact lens-related keratitis that grew Nocardia asteroides. Corneal cultures and drug sensitivity testing revealed a strain of N. asteroides resistant to amikacin and imipenem, but sensitive to tobramycin. After a protracted clinical course, the keratitis ultimately responded to topical tobramycin leaving the patient with a pericentral corneal scar.\n\n\nCONCLUSIONS\nNocardia keratitis is an atypical infection for which standard management algorithms exist. However, atypical cases require that these patients be followed closely for the response to therapy.",
"affiliations": "*Department of Ophthalmology, Penn State Hershey Medical Center, Hershey, PA; †Bascom Palmer Eye Institute, University of Miami, Miami, FL; and ‡Cullen Eye Institute, Baylor College of Medicine, Houston, TX.",
"authors": "Patel|Ravi|R|;Sise|Adam|A|;Al-Mohtaseb|Zaina|Z|;Garcia|Noel|N|;Aziz|Hassan|H|;Amescua|Guillermo|G|;Pantanelli|Seth M|SM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D009883:Ophthalmic Solutions; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D000583:Amikacin; D014031:Tobramycin",
"country": "United States",
"delete": false,
"doi": "10.1097/ICO.0000000000000634",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-3740",
"issue": "34(12)",
"journal": "Cornea",
"keywords": null,
"medline_ta": "Cornea",
"mesh_terms": "D000287:Administration, Topical; D000583:Amikacin; D000900:Anti-Bacterial Agents; D003263:Contact Lenses, Hydrophilic; D003320:Corneal Ulcer; D015818:Eye Infections, Bacterial; D005260:Female; D006801:Humans; D007613:Kanamycin Resistance; D008826:Microbial Sensitivity Tests; D009617:Nocardia Infections; D009616:Nocardia asteroides; D009883:Ophthalmic Solutions; D014031:Tobramycin; D015662:Trimethoprim, Sulfamethoxazole Drug Combination; D055815:Young Adult",
"nlm_unique_id": "8216186",
"other_id": null,
"pages": "1617-9",
"pmc": null,
"pmid": "26418432",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Nocardia asteroides Keratitis Resistant to Amikacin.",
"title_normalized": "nocardia asteroides keratitis resistant to amikacin"
} | [
{
"companynumb": "US-GLENMARK PHARMACEUTICALS-2016GMK023419",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "SULFAMETHOXAZOLE\\TRIMETHOPRIM"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "090828",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NOCARDIOSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TRIMETHOPRIM SULFAMETHOXAZOLE"
}
],
"patientagegroup": null,
"patientonsetage": "24",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Therapeutic response unexpected",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use issue",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PATEL R, SISE A, AL-MOHTASEB Z, GARCIA N, AZIZ H, AMESCUA G, PANTANELLI SM. NOCARDIA ASTEROIDES KERATITIS RESISTANT TO AMIKACIN. CORNEA. 2015;34(12):1617-9",
"literaturereference_normalized": "nocardia asteroides keratitis resistant to amikacin",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170213",
"receivedate": "20170213",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13225115,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20170428"
}
] |
{
"abstract": "We report two elderly patients receiving peritoneal dialysis with castration-resistant prostate cancer (CRPC). Herein, we show that the patients were safely treated using abiraterone acetate (750 mg/day orally once daily) and prednisolone (5 mg/day orally once daily). Although the prostate-specific antigen (PSA) level increased in both cases, there was no manifestation of disease progression (clinical and radiographic) for 22 months in case 1 and 8 months in case 2. In case 2, the only adverse event was hypokalemia, which was treated using potassium preparations.",
"affiliations": "Department of Urology, Nippon Medical School Musashi Kosugi Hospital.;Department of Urology, Nippon Medical School Musashi Kosugi Hospital.;Department of Urology, Nippon Medical School.",
"authors": "Kimata|Ryoji|R|;Tomita|Yuji|Y|;Kondo|Yukihiro|Y|",
"chemical_list": "D000970:Antineoplastic Agents; D011239:Prednisolone; D000069501:Abiraterone Acetate; D011188:Potassium",
"country": "Japan",
"delete": false,
"doi": "10.1272/jnms.JNMS.2019_86-211",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1345-4676",
"issue": "86(2)",
"journal": "Journal of Nippon Medical School = Nippon Ika Daigaku zasshi",
"keywords": "abiraterone acetate; castration-resistant prostate cancer; peritoneal dialysis",
"medline_ta": "J Nippon Med Sch",
"mesh_terms": "D000069501:Abiraterone Acetate; D000284:Administration, Oral; D000369:Aged, 80 and over; D000970:Antineoplastic Agents; D002369:Castration; D006801:Humans; D007008:Hypokalemia; D008297:Male; D010530:Peritoneal Dialysis; D011188:Potassium; D011239:Prednisolone; D064129:Prostatic Neoplasms, Castration-Resistant; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "100935589",
"other_id": null,
"pages": "135-138",
"pmc": null,
"pmid": "31130566",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Safety of Abiraterone Acetate Administration in Elderly Patients Receiving Peritoneal Dialysis with Castration-Resistant Prostate Cancer: Two Case Reports.",
"title_normalized": "safety of abiraterone acetate administration in elderly patients receiving peritoneal dialysis with castration resistant prostate cancer two case reports"
} | [
{
"companynumb": "PHHY2019JP146470",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ABIRATERONE ACETATE"
},
"drugadditional": "3",
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "750 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HORMONE-REFRACTORY PROSTATE CANCER",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": "201506",
"drugstartdateformat": "610",
"drugstructuredosagenumb": "750",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ABIRATERONE ACETATE."
},
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "1",
"drugadministrationroute": "048",
"drugauthorizationnumb": "017469",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "5 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": "201506",
"drugstartdateformat": "610",
"drugstructuredosagenumb": "5",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISOLONE."
},
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "017469",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "10 MG, UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "HORMONE-REFRACTORY PROSTATE CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "10",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISOLONE."
}
],
"patientagegroup": null,
"patientonsetage": "87",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypokalaemia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "2"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 201508"
}
},
"primarysource": {
"literaturereference": "KIMATA R, TOMITA Y, KONDO Y. SAFETY OF ABIRATERONE ACETATE ADMINISTRATION IN ELDERLY PATIENTS RECEIVING PERITONEAL DIALYSIS WITH CASTRATION-RESISTANT PROSTATE CANCER: TWO CASE REPORTS. JOURNAL OF NIPPON MEDICAL SCHOOL. 2019?86(2):135-8",
"literaturereference_normalized": "safety of abiraterone acetate administration in elderly patients receiving peritoneal dialysis with castration resistant prostate cancer two case reports",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20190628",
"receivedate": "20190628",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16492848,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190711"
}
] |
{
"abstract": "Thiamine (vitamin B1) is a sulfur-containing, water-soluble vitamin that plays an essential role in energy metabolism and the tricarboxylic acid cycle. There is an increased need for vitamin B1 (1-1.2 mg daily) during pregnancy and lactation. Hyperemesis during pregnancy can cause severe polyneuropathy (Wernicke's encephalopathy) as a result of thiamine deficiency. Thiamine deficiency has also been associated with beriberi. A number of atypical cases with reversible right heart failure and severe pulmonary hypertension have also been reported in non-pregnant individuals, but have never been reported in pregnancy. Here we present five such cases of thiamine deficiency with neurological and cardio-pulmonary manifestations.",
"affiliations": "Department of Obstetrics and Gynaecology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India.;Department of Cardiology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India.;Department of Obstetrics and Gynaecology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India.;Department of Radiology, Kasturba Medical College, Manipal Academy of Higher Education, Manipal, India.",
"authors": "Hegde|Nivedita|N|https://orcid.org/0000-0003-2357-2522;Ashwal|A J|AJ|;Deekonda|Shrayva|S|;Suresh|K K|KK|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1753495X20960906",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1753-495X",
"issue": "14(4)",
"journal": "Obstetric medicine",
"keywords": "Thiamine deficiency; Wernicke’s encephalopathy; beriberi; pulmonary hypertension; right heart failure",
"medline_ta": "Obstet Med",
"mesh_terms": null,
"nlm_unique_id": "101464191",
"other_id": null,
"pages": "263-268",
"pmc": null,
"pmid": "34880943",
"pubdate": "2021-12",
"publication_types": "D002363:Case Reports",
"references": "30151974;7919625;14222020;15303623;17346820;30716232;19913987;16551377;26989522;28661435;20642790;16550223;22703952;28873391;21423705;21565430;5539573",
"title": "A case series of rare neurological and cardio-pulmonary manifestations of thiamine deficiency in pregnancy and lactation.",
"title_normalized": "a case series of rare neurological and cardio pulmonary manifestations of thiamine deficiency in pregnancy and lactation"
} | [
{
"companynumb": "IN-LUPIN PHARMACEUTICALS INC.-2022-03870",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MEMANTINE"
},
"drugadditional": "4",
"drugadministrationroute": "048",
"drugauthorizationnumb": "090051",
"drugbatchnumb": "Unknown",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Disturbance in attention",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MEMANTINE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MEMANTINE"
},
"drugadditional": "4",
"drugadministrationroute": "048",
"drugauthorizationnumb": "090051",
"drugbatchnumb": "Unknown",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK UNK, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "Memory impairment",
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{
"abstract": "Pheochromocytomas in pregnancy are rare but potentially lethal. Even rarer is the combination of pheochromocytoma in pregnancy with subsequent development of ectopic Cushing's syndrome. We report a 36-year-old woman, previously diagnosed with essential hypertension, who developed severe hypertension in pregnancy complicated by insulin-dependent gestational diabetes. A cesarean section was performed at 32 weeks following a hypertensive crisis after routine administration of betamethasone. Postnatal persistence of signs and symptoms of catecholamine excess led to the diagnosis of a left adrenal pheochromocytoma. Between diagnosis and planned tumor removal, the patient developed signs and symptoms of Cushing's syndrome (facial edema and hirsutism, myopathy and fatigue). Biochemical testing confirmed hypercortisolism with extremely elevated levels of plasma adrenocorticotropin, urinary cortisol and multiple steroids of a plasma panel that were all normal at previous testing. The previously noradrenergic tumor also started producing epinephrine. Histopathological examination confirmed the pheochromocytoma, which was also immunohistochemically positive for adrenocorticotropin. Full post-surgical recovery was sustained with normal blood pressure and biochemical findings after one year. This report not only underlines the chameleon behavior of pheochromocytoma but also illustrates its potential for a metamorphosing presentation. Corticosteroid administration in pregnancy requires a cautious approach in patients with hypertension.",
"affiliations": "a Institute of Clinical Chemistry and Laboratory Medicine , University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.;b Department of Medicine III , University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.;b Department of Medicine III , University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.;b Department of Medicine III , University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.;a Institute of Clinical Chemistry and Laboratory Medicine , University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.;c Institute of Pathology , University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.;b Department of Medicine III , University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.;b Department of Medicine III , University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.;a Institute of Clinical Chemistry and Laboratory Medicine , University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden , Dresden , Germany.",
"authors": "Langton|Katharina|K|;Gruber|Matthias|M|;Masjkur|Jimmy|J|;Steenblock|Charlotte|C|;Peitzsch|Mirko|M|;Meinel|Jörn|J|;Lenders|Jacques|J|;Bornstein|Stefan|S|;Eisenhofer|Graeme|G|",
"chemical_list": "D000324:Adrenocorticotropic Hormone; D001623:Betamethasone; D006854:Hydrocortisone",
"country": "England",
"delete": false,
"doi": "10.1080/09513590.2017.1379497",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0951-3590",
"issue": "34(1)",
"journal": "Gynecological endocrinology : the official journal of the International Society of Gynecological Endocrinology",
"keywords": "Pheochromocytoma; adrenocorticotropin; ectopic Cushing’s syndrome; hypertensive crisis; pregnancy; steroid profiling",
"medline_ta": "Gynecol Endocrinol",
"mesh_terms": "D000310:Adrenal Gland Neoplasms; D000324:Adrenocorticotropic Hormone; D000328:Adult; D001623:Betamethasone; D002585:Cesarean Section; D003480:Cushing Syndrome; D016640:Diabetes, Gestational; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D006973:Hypertension; D007231:Infant, Newborn; D007234:Infant, Premature; D010673:Pheochromocytoma; D049590:Postpartum Period; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome",
"nlm_unique_id": "8807913",
"other_id": null,
"pages": "20-24",
"pmc": null,
"pmid": "28937294",
"pubdate": "2018-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hypertensive crisis in pregnancy due to a metamorphosing pheochromocytoma with postdelivery Cushing's syndrome.",
"title_normalized": "hypertensive crisis in pregnancy due to a metamorphosing pheochromocytoma with postdelivery cushing s syndrome"
} | [
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"reaction": [
{
"reactionmeddrapt": "Cushing^s syndrome",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Maternal exposure during delivery",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
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"reactionmeddrapt": "Hypertensive crisis",
"reactionmeddraversionpt": "20.1",
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"primarysource": {
"literaturereference": "LANGTON K, GRUBER M, MASJKUR J, STEENBLOCK C, PEITZSCH M, MEINEL J ET AL.. HYPERTENSIVE CRISIS IN PREGNANCY DUE TO A METAMORPHOSING PHEOCHROMOCYTOMA WITH POSTDELIVERY CUSHING^S SYNDROME.. GYNECOLOGICAL ENDOCRINOLOGY.. 2017;1-5",
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"qualification": "3",
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},
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{
"abstract": "OBJECTIVE\nPeriprocedural symptomatic intracranial hemorrhage (sICH) unrelated to coil embolization of intracranial aneurysm has been rarely reported. The incidence and characteristics of this complication remain unclear. This study was designed to elucidate the incidence and characteristics of periprocedural sICH unrelated to coiling of intracranial aneurysm, and to explore the possible mechanisms underlying this complication.\n\n\nMETHODS\nIncluded in this retrospective study were 1287 patients with 1394 aneurysms who were treated with coil embolization (476 patients with stent assistance and 811 patients without stents) between May 2008 and August 2017. All procedure-unrelated sICHs that occurred within 30 days after coiling were selected. The technical details of the procedure, clinical characteristics, and medical therapy were recorded.\n\n\nRESULTS\nA total of 6 patients developed periprocedural sICH unrelated to coil embolization. All these six patients underwent stent-assisted coiling (SAC). Therefore, there was a 1.3% (6/476) procedure-unrelated sICH rate of SAC and 0% (0/811) in patients underwent coiling without stent during the periprocedural period (P = 0.005, RR 0.987; 95% CI, 0.977-0.997). These phenomena occurred more often in patients who received SAC for ruptured aneurysms vs patients underwent this technique for unruptured aneurysms (2.0 vs 0.7%, P = 0.390, RR 2.896; 95% CI, 0.525-15.968). All these phenomena occurred within 7 days after coiling, and resulted in one mortality, one unfavorable outcome (mRS Score 3), and other four favorable outcomes (mRS Scores 0-2) at 90 days after procedure.\n\n\nCONCLUSIONS\nOur findings suggest that the procedure-unrelated sICH, though less frequent, may exist following stent-assisted coiling of intracranial aneurysm during the periprocedural period. Extra caution may be warranted in patients who were treated with SAC for ruptured aneurysms.",
"affiliations": "Department of Neurointerventional Radiology, The First Affiliated Hospital of Zhengzhou University, Road Jianshe No 1, Zhengzhou City, 450052, China.;Department of Neurology, Children Hospital of Zhengzhou City, Zhengzhou City, China.;Department of Neurointerventional Radiology, The First Affiliated Hospital of Zhengzhou University, Road Jianshe No 1, Zhengzhou City, 450052, China.;Department of Neurointerventional Radiology, The First Affiliated Hospital of Zhengzhou University, Road Jianshe No 1, Zhengzhou City, 450052, China.;Department of Neurointerventional Radiology, The First Affiliated Hospital of Zhengzhou University, Road Jianshe No 1, Zhengzhou City, 450052, China. touxingaoshou@qq.com.",
"authors": "Xu|Haowen|H|;Wang|Li|L|;Guan|Sheng|S|;Li|Dongdong|D|;Quan|Tao|T|http://orcid.org/0000-0002-5056-7123",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00234-018-2049-6",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-3940",
"issue": "60(8)",
"journal": "Neuroradiology",
"keywords": "Coil embolization; Intracranial aneurysm; Intracranial hemorrhage; Periprocedural period",
"medline_ta": "Neuroradiology",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D004621:Embolization, Therapeutic; D005260:Female; D006801:Humans; D015994:Incidence; D002532:Intracranial Aneurysm; D020300:Intracranial Hemorrhages; D008297:Male; D008875:Middle Aged; D012189:Retrospective Studies; D012307:Risk Factors; D015607:Stents",
"nlm_unique_id": "1302751",
"other_id": null,
"pages": "853-859",
"pmc": null,
"pmid": "29959462",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article",
"references": "16091521;8918275;16575324;23275598;16139655;9788453;24834945;16331157;11213960;9851479;9802487;24088101;22403783;24081287;15276392;20559093;23321438;7354892;21990545;16463889;46957;12775880;18518714;12414200;20720074",
"title": "Symptomatic periprocedural intracranial hemorrhage unrelated to coil embolization in 1287 patients with intracranial aneurysms.",
"title_normalized": "symptomatic periprocedural intracranial hemorrhage unrelated to coil embolization in 1287 patients with intracranial aneurysms"
} | [
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{
"abstract": "Oxaliplatin-based chemotherapy is widely used to treat advanced cancer. Oxaliplatin-induced hyperammonemic encephalopathy is rarely reported. Here, we report a case of oxaliplatin-induced hyperammonemic encephalopathy occurring after gemcitabine plus oxaliplatin (GEMOX) chemotherapy in a patient with pancreatic cancer. A 76-year-old man received GEMOX regimen as first-line treatment for pancreatic adenocarcinoma with peritoneal dissemination. GEMOX consists of gemcitabine (1,000 mg/m2) and oxaliplatin (100 mg/m2) on day 1, repeated every 2 weeks. The second cycle of GEMOX was administered as planned. However, he appeared to have difficulties with daily activities. Two days later, he visited the emergency room complaining of drowsiness. On examination, the patient had a Glasgow Coma Scale (GCS) score of 14 (E4V4M6), and asterixis was not present. Blood examination revealed a serum ammonia level of 202 µg/dL. The levels of serum hepatic enzymes were only mildly elevated, and the hemoglobin level was typical for this patient. Computed tomography, magnetic resonance imaging, lumbar puncture test, and blood culture showed no abnormality. Based on these results, he was diagnosed with oxaliplatin-induced hyperammonemia. One day after hospitalization, GCS score had significantly decreased to 6 (E1V1M4). His consciousness disorder improved after administration of a nutritional supplement containing a high concentration of branched-chain amino acids for 5 days, and the level of serum ammonia improved to 79 µg/dL. He stated that he could not remember the episode. The findings of this case suggest the importance of examining serum ammonia levels in patients receiving an oxaliplatin-containing regimen who develop disordered consciousness.",
"affiliations": "Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan.;Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan.",
"authors": "Ogata|Takatsugu|T|;Satake|Hironaga|H|;Ogata|Misato|M|;Hatachi|Yukimasa|Y|;Yasui|Hisateru|H|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000481398",
"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 10.1159/000481398cro-0010-0885Case ReportOxaliplatin-Induced Hyperammonemic Encephalopathy in a Patient with Metastatic Pancreatic Cancer: A Case Report Ogata Takatsugu Satake Hironaga *Ogata Misato Hatachi Yukimasa Yasui Hisateru Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan*Hironaga Satake, Department of Medical Oncology, Kobe City Medical Center General Hospital, 2-1-1, Minatojima minamimachi, chuo-ku, Kobe City, Hyogo 650-0047 (Japan), E-Mail takeh1977@gmail.comSep-Dec 2017 10 10 2017 10 10 2017 10 3 885 889 11 9 2017 11 9 2017 Copyright © 2017 by S. Karger AG, Basel2017This 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.Oxaliplatin-based chemotherapy is widely used to treat advanced cancer. Oxaliplatin-induced hyperammonemic encephalopathy is rarely reported. Here, we report a case of oxaliplatin-induced hyperammonemic encephalopathy occurring after gemcitabine plus oxaliplatin (GEMOX) chemotherapy in a patient with pancreatic cancer. A 76-year-old man received GEMOX regimen as first-line treatment for pancreatic adenocarcinoma with peritoneal dissemination. GEMOX consists of gemcitabine (1,000 mg/m2) and oxaliplatin (100 mg/m2) on day 1, repeated every 2 weeks. The second cycle of GEMOX was administered as planned. However, he appeared to have difficulties with daily activities. Two days later, he visited the emergency room complaining of drowsiness. On examination, the patient had a Glasgow Coma Scale (GCS) score of 14 (E4V4M6), and asterixis was not present. Blood examination revealed a serum ammonia level of 202 µg/dL. The levels of serum hepatic enzymes were only mildly elevated, and the hemoglobin level was typical for this patient. Computed tomography, magnetic resonance imaging, lumbar puncture test, and blood culture showed no abnormality. Based on these results, he was diagnosed with oxaliplatin-induced hyperammonemia. One day after hospitalization, GCS score had significantly decreased to 6 (E1V1M4). His consciousness disorder improved after administration of a nutritional supplement containing a high concentration of branched-chain amino acids for 5 days, and the level of serum ammonia improved to 79 µg/dL. He stated that he could not remember the episode. The findings of this case suggest the importance of examining serum ammonia levels in patients receiving an oxaliplatin-containing regimen who develop disordered consciousness.\n\nKeywords\nHyperammonemiaOxaliplatinGEMOXPancreatic cancerUrea cycleHyperammonemic encephalopathy\n==== Body\nIntroduction\nOxaliplatin-based chemotherapy is widely used to treat advanced colorectal, gastric, and pancreatic cancer. The common side effects related to oxaliplatin are nausea, vomiting, bone marrow suppression, and peripheral neuropathy [1]. Oxaliplatin-induced hyperammonemic encephalopathy is rarely reported. Hyperammonemic encephalopathy is a rare complication that can occur after oxaliplatin-based chemotherapy, and it manifests as altered mental status without any radiologic abnormality or abnormal laboratory test results, except for elevated serum ammonia levels. Herein, we report a case of oxaliplatin-induced hyperammonemic encephalopathy that occurred after gemcitabine plus oxaliplatin (GEMOX) chemotherapy in a patient with pancreatic cancer.\n\nCase Report\nA 76-year-old man with no history of hepatitis B virus or hepatitis C virus infection had pancreatic adenocarcinoma with peritoneal dissemination. The clinical stage was IV (cT3N1M1). The main site of metastasis was the peritoneum, and there was no liver metastasis. With respect to his family history, his father had been diagnosed with pancreatic cancer. The level of serum carcinoembryonic antigen was 87.6 ng/dL (reference value, <5.0 ng/dL) and that of serum carbohydrate antigen 19-9 was 15,030 U/mL (reference value, <37.0 U/mL). The patient received a GEMOX regimen as first-line therapy as part of a clinical trial. GEMOX consists of gemcitabine (1,000 mg/m2) and oxaliplatin (100 mg/m2) on day 1, and administration is repeated every 2 weeks. The second cycle of GEMOX was administered as planned. However, the patient appeared to have difficulty performing daily activities on the night of admission. Two days later (day 3), he visited the emergency room complaining of drowsiness. His body temperature, pulse rate, and blood pressure were 37.1°C, 80 beats per min, and 133/74 mm Hg, respectively. His Glasgow Coma Scale (GCS) score was 14 (E4V4M6). Upon examination, asterixis was not present, nor were dehydration or constipation. Blood examination revealed a serum ammonia level of 202 µg/dL (reference value, 19–54 µg/dL). Levels of serum hepatic enzymes were mildly elevated (aspartate aminotransferase, 101 IU/L [reference value, 8–40 IU/L]; alanine aminotransferase, 69 IU/L [reference value, 8–40 IU/L]). Serum hemoglobin level was 12.8 g/dL (reference value, 13.4–17.6 g/dL) and it had not decreased compared with the usual level for this patient. Serum sodium, serum albumin, and serum cholinesterase levels were 136 mEq/L (reference value, 136–148 mEq/L), 3.8 g/dL (reference value, 3.9–4.9 g/dL), and 124 U/L (reference value, 165–470 U/L), respectively. Serum C-reactive protein and serum white blood cell count were 0.09 mg/dL (reference value, 0–0.5 mg/dL) and 6,000/µL (reference value, 3,900–9,000/µL), respectively. Serum blood urea nitrogen and serum creatinine levels were 24.5 mg/dL (reference value, 8.0–20.0 mg/dL) and 0.58 mg/dL (reference value, 0.60–1.10 mg/dL), respectively. Computed tomography revealed no liver metastasis or splenomegaly, but there was collateral circulation due to portal vein stenosis. Magnetic resonance imaging, cerebrospinal fluid examination, and blood culture revealed no abnormalities.\n\nBased on these results, the patient was diagnosed with oxaliplatin-induced hyperammonemia. One day after hospitalization, his GCS score decreased to 6 (E1V1M4), which was his worst value. His consciousness disorder improved after administration of a nutritional supplement containing a high concentration of branched-chain amino acids for 5 days, and his level of serum ammonia improved to 79 µg/dL. The patient was discharged 13 days later and hyperammonemia has not recurred despite the absence of predictive medication. We considered hyperammonemic encephalopathy was a severe adverse event of chemotherapy and thus ceased administration of this regimen in his case.\n\nDiscussion\nCurrently, FOLFIRINOX (5-fluorouracil [5-FU], oxaliplatin, and irinotecan) and gemcitabine plus nab-paclitaxel are standard therapies for metastatic pancreatic adenocarcinoma. However, many clinical trials have used other regimens, including GEMOX, gemcitabine plus cisplatin, or gemcitabine plus S-1 [2, 3, 4]. Especially in the case of patients who have a family history of either breast, ovarian, or pancreatic cancers, chemotherapy including a platinum agent is associated with a better survival rate [5]. In this case, the patient had a family history of pancreatic cancer. The FOLFIRINOX regimen is not recommended for patients aged >76 years because they are typically excluded from clinical trials, and the adverse events caused by this regimen can be severe [6]. Our patient received GEMOX because he participated in a clinical trial.\n\nHyperammonemic encephalopathy is uncommon, and 5-FU, cytarabine, and vincristine are known to be associated with this adverse event [7]. Hyperammonemic encephalopathy is a severe adverse event of oxaliplatin, and its frequency is reported to be 0.07% when oxaliplatin is used in combination with 5-FU. In contrast, gemcitabine has not been reported to be associated with hyperammonemic encephalopathy. It is possible that, in this case, the patient actually experienced gemcitabine-induced hyperammonemia; however, based on previous reports, we concluded that this was a case of oxaliplatin-induced hyperammonemic encephalopathy.\n\nThe risk factors for chemotherapy-induced hyperammonemia are dehydration, constipation, renal dysfunction, infection, or catabolism of skeletal muscle due to malnutrition [8]. However, our patient did not have any obvious risk factors. One study reported a case of hyperammonemia due to collateral circulation, and, in this case, collateral circulation was identified by computed tomography [9]. Hyperammonemic encephalopathy due to collateral circulation usually shows recurrence [10]. Our patient did not develop recurrent hyperammonemia; hence, we concluded that collateral circulation was not the cause of this event.\n\nThe findings of our case indicate the importance of analyzing serum ammonia levels in patients receiving an oxaliplatin-containing regimen who develop disordered consciousness. In cases of chemotherapy-induced hyperammonemic encephalopathy, one suggested mechanism includes a catabolic state induced by chemotherapeutic agents that overwhelm the capacity of the urea cycle [11]. The mechanism of action of oxaliplatin involves the mitochondrial pathway; hence, it is possible that oxaliplatin impairs the urea cycle [12]. To identify whether oxaliplatin impairs the activity of the urea cycle enzyme, it is effective that the laboratory tests of plasma amino acid and urinary orotic acid are performed. When the activity of the urea cycle enzyme is impaired, plasma amino acid levels reveal low ornithine with normal alanine and glutamine, and the urinary orotic acid level is elevated [13]. While cisplatin-related hyperammonemia has been reported, cisplatin was administered only in combination with 5-FU in previous studies [14]. To our knowledge, no study has reported a case of carboplatin-associated hyperammonemia. The half-life of oxaliplatin is longer than that of other platinum-based agents (Table 1) [15]. It is hypothesized that, because oxaliplatin persists for a longer time than other platinum agents, hyperammonemia does not occur with cisplatin or nedaplatin, but does with oxaliplatin.\n\nConclusion\nWe suggest that oxaliplatin-induced hyperammonemia is caused by a disturbance of the urea cycle. Further studies should be undertaken to clarify the mechanism involved.\n\nStatement of Ethics\nThe Ethics Committee of Kobe City Medical Center General Hospital approved the study.\n\nWritten informed consent was obtained from the deceased's wife for publication of this case report.\n\nDisclosure Statement\nThe authors report no conflict of interest.\n\nTable 1 Half-life of platinum-based agents\n\n\tOxaliplatin\tCisplatin\tCarboplatin\tTetraplatin\t\nt1/2α, h\t7.30±4.9\t0.22±0.15\t0.37±0.17\t0.16\t\nt1/2β, h\t239±54.4\t0.72±0.4\t1.93±0.23\t25.8\n==== Refs\nReferences\n1 DeVita VT Lawrence TS Rosenberg SA DeVita, Hellman, and Rosenberg's Cancer Principles & Practice of Oncology 2015 Philadelphia Wolters Kluwer \n2 Heinemann V Quietzsch D Gieseler F Gonnermann M Schonekas H Rost A Neuhaus H Haag C Clemens M Heinrich B Vehling-Kaiser U Fuchs M Fleckenstein D Gesierich W Uthgenannt D Einsele H Holstege A Hinke A Schalhorn A Wilkowski R Randomized phase III trial of gemcitabine plus cisplatin compared with gemcitabine alone in advanced pancreatic cancer J Clin Oncol 2006 32 3946 3952 \n3 Louvet C Labianca R Hammel P Lledo G Zampino MG Andre T Zaniboni A Ducreux M Aitini E Taieb J Faroux R Lepere C de Gramont A GERCOR, GISCADGemcitabine in combination with oxaliplatin compared with gemcitabine alone in locally advanced or metastatic pancreatic cancer: results of a GERCOR and GISCAD phase III trial J Clin Oncol 2005 32 3509 3516 \n4 Ueno H Okusaka T Furuse J Yamao K Funakoshi A Boku N Ohkawa S Yokosuka O Tanaka K Moriyasu F Nakamori S Sato T Multicenter phase II study of gemcitabine and S-1 combination therapy (GS therapy) in patients with metastatic pancreatic cancer Jpn J Clin Oncol 2011 32 953 958 \n5 Fogelman D Sugar EA Oliver G Shah N Klein A Alewine C Wang H Javle M Shroff R Wolff RA Abbruzzese JL Laheru D Diaz LA Jr Family history as a marker of platinum sensitivity in pancreatic adenocarcinoma Cancer Chemother Pharmacol 2015 32 489 498 \n6 Conroy T Desseigne F Ychou M Bouche O Guimbaud R Becouarn Y Adenis A Raoul JL Gourgou-Bourgade S de la Fouchardiere C Bennouna J Bachet JB Khemissa-Akouz F Pere-Verge D Delbaldo C Assenat E Chauffert B Michel P Montoto-Grillot C Ducreux M Groupe Tumeurs Digestives of Unicancer; PRODIGE Intergroup FOLFIRINOX versus gemcitabine for metastatic pancreatic cancer N Engl J Med 2011 32 1817 1825 \n7 Chang YY Lin JK Jiang JK Oxaliplatin-related hyperammonaemic encephalopathy in a patient with colon cancer Colorectal Dis 2012 14 e821 22330089 \n8 Yi HJ Hong KS Moon N Chung SS Lee RA Kim KH Acute hyperammonemic encephalopathy after 5-fluorouracil based chemotherapy Ann Surg Treat Res 2016 32 179 182 \n9 Sherlock S Summerskill WH White LP Phear EA Portal-systemic encephalopathy; neurological complications of liver disease Lancet 1954 32 454 457 \n10 Inoue H Emori K Toyonaga A Oho K Kumamoto M Haruta T Mitsuyama K Tsuruta O Sata M Long term results of balloon-occluded retrograde transvenous obliteration for portosystemic shunt encephalopathy in patients with liver cirrhosis and portal hypertension Kurume Med J 2014 32 1 8 \n11 Lazier J Lupichuk SM Sosova I Khan AA Hyperammonemic encephalopathy in an adenocarcinoma patient managed with carglumic acid Curr Oncol 2014 21 e736 e739 25302046 \n12 Gourdier I Del Rio M Crabbe L Candeil L Copois V Ychou M Auffray C Martineau P Mechti N Pommier Y Pau B Drug specific resistance to oxaliplatin is associated with apoptosis defect in a cellular model of colon carcinoma FEBS Lett 2002 32 232 236 \n13 Chapuy CI Sahai I Sharma R Zhu AX Kozyreva ON Hyperammonemic encephalopathy associated with fibrolamellar hepatocellular carcinoma: case report, literature review, and proposed treatment algorithm Oncologist 2016 32 514 520 \n14 Kim YA Chung HC Choi HJ Rha SY Seong JS Jeung HC Intermediate dose 5-fluorouracil-induced encephalopathy Jpn J Clin Oncol 2006 32 55 59 \n15 Graham MA Lockwood GF Greenslade D Brienza S Bayssas M Gamelin E Clinical pharmacokinetics of oxaliplatin: a critical review Clin Cancer Res 2000 32 1205 1218\n\n",
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"abstract": "BACKGROUND\nPaclitaxel plus bevacizumab have shown a high response rate and prolonged progression-free survival in metastatic breast cancer patients. However, overall survival was not prolonged. Thus, no conclusion has been made on the effectiveness of bevacizumab. In our report, taxane plus bevacizumab were used to treat a metastatic breast cancer patient with taxane resistance, and a good therapeutic result was obtained.\n\n\nMETHODS\nThe patient was a 68-year-old woman with a non-contributory history. In September 2004, she underwent a pectoral muscle-conserving mastectomy with axillary dissection for right-sided breast cancer (pT3N0M0-stage IIB, estrogen receptor positive, progesterone receptor negative, and human epidermal growth factor receptor type 2 negative). Adjuvant therapy consisted of 6 cycles of cyclophosphamide, epirubicin and fluorouracil, and subsequent oral anastrozole. In August 2007, the patient developed a recurrence in the left axillary lymph node. The chemotherapy was changed to high-dose toremifene, and radiation therapy was also performed. The patient achieved a complete response. In April 2009, CT showed left axillary lymph node enlargement once again and multiple lung metastases. Hormone therapy was changed to exemestane and long-term stable disease was achieved. In March 2011, the lung and left axillary lymph node metastases were enlarged and progressive disease was noted. Thus, the tumors were determined to be resistant to hormone therapy, and weekly paclitaxel was begun in May. Since partial response was achieved, this therapy was continued. In December, CT showed that lung and axillary lymph node metastases were enlarged and progressive disease was observed. Therefore, the tumors were determined to be resistant to paclitaxel. In January 2012, bevacizumab and weekly paclitaxel were begun. In April, lung and axillary lymph node metastases were reduced in size, and partial response was achieved. Thereafter the same treatment has been continued, and the patient has been followed up without clinical exacerbation as of January 2013.\n\n\nCONCLUSIONS\nTaxane plus bevacizumab were used to treat a metastatic breast cancer patient with taxane resistance, and a good therapeutic result was obtained. This result is considered important in increasing treatment options for patients with taxane resistance or patients using adjuvant taxane-based therapy and in examining the effectiveness of bevacizumab in metastatic breast cancer patients.",
"affiliations": null,
"authors": "Ishizuna|Kazuo|K|;Ninomiya|Jun|J|;Kojima|Makoto|M|;Kawashima|Miho|M|;Nozaki|Miwako|M|;Yamagishi|Hidetsugu|H|;Ueda|Yoshihiko|Y|;Oya|Masatoshi|M|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D017239:Paclitaxel",
"country": "England",
"delete": false,
"doi": "10.1186/1756-0500-6-254",
"fulltext": "\n==== Front\nBMC Res NotesBMC Res NotesBMC Research Notes1756-0500BioMed Central 1756-0500-6-2542383041510.1186/1756-0500-6-254Case ReportPaclitaxel-resistant advanced recurrent breast cancer: a case of partial response due to addition of bevacizumab to paclitaxel therapy: a case report Ishizuna Kazuo 1k.ishizuna@hotmail.co.jpNinomiya Jun 12jninomiya@grape.plala.or.jpKojima Makoto 1kojima-m@dokkyomed.ac.jpKawashima Miho 3miho-kw@dokkyomed.ac.jpNozaki Miwako 3miwako@dokkyomed.ac.jpYamagishi Hidetsugu 4yamagisi@dokkyomed.ac.jpUeda Yoshihiko 4yoshi@dokkyomed.ac.jpOya Masatoshi 1masaoya@dokkyomed.ac.jp1 Breast Center, Dokkyo Medical University Koshigaya Hospital, 2-1-50 Minami-Koshigaya, Saitama 343–8555, Koshigaya, Japan2 Ninomiya Hospital, 491–6 Shin-eicho, Soka, Saitama 340–0056, Koshigaya, Japan3 Department of Radiology, Dokkyo Medical University Koshigaya Hospital, 2-1-50 Minami-Koshigaya, Saitama 343–8555, Koshigaya, Japan4 Department of Pathology, Dokkyo Medical University Koshigaya Hospital, 2-1-50 Minami-Koshigaya, Saitama 343–8555, Koshigaya, Japan2013 6 7 2013 6 254 254 12 1 2013 1 7 2013 Copyright © 2013 Ishizuna et al.; licensee BioMed Central Ltd.2013Ishizuna et al.; licensee BioMed Central Ltd.This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nPaclitaxel plus bevacizumab have shown a high response rate and prolonged progression-free survival in metastatic breast cancer patients. However, overall survival was not prolonged. Thus, no conclusion has been made on the effectiveness of bevacizumab. In our report, taxane plus bevacizumab were used to treat a metastatic breast cancer patient with taxane resistance, and a good therapeutic result was obtained.\n\nCase presentation\nThe patient was a 68-year-old woman with a non-contributory history. In September 2004, she underwent a pectoral muscle-conserving mastectomy with axillary dissection for right-sided breast cancer (pT3N0M0-stage IIB, estrogen receptor positive, progesterone receptor negative, and human epidermal growth factor receptor type 2 negative). Adjuvant therapy consisted of 6 cycles of cyclophosphamide, epirubicin and fluorouracil, and subsequent oral anastrozole. In August 2007, the patient developed a recurrence in the left axillary lymph node. The chemotherapy was changed to high-dose toremifene, and radiation therapy was also performed. The patient achieved a complete response. In April 2009, CT showed left axillary lymph node enlargement once again and multiple lung metastases. Hormone therapy was changed to exemestane and long-term stable disease was achieved. In March 2011, the lung and left axillary lymph node metastases were enlarged and progressive disease was noted. Thus, the tumors were determined to be resistant to hormone therapy, and weekly paclitaxel was begun in May. Since partial response was achieved, this therapy was continued. In December, CT showed that lung and axillary lymph node metastases were enlarged and progressive disease was observed. Therefore, the tumors were determined to be resistant to paclitaxel. In January 2012, bevacizumab and weekly paclitaxel were begun. In April, lung and axillary lymph node metastases were reduced in size, and partial response was achieved. Thereafter the same treatment has been continued, and the patient has been followed up without clinical exacerbation as of January 2013.\n\nConclusion\nTaxane plus bevacizumab were used to treat a metastatic breast cancer patient with taxane resistance, and a good therapeutic result was obtained. This result is considered important in increasing treatment options for patients with taxane resistance or patients using adjuvant taxane-based therapy and in examining the effectiveness of bevacizumab in metastatic breast cancer patients.\n\nBreast cancerBevacizumabPaclitaxel\n==== Body\nBackground\nIt is often difficult to cure metastatic and recurrent breast cancer, except for some local recurrences. Improvement of QOL and extension of survival are the objectives of treatment for metastatic and recurrent breast cancer. In recent years, various new drugs have been used clinically in an effort to achieve these objectives.\n\nBevacizumab is a humanized monoclonal antibody that targets vascular endothelial growth factor (VEGF), which is a major regulator of angiogenesis. In Japan, its indications are colon cancer and lung cancer and have expanded to include breast cancer in September 2011.\n\nIn this report, we describe a case of paclitaxel (PTX) resistant advanced recurrent breast cancer that achieved partial response due to addition of bevacizumab to paclitaxel therapy. We also include a brief literature review.\n\nCase presentation\nThe patient was a 68-year-old postmenopausal woman with a non-contributory history. In September 2004, she underwent a pectoral muscle-conserving mastectomy with axillary dissection for right-sided breast cancer. Pathological diagnosis was papillotubular carcinoma, n = 0/12, nuclear grade 1, ly+, v-, estrogen receptor positive, progesterone receptor negative, and human epidermal growth factor receptor type 2 negative (UICC classification: pT3N0M0-stage IIB). Adjuvant therapy consisted of 6 cycles of CEF (cyclophosphamide 75 mg/m2 (days 1–14), epirubicin 60 mg/m2 (days 1 and 8), and fluorouracil 500 mg/m2 (days 1 and 8), every 4 weeks) and subsequent oral anastrozole (1 mg/day). In August 2007, the patient developed a recurrence in the left axillary lymph node. The chemotherapy was changed to high-dose toremifene (120 mg/day), and radiation therapy was also performed (left axilla: 63 Gy). The patient achieved a complete response (CR) in March 2008. In April 2009, CT showed left axillary lymph node enlargement once again and multiple lung metastases. Hormone therapy was changed to exemestane (25 mg/day) and long-term stable disease was achieved. In March 2011, the lung and left axillary lymph node metastases were enlarged and progressive disease was noted. Thus, the tumors were determined to be resistant to hormone therapy. In May, weekly paclitaxel was begun (80 mg/m2, 3 weeks on and 1 week off). Since partial response was achieved, this therapy was continued. In December 2011, CT showed that lung and axillary lymph node metastases were enlarged and progressive disease was observed. Therefore, the tumors were determined to be resistant to PTX (tumor markers, CEA: 2.8 ng/ml, CA 15–3: 27.7 U/ml) (Figure 1a and b). Since the patient became resistant to PTX and developed progressive disease, a change to other drugs was considered. However, metastases enlarged only slightly. Thus, PTX was continued in combination with bevacizumab whose indications had been newly expanded to include breast cancer. PTX was continued to exhaust the therapeutic options based on taxanes – a key drug for metastatic and recurrent breast cancer.\n\nFigure 1 a and b (CT from December 2011). CT showed a left axillary lymph node that had enlarged to 2.5 cm and lung metastases that had also enlarged.\n\nIn January 2012, bevacizumab and weekly PTX were begun (paclitaxel 90 mg/m2, 3 weeks on and 1 week off; bevacizumab 10 mg/kg, once every 2 weeks). In April, CT showed reduction of size of lung and axillary lymph node metastases, and partial response was achieved (tumor markers, CEA: 2.0 ng/ml, CA 15–3: 20.9 U/ml) (Figure 2a and b). Thereafter the same treatment has been continued, and the patient has been followed up without clinical exacerbation as of January 2013.\n\nFigure 2 a and b (CT from April 2012). Three months after bevacizumab and weekly PTX were begun, the left axillary lymph node reduced in size to 1.4 cm and the lung metastases also became smaller.\n\nDiscussion\nTumor growth requires oxygen and nutrients. Tumors vessels are needed to supply sufficient oxygen and nutrients as the tumor size increases. Therefore, angiogenesis plays an important role in tumor growth and metastasis. VEGF is a major regulator involved in tumor angiogenesis, growth, and metastasis. It acts as a ligand and binds to VEGF receptors on the endothelial cell surface [1,2].\n\nThe molecularly targeted drug bevacizumab (Avastin; Genentech, South San Francisco, CA) selectively binds to a VEGF family member, VEGF-A. Bevacizumab inhibits binding of VEGF-A to VEGF receptors (VEGFR-1, VEGFR-2, and neuropilin 1) expressed on endothelial cells, thereby blocking the signal transduction pathway. It inhibits angiogenesis in tumor tissue and suppresses tumor growth as a result [3]. In addition, it has been shown to normalize the vascular structure, decrease vascular permeability, and lower increased tumor interstitial pressure [4,5]. When the tumor interstitial pressure is reduced by bevacizumab, paclitaxel delivery to the tumor tissue is improved. Thus, the drug concentration increases in the tumor tissue [6].\n\nOur patient developed resistance to PTX and subsequently achieved a partial response when bevacizumab was added to PTX therapy. The reason is that bevacizumab inhibits angiogenesis and improves paclitaxel delivery into tumor tissue.\n\nIn 2007, there was a report on a phase III randomized trial (E2100) which compared paclitaxel plus bevacizumab and paclitaxel alone as initial chemotherapy for patients with untreated advanced and recurrent breast cancer (n = 722). Although the overall survival was not significantly prolonged (median: 26.7 months vs 25.2 months, respectively, HR: 0.88, p = 0.16), the median progression-free survival was prolonged (11.8 months vs 5.9 months, HR: 0.60, p < 0.001) and the response rate increased (36.9% vs 21.2%, p < 0.001) [7]. In the U.S., bevacizumab was promptly approved for metastatic breast cancer in February 2008 based on these results. In Japan, its indications were expanded to include breast cancer patients in September 2011.\n\nWhen additional trials were conducted (AVADO and RIBBON-1 trials), the results showed that the progression-free survival was prolonged and the response rate increased. However, the overall survival was not prolonged. In addition, the results suggested that the risks for adverse events could outweigh the benefits [7-9]. In November 2011, the FDA revoked the approval of bevacizumab for breast cancer. At the present time, it is necessary to thoroughly examine the risks and benefits of bevacizumab.\n\nWhen bevacizumab is used in combination with another chemotherapeutic agent, a high response rate can be obtained. Thus, bevacizumab is currently considered a drug with major benefits, particularly in patients with life-threatening metastasis. When patients develop resistance to taxane during adjuvant therapy (as in our patient), our results suggest that the combination therapy of taxane and bevacizumab can be considered for treatment. Thus, our finding can have major significance. In the E2100 trial, metastatic breast cancer patients who had a history of adjuvant taxane chemotherapy were examined. Paclitaxel plus bevacizumab significantly prolonged progression-free survival as compared with paclitaxel alone (12 months vs 3 months, respectively; HR: 0.46, P < 0.001) [7].\n\nIn Japan, it has not been very long since bevacizumab has been indicated for metastatic and recurrent breast cancer. However, since it has not been shown to prolong survival, its blind use is also not recommended from the aspect of health economics [10]. However, bevacizumab has been shown to achieve a high response rate and to prolong progression-free survival. Thus, it could be very beneficial depending on the case. In the future, more cases should be accumulated, and it would be necessary to identify a subset of patients in which bevacizumab will be more effective.\n\nConclusion\nWe reported a case of paclitaxel-resistant metastatic recurrent breast cancer that achieved partial response due to addition of bevacizumab to paclitaxel therapy. The clinical value of bevacizumab has not yet been established in treating advanced and recurrent cancer. It will be necessary to accumulate more cases.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this manuscript and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nAbbreviations\nVEGF: Vascular endothelial growth factor; PTX: Paclitaxel.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors’ contributions\nKI, JN, MK, MK and MN participated in the clinical diagnosis. HY and YU performed the histological examination. KI and JN contributed to drafting of the manuscript. MO supervised the concept and design of the manuscript. All authors read and approved the final manuscript.\n==== Refs\nBossung V Harbeck N Angiogenesis inhibitors in the management of breast cancer Curr Opin Obstet Gynecol 2010 22 1 79 86 10.1097/GCO.0b013e328334e462 19952746 \nFerrara N The role of vascular endothelial growth factor in pathological angiogenesis Breast Cancer Res Treat 1995 36 2 127 137 10.1007/BF00666035 8534862 \nKim KJ Li B Winer J Armanini M Gillett N Inhibition of vascular endothelial growth factor-induced angiogenesis suppresses tumor growth in vivo Nature 1993 362 6423 841 844 10.1038/362841a0 7683111 \nWillett CG Boucher Y Di Tomaso E Duda DG Munn LL Direct evidence that the VEGF-specific antibody bevacizumab has antivascular effects in human rectal cancer Nat Med 2004 10 2 145 147 10.1038/nm988 14745444 \nPresta LG Chen H O’Connor SJ Chisholm V Meng YG Humanization of an anti-vascular endothelial growth factor monoclonal antibody for the therapy of solid tumors and other disorders Cancer Res 1997 57 20 4593 4599 9377574 \nYanagisawa M Yorozu K Kurasawa M Nakano K Furugiki K Bevacizumab improves the delivery and efficacy of paclitaxel Anticancer Drugs 2010 21 7 687 694 20559127 \nMiller K Wang M Gralow J Dickler M Cobleigh M Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer N Engl J Med 2007 357 26 2666 2676 10.1056/NEJMoa072113 18160686 \nMiles DW Chan A Dirix LY Cortes J Pivot X Phase III study of bevacizumab plus docetaxel compared with placebo plus docetaxel for the first-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer J Clin Oncol 2010 28 20 3239 3247 10.1200/JCO.2008.21.6457 20498403 \nRobert NJ Dieras V Glaspy J Brufsky AM Bondarenko I RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab for first-line treatment of human epidermal growth factor receptor 2-negative, locally recurrent or metastatic breast cancer J Clin Oncol 2011 29 10 1252 1260 10.1200/JCO.2010.28.0982 21383283 \nDedes KJ Matter-Walstra K Schwenkglenks M Pestolozzi BC Fink D Bevacizumab in combination with paclitaxel for HER-2 negative metastatic breast cancer: An economic evaluation Eur J Cancer 2009 45 8 1397 1406 10.1016/j.ejca.2008.12.016 19147344\n\n",
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"abstract": "We report a case of a 41-year-old male who presented with tachycardia and swelling of his left arm six weeks after he started antituberculosis treatment and stopped his rheumatoid arthritis infliximab treatment. He was diagnosed with pulmonary embolism by chest CT and initially treated with warfarin, which interacted with his antituberculosis treatment. This presentation of deep vein thrombosis and pulmonary embolism as part of immune reconstitution inflammatory syndrome has not been previously reported for infliximab treated patients.",
"affiliations": "Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107, USA.;Attending, Pulmonary and Critical Care Section, Christiana Care Health System, 4745 Ogletown-Stanton Road, Map 1, Suite 220, Newark, DE 19713, USA.",
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"fulltext": "\n==== Front\nCase Rep PulmonolCase Rep PulmonolCRIPUCase Reports in Pulmonology2090-68462090-6854Hindawi Publishing Corporation 10.1155/2014/479025Case ReportPulmonary Embolism following Cessation of Infliximab for Treatment of Miliary Tuberculosis http://orcid.org/0000-0001-8515-345XLee Brian \n1\nMoosavy Farid \n2\n\n*\n1Thomas Jefferson University, 1025 Walnut Street, Philadelphia, PA 19107, USA2Attending, Pulmonary and Critical Care Section, Christiana Care Health System, 4745 Ogletown-Stanton Road, Map 1, Suite 220, Newark, DE 19713, USA*Farid Moosavy: fmoosavy@christianacare.orgAcademic Editor: Hasan Bayram\n\n2014 29 10 2014 2014 47902523 6 2014 15 9 2014 18 9 2014 Copyright © 2014 B. Lee and F. Moosavy.2014This 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.We report a case of a 41-year-old male who presented with tachycardia and swelling of his left arm six weeks after he started antituberculosis treatment and stopped his rheumatoid arthritis infliximab treatment. He was diagnosed with pulmonary embolism by chest CT and initially treated with warfarin, which interacted with his antituberculosis treatment. This presentation of deep vein thrombosis and pulmonary embolism as part of immune reconstitution inflammatory syndrome has not been previously reported for infliximab treated patients.\n==== Body\n1. Introduction\nBiologic agents are increasingly used as disease-modifying antirheumatic drugs (DMARDS) because of their ability to slow down progression of the disease. However, their use can lead to increased susceptibility to tuberculosis. Tuberculosis treatment, in turn, typically involves elimination of immunosuppression by these biologic agents. Rapid changes in the immune system can lead to a heightened and generalized inflammatory response, usually referred to as immune reconstitution inflammatory syndrome.\n\n2. Case Presentation\nA 41-year-old male, a recent immigrant, presented to the emergency room with swelling and pain in his neck and left arm. He had a history of rheumatoid arthritis and started treatment with infliximab, methotrexate, and high dose prednisone one year prior to admission. Six weeks prior to admission, he developed night sweats and weight loss, which was diagnosed as miliary tuberculosis by CT imaging and positive sputum culture. His tuberculosis was treated with rifampin, pyrazinamide, isoniazid, and ethambutol. His anti-TNF and steroid therapy were discontinued and replaced with hydroxychloroquine and sulfasalazine. The day before his admission, the patient noticed swelling and pain in his left neck and mild dyspnea. The swelling progressed down his entire arm over the course of the day. The patient was a lifelong nonsmoker and had no prior history of deep vein thrombosis (DVT).\n\nOn physical examination, he had a BMI of 24 and was afebrile but tachycardic to 130. He had cervical and supraclavicular lymphadenopathy. His entire left arm was erythematous, swollen, and tender to palpation. Range of motion of that extremity was reduced secondary to pain.\n\nCT of neck revealed a thrombus within the left axillary and left subclavian veins extending to the proximal left brachiocephalic vein, in addition to enlarged right and left supraclavicular lymph nodes, without obvious vascular compression (Figure 1). CT angiography of chest showed pulmonary emboli involving the right lower lobe in addition to previously noted nodular opacities of miliary tuberculosis (Figure 2).\n\nHis hemogram was significant for normocytic anemia and neutrophilia. Electrolytes, renal and liver function tests, hepatitis panels, and blood cultures were normal and his acid-fast smear was now negative. His coagulation profile was normal except for an elevated D-dimer of greater than 1000 ng/mL. An extensive work-up for thrombophilia was unremarkable with normal lupus anticoagulant, silicone-clotting test, Factor V Leiden, prothrombin 20210, Cardiolipin IgG, IgM 5, and beta-2 glycoprotein.\n\nThe patient was treated with enoxaparin and his swelling and dyspnea subsided. A warfarin regimen was attempted at 5 mg, but his INR remained 1.2. The patient was subsequently discharged being on rivaroxaban, prednisone 20 mg, and trimethoprim-sulfonamide prophylaxis, in addition to his antituberculosis regimen.\n\n3. Discussion\nIt is well known that disease-modifying antirheumatics, such as infliximab, significantly increase the risk of tuberculosis [1]. Patients receiving interferon and adalimumab are more at risk compared to those receiving etanercept [2]. Recent reports indicate cumulative incidence rates as high as 499/100,000 in rheumatoid arthritis and 287/100,000 in inflammatory bowel disease [3].\n\nThus, both active and latent tuberculosis are contraindications to the use of anti-TNF-alpha drugs, and candidates for infliximab therapy are screened with a tuberculin skin test, which, for this group, is positive if it is greater than 6 mm [4]. However, these patients are often on anti-inflammatory medication such as steroids and thus are more likely to have negative tuberculin skin tests [5].\n\nImmune reconstitution inflammatory syndrome (IRIS) has been well described in HIV-positive patients upon initiation of antiretroviral therapy [6]. IRIS has also been reported in patients on infliximab who develop tuberculosis [7, 8]. There is a five-to-sixteen-week period between cessation of infliximab treatment and onset of symptoms, such as progression of lymph node swelling, infiltrates, or pleural effusion [9].\n\nTo our knowledge, however, the development of pulmonary thromboembolic disease has never been described in the setting of IRIS specifically occurring as a consequence of discontinuation of anti-TNF therapy. We speculate that this complication was the result of concurrent biomechanical and biochemical factors as delineated below.\n\nVirchow's triad has been used to explain the association of lower extremity DVT with TB in multiple reports [10]. In our case, lymph node enlargement could have mechanically contributed to this unusual case of upper extremity DVT, presumably with impeding the flow in the adjacent veins at least in certain positions. Cervical lymphadenopathy is the most common lymphadenopathy in TB [11], but any lymphatic chain, including the supraclavicular lymph nodes, can easily be involved in the setting of generalized inflammatory resurgence as part of immune reconstitution as in this case.\n\nBoth RA and TB could have presumably contributed to a hypercoagulable state in this patient. Early in tuberculosis, procoagulants such as fibrin degradation products (FDP) and tissue plasminogen activator (t-PA) are increased [12]. Although their levels normalize over the course of 12 weeks of treatment, they can still be susceptible to DVT [12]. In a review of autopsies in 1948, Zahn and Peirce found that 1.5% of tuberculosis subjects had DVT and less than 0.1% had pulmonary embolism as the cause of death [13]. In a 2013 review of 30 subjects who had DVT after receiving antituberculosis therapy, Kouismi et al. documented 5 cases of pulmonary tuberculosis that resulted in pulmonary embolism [10]. While pulmonary embolism is a rare complication of tuberculosis, rheumatoid arthritis is also an autoinflammatory disorder associated with endothelial dysfunction through the rise in immune mediators and cytokines and can have similar thromboembolic complications [14].\n\nOverall, in our patient, the reduction in RA treatment and initiation of antituberculous treatment could have conceivably created an immune reconstitution inflammatory syndrome leading to a procoagulant milieu. To our knowledge, this is the first report of a pulmonary thromboembolic manifestation of immune reconstitution inflammatory syndrome as a result of withdrawal of infliximab treatment following miliary tuberculosis.\n\nConflict of Interests\nThe authors declare that there is no conflict of interests regarding the publication of this paper.\n\nFigure 1 CT angiography showing (a) thrombus (arrow) in the left subclavian vein extending into the proximal innominate. Bilateral necrotic supraclavicular lymphadenopathy (star) does not show compression of the subclavian vein in the (b) axial and (c) coronal views.\n\nFigure 2 CT angiography demonstrating lobar and segmental pulmonary emboli (arrow) in the right lower lobe.\n==== Refs\n1 Keane J. Gershon S. Wise R. P. Mirabile-Levens E. Kasznica J. Schwieterman W. D. Siegel J. N. Braun M. M. Tuberculosis associated with infliximab, a tumor necrosis factor α -neutralizing agent The New England Journal of Medicine 2001 345 15 1098 1104 10.1056/NEJMoa011110 2-s2.0-0035846326 11596589 \n2 Dixon W. G. Hyrich K. L. Watson K. D. Lunt M. Galloway J. Ustianowski A. Symmons D. P. M. Drug-specific risk of tuberculosis in patients with rheumatoid arthritis treated with anti-TNF therapy: results from the British Society for Rheumatology Biologics Register (BSRBR) Annals of the Rheumatic Diseases 2010 69 3 522 528 2-s2.0-77949477575 10.1136/ard.2009.118935 19854715 \n3 Cheng J. Cao Q. P-030 infliximab and tuberculosis infection: a meta-analysis Inflammatory Bowel Diseases 2013 19, supplement 1 S37 10.1097/01.MIB.0000438671.06875.b7 \n4 Saag K. G. Gim G. T. Patkar N. M. Anuntiyo J. Finney C. Curtis J. R. Paulus H. E. Mudano A. Pisu M. Elkins-Melton M. Outman R. Allison J. J. Almazor M. S. Bridges S. L. Jr. Chatham W. W. Hochberg M. Maclean C. Mikuls T. Moreland L. W. O'Dell J. Turkiewicz A. M. Furst D. E. American College of Rheumatology 2008 recommendations for the use of nonbiologic and biologic disease-modifying antirheumatic drugs in rheumatoid arthritis Arthritis Care and Research 2008 59 6 762 784 10.1002/art.23721 2-s2.0-45349090538 18512708 \n5 Agarwal S. Das S. K. Agarwal G. G. Srivastava R. Steroids decrease prevalence of positive tuberculin skin test in rheumatoid arthritis: implications on anti-TNF therapies Interdisciplinary Perspectives on Infectious Diseases 2014 2014 5 430134 10.1155/2014/430134 2-s2.0-84897859329 \n6 Sun H.-Y. Singh N. Immune reconstitution inflammatory syndrome in non-HIV immunocompromised patients Current Opinion in Infectious Diseases 2009 22 4 394 402 10.1097/QCO.0b013e32832d7aff 2-s2.0-67651154542 19483618 \n7 Arend S. M. Leyten E. M. S. Franken W. P. J. Huisman E. M. van Dissel J. T. A patient with de novo tuberculosis during anti-tumor necrosis factor-α therapy illustrating diagnostic pitfalls and paradoxical response to treatment Clinical Infectious Diseases 2007 45 11 1470 1475 10.1086/522993 2-s2.0-38449091454 17990230 \n8 Salvana E. M. T. Cooper G. S. Salata R. A. Mycobacterium other than tuberculosis (MOTT) infection: an emerging disease in infliximab-treated patients Journal of Infection 2007 55 6 484 487 10.1016/j.jinf.2007.08.007 2-s2.0-36049039854 17920687 \n9 Vidal C. G. Fernández S. R. Lacasa J. M. Paradoxical response to antituberculous therapy in infliximab-treated patients with disseminated tuberculosis Clinical Infectious Diseases 2005 40 5 756 759 10.1086/427941 2-s2.0-15044361763 15714425 \n10 Kouismi H. Laine M. Bourkadi J.-E. Iraqi G. Association of deep venous thrombosis with pulmonary tuberculosis Egyptian Journal of Chest Diseases and Tuberculosis 2013 62 3 541 543 10.1016/j.ejcdt.2013.06.001 \n11 Jha B. C. Dass A. Nagarkar N. M. Gupta R. Singhal S. Cervical tuberculous lymphadenopathy: changing clinical pattern and concepts in management Postgraduate Medical Journal 2001 77 905 185 187 10.1136/pmj.77.905.185 2-s2.0-0035097497 11222827 \n12 Robson S. C. White N. W. Aronson I. Woollgar R. Goodman H. Jacobs P. Acute-phase response and the hypercoagulable state in pulmonary tuberculosis British Journal of Haematology 1996 93 4 943 949 10.1046/j.1365-2141.1996.d01-1722.x 2-s2.0-0029971158 8703831 \n13 Zahn D. W. Peirce C. T. Venous thrombosis and pulmonary embolism in tuberculosis The American Journal of Medicine 1948 5 5 716 728 10.1016/0002-9343(48)90149-1 2-s2.0-49749208645 18890242 \n14 Chung W.-S. Peng C.-L. Lin C.-L. Rheumatoid arthritis increases the risk of deep vein thrombosis and pulmonary thromboembolism: a nationwide cohort study Annals of the Rheumatic Diseases 2014 73 1774 1780 10.1136/annrheumdis-2013-203380 23926057\n\n",
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] |
{
"abstract": "Lung-volume reduction using coils is an effective and safe treatment for selected patients presenting severe emphysema and hyperinflation. Most complications occur during the first 30 days after the procedure. Although frequent, hemoptysis is usually transient and minor. Antiaggregation therapy is common in patients with emphysema who, very often, have additional tobacco-associated comorbidities. Aspirin is considered safe for most major interventions; however, clopidogrel is mainly contraindicated and considered an exclusion criterion. We present a case of life-threatening hemoptysis caused by dual antiaggregation therapy \"accidentally\" introduced 3 months after the procedure. So far no recommendations exist on the optimal therapeutic strategy after lung-volume reduction with coils.",
"affiliations": "Respiratory Medicine Department, Regional Hospital of Lugano, Lugano, Switzerland.;Medicine Department, Regional Hospital of Lugano, Lugano, Switzerland.;Respiratory Medicine Department, University Hospital of Lausanne, Lausanne, Switzerland.;Haematology Department, University Hospital of Lausanne, Lausanne, Switzerland.;Thoracic Surgery Department, University Hospital of Lausanne, Lausanne, Switzerland.;Thoracic Surgery Department, University Hospital of Lausanne, Lausanne, Switzerland.;Respiratory Medicine Department, Regional Hospital of Lugano, Lugano, Switzerland; Medicine Department, Regional Hospital of Lugano, Lugano, Switzerland.;Respiratory Medicine Department, University Hospital of Lausanne, Lausanne, Switzerland.;Respiratory Medicine Department, University Hospital of Lausanne, Lausanne, Switzerland. Electronic address: alban.lovis@chuv.ch.",
"authors": "Valenti|Antonio|A|;Casutt|Alessio|A|;Koutsokera|Angela|A|;Noetzli|Jasmine|J|;Perentes|Jean Yannis|JY|;Krueger|Thorsten|T|;Pons|Marco|M|;Nicod|Laurent P|LP|;Lovis|Alban|A|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D013988:Ticlopidine; D001241:Aspirin",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4975",
"issue": "101(2)",
"journal": "The Annals of thoracic surgery",
"keywords": null,
"medline_ta": "Ann Thorac Surg",
"mesh_terms": "D001241:Aspirin; D000077144:Clopidogrel; D006469:Hemoptysis; D006801:Humans; D008297:Male; D008875:Middle Aged; D010975:Platelet Aggregation Inhibitors; D011013:Pneumonectomy; D011183:Postoperative Complications; D011656:Pulmonary Emphysema; D012720:Severity of Illness Index; D013988:Ticlopidine; D013997:Time Factors",
"nlm_unique_id": "15030100R",
"other_id": null,
"pages": "e49-50",
"pmc": null,
"pmid": "26777971",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Late Major Hemoptysis After Lung Volume Reduction With Coils Induced by Dual Antiaggregation Therapy.",
"title_normalized": "late major hemoptysis after lung volume reduction with coils induced by dual antiaggregation therapy"
} | [
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"abstract": "BACKGROUND\nFilamentous fungi are ubiquitous in plants, water, and soil. The predominant fungi that infect the human cornea include Fusarium and Aspergillus species. The onset of fungal endophthalmitis is indolent, and typically takes weeks to months to develop after corneal infection. We report a case of Fusarium infection complicating rheumatic keratitis that acutely progressed to endophthalmitis during intravenous tocilizumab therapy.\n\n\nMETHODS\nA 65-year-old female patient was referred to our department due to pain and decreased vision in her left eye. Slit-lamp examination showed a white focus on the upper peripheral cornea, hypopyon, anterior chamber fibrin formation, marked ciliary hyperemia, and whole corneal epithelial defects. As the corneal scraping smear was positive for filamentous fungi and Fusarium species were detected by aqueous humor polymerase chain reaction, anti-fungal therapy was started. Although the initial response to anti-fungal therapy was good, we observed corneal infiltration, worsening hypopyon, and vitreous opacity after tocilizumab infusion. Given that the infection continued to progress despite conservative therapy, we performed penetrating keratoplasty combined with vitrectomy. After removal of the white focus beneath the intraocular lens, a temporary corneal prosthesis was mounted and the dense vitreous opacity was removed. Finally, a frozen donor graft was sutured in place. The corneal infiltration, hypopyon, and vitreous opacity all disappeared after the operation.\n\n\nCONCLUSIONS\nThe rapid progression of Fusarium keratitis to endophthalmitis in a patient who was receiving a regular infusion of tocilizumab demonstrates that ocular condition should be closely monitored during systemic tocilizumab administration due to increased risk of infection.",
"affiliations": "Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan. soma@ophthal.med.osaka-u.ac.jp.;Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.;Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.",
"authors": "Mitsuoka|Yusuke|Y|;Soma|Takeshi|T|http://orcid.org/0000-0002-0985-530X;Maruyama|Kazuichi|K|;Nishida|Kohji|K|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D000935:Antifungal Agents; C502936:tocilizumab",
"country": "England",
"delete": false,
"doi": "10.1186/s12886-021-01981-9",
"fulltext": "\n==== Front\nBMC Ophthalmol\nBMC Ophthalmol\nBMC Ophthalmology\n1471-2415\nBioMed Central London\n\n1981\n10.1186/s12886-021-01981-9\nCase Report\nFusarium infection complicating rheumatic keratitis that acutely progressed to endophthalmitis during regular infusion of tocilizumab: a case report\nMitsuoka Yusuke 1\nhttp://orcid.org/0000-0002-0985-530X\nSoma Takeshi soma@ophthal.med.osaka-u.ac.jp\n\n1\nMaruyama Kazuichi 12\nNishida Kohji 1\n1 grid.136593.b 0000 0004 0373 3971 Department of Ophthalmology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan\n2 grid.136593.b 0000 0004 0373 3971 Department of Vision Informatics, Osaka University Graduate School of Medicine, Suita, Osaka, Japan\n19 5 2021\n19 5 2021\n2021\n21 2244 9 2020\n6 5 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis 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/. 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 in a credit line to the data.\nBackground\n\nFilamentous fungi are ubiquitous in plants, water, and soil. The predominant fungi that infect the human cornea include Fusarium and Aspergillus species. The onset of fungal endophthalmitis is indolent, and typically takes weeks to months to develop after corneal infection. We report a case of Fusarium infection complicating rheumatic keratitis that acutely progressed to endophthalmitis during intravenous tocilizumab therapy.\n\nCase presentation\n\nA 65-year-old female patient was referred to our department due to pain and decreased vision in her left eye. Slit-lamp examination showed a white focus on the upper peripheral cornea, hypopyon, anterior chamber fibrin formation, marked ciliary hyperemia, and whole corneal epithelial defects. As the corneal scraping smear was positive for filamentous fungi and Fusarium species were detected by aqueous humor polymerase chain reaction, anti-fungal therapy was started. Although the initial response to anti-fungal therapy was good, we observed corneal infiltration, worsening hypopyon, and vitreous opacity after tocilizumab infusion. Given that the infection continued to progress despite conservative therapy, we performed penetrating keratoplasty combined with vitrectomy. After removal of the white focus beneath the intraocular lens, a temporary corneal prosthesis was mounted and the dense vitreous opacity was removed. Finally, a frozen donor graft was sutured in place. The corneal infiltration, hypopyon, and vitreous opacity all disappeared after the operation.\n\nConclusion\n\nThe rapid progression of Fusarium keratitis to endophthalmitis in a patient who was receiving a regular infusion of tocilizumab demonstrates that ocular condition should be closely monitored during systemic tocilizumab administration due to increased risk of infection.\n\nKeywords\n\nFusarium keratitis\nEndophthalmitis\nTocilizumab\nElectroretinogram\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nFilamentous fungi are ubiquitous; they are present in plants, water, and soil. Fusarium species and Aspergillus species are the main fungi that infect the human cornea. The major route of infection is corneal trauma, and the most frequent cause of traumatic fungal endophthalmitis is filamentous fungal infection [1]. Contact lens wear, corneal transplantation, and steroid use have also been reported as causes of infection [2].\n\nThe clinical features of a typical filamentous fungal keratitis include a grayish-white ulcer accompanied by peripheral feathery corneal infiltrate, endothelial plaque formation, and hypopyon. Resistance to antifungal agents is frequently encountered and surgical treatment, including corneal transplantation, is sometimes required [3].\n\nSevere fungal keratitis can lead to endophthalmitis [4, 5]. The onset of fungal endophthalmitis is typically indolent, and occurs weeks or months after corneal infection. We report a case of Fusarium infection complicating rheumatic keratitis that acutely progressed to endophthalmitis while the patient was receiving regular infusion of the anti-interleukin-6 (IL-6) receptor antibody tocilizumab to treat rheumatoid arthritis.\n\nCase presentation\n\nA 65-year-old female patient was referred to our department due to pain and decreased vision in her left eye. Her medical history included rheumatoid arthritis, for which she received monthly intravenous tocilizumab injections (8 mg/kg). There was no family history. She was followed by her previous doctor for secondary glaucoma and recurrent rheumatic keratitis. She had a prior history of bilateral cataract surgery.\n\nThe patient was aware of the pain in her left eye 10 days before admission. At this time, 0.1% betamethasone 4 times daily and 0.1% tacrolimus 2 times daily were continued for the treatment of rheumatic keratitis. Five days before the patient came to our department, slit-lamp examination at the previous clinic showed a white stromal infiltrate on the peripheral cornea at the 12 o’ clock position. Since exacerbation of rheumatic keratitis was suspected, oral prednisolone (10 mg) was started, dexamethasone was administered via subconjunctival injection, and 0.1% betamethasone administration was increased to 6 times daily.\n\nThree days before admission to our department, when the patient first experienced decreased vision, the stromal infiltrate in her left eye worsened and a hypopyon emerged. At this point, microbial keratitis was suspected, and hourly topical 0.5% moxifloxacin, hourly 0.3% tobramycin, and systemic ceftriaxone (2 g every 24 h) were prescribed, whereas oral prednisolone was withdrawn and 0.1% betamethasone administration was reduced to 3 times daily.\n\nOn initial examination in our department, her visual acuity in the left eye allowed her to count fingers at a distance of 0.3 ft. Slit-lamp examination showed a white focus on the upper peripheral cornea, hypopyon, anterior chamber fibrin formation, marked ciliary hyperemia, and whole epithelial defects in the left eye (Fig. 1a,b). Anterior segment optical coherence tomography (OCT; CASIA2, Tomey) also revealed hypopyon, anterior chamber fibrin formation, and keratic precipitates (Fig. 1c). As echography showed no evident vitreous opacity, we speculated that infection had not advanced to the posterior chamber at this point (Fig. 1d). The full-field electroretinogram (ERG) waveform had no amplitude reduction or latency delay, which suggested that retinal function was not impaired by the infection (Fig. 1e). She was emergently hospitalized for infectious keratitis, and anti-bacterial treatment was continued. Fig. 1 a Slit-lamp examination on the patient’s first visit. A white infiltrate on the upper cornea, hypopyon, anterior chamber fibrin formation, and ciliary hyperemia were observed. b A whole corneal epithelial defect was observed by fluorescein staining. c Anterior segment OCT with a CASIA2 showed a hypopyon, anterior chamber fibrin deposits, and keratic precipitates. d Echography showed no evident vitreous opacity. e The waveform of full-field ERG had no amplitude reduction or latency delay\n\nThe corneal scraping smear was positive for filamentous fungi and Fusarium species were detected by aqueous humor polymerase chain reaction (PCR). Antifungal susceptibility tests were performed and the MIC values were as follows: > 16 μg/ml for Micafungin, > 64 μg/ml for Flucytosine, > 64 μg/ml for Fluconazole, > 16 μg/ml for Miconazole, > 8 μg/ml for Itraconazole, 4 μg/ml for Voriconazole, and 2 μg/ml for amphotericin B. Thereafter, her treatment was shifted to anti-fungal therapy 2 days after hospitalization. The patient received topical 1% voriconazole hourly, 1% natamycin ointment 6 times daily, and intravenous liposomal amphotericin B injection (125 mg/day), whereas 0.1% betamethasone was replaced with 0.1% fluorometholone, and 0.1% tacrolimus was withdrawn. Adherence to topical medical therapy was checked by nursing staff by filling in the list of eyedrops.\n\nTwo days after the onset of anti-fungal therapy, anterior inflammation improved, as characterized by a smaller corneal infiltrate and improved ciliary hyperemia; in addition, anterior segment OCT demonstrated a smaller hypopyon and anterior chamber fibrin deposits (Fig. 2a,b). However, after the patient’s monthly intravenous tocilizumab injection was administered 7 days after hospitalization (anterior chamber irrigation was performed on the same day), signs of recurrent inflammation were observed. Ciliary hyperemia markedly worsened, and vitreous opacity emerged on echography the day after tocilizumab injection (Fig. 2c–e). Fig. 2 a The corneal infiltrate shrank and ciliary hyperemia improved 2 days after the onset of anti-fungal therapy. b Anterior segment OCT demonstrated decreased hypopyon and anterior chamber fibrin deposition. c and d The day after intravenous tocilizumab injection, aggravation of ciliary hyperemia was noted, although the hypopyon decreased due to anterior chamber irrigation. e Vitreous opacity emerged on echography 2 days after tocilizumab infusion. f and g Slit-lamp examination and anterior segment OCT 10 days after tocilizumab infusion. The range of corneal infiltration increased and the hypopyon worsened. h Hyperechogenic foci on B-scan ultrasonography also worsened. i Reduction of both a-wave and b-wave amplitude was confirmed on full-field ERG 9 days after tocilizumab administration\n\nAs the initial response to anti-fungal therapy was good, and the vitreous opacity appeared to be a transient effect of tocilizumab application, therapy was continued without modification. However, 17 days after hospitalization, the degree of corneal infiltration, hypopyon, and vitreous opacity worsened, which suggested progression to endophthalmitis (Fig. 2f–h). In addition, both the a-wave and b-wave amplitude of the full-field ERG diminished, which suggested malfunction of the retina caused by advancement of the infection to the posterior segment (Fig. 2i). Given that the infection worsened in spite of conservative therapy, we determined that surgical treatment was required. After obtaining informed consent from the patient, penetrating keratoplasty (PKP) combined with vitrectomy was performed 19 days after hospitalization.\n\nWe used an intraocular infusion solution containing 10 mg/500 ml voriconazole. The host cornea was punched out with a 7-mm trephine. When the intraocular lens (IOL) was removed together with the lens capsule, a white focus ranging from the pupillary area to the back of the temporal iris became evident (Fig. 3a). After mounting the temporary corneal prosthesis (DORC, Fig. 3b), we performed a 25-gauge 4-port vitrectomy using the Constellation Vitrectomy System. The white focus in the pupillary area was removed during the anterior vitrectomy. Fundus examination revealed dense white vitreous opacity which was removed during the core vitrectomy and shaving (Fig. 3c). However, the focus in the vitreous had not adhered to the retina. A small white focus and dot hemorrhages were sparsely distributed on the peripheral retina (Fig. 3d). After removing the vitreous opacity completely, we removed the temporary corneal prosthesis and sutured in a frozen donor graft (7.75 mm in diameter). Pathological examination of the removed cornea by PAS and Grocott staining revealed filamentous fungi in the stroma. Fig. 3 a A white focus at the rear of the IOL became evident after the IOL was removed together with the lens capsule. b A temporary corneal prosthesis was mounted. c Fundus examination revealed dense white vitreous opacity. d Dot hemorrhages and white foci (not pictured) were sparsely distributed on the peripheral retina\n\nThe hypopyon and corneal infiltration were completely absent 3 weeks after the operation (Fig. 4a). The vitreous opacity was nearly absent by echography, and the waveform of the full-field ERG normalized at the same time (Fig. 4b,c). Although mild vitreous opacity emerged 4 days after the monthly intravenous tocilizumab injection (3 weeks after the operation), it showed spontaneous remission (Fig. 4d). As signs of inflammation improved, the amphotericin B infusion was discontinued and topical voriconazole and natamycin were both reduced to 4 times daily 1 month after the operation. The patient was discharged 2 months after the operation. Fig. 4 a Hypopyon and corneal infiltration were both absent 3 weeks after the surgery. (b and c) Vitreous opacity was largely absent on B-scan ultrasonography, and the full-field ERG waveform acquired at the same time had no amplitude reduction or latency delay. d Although mild vitreous opacity was confirmed on ultrasonography 4 days after tocilizumab infusion, it spontaneously improved. e and f There were no signs of infection relapse in the slit-lamp examination, and no vitreous opacity on B-scan ultrasonography 4 months after the surgery\n\nWhen she came to our department 4 months after the operation, the visual acuity of her left eye was 20/100. We observed neither relapse of infection nor vitreous opacity on echography (Fig. 4e,f). Optical PKP and IOL suture were performed 1 year after the initial therapeutic PKP combined with vitrectomy. The patient continues to visit our office (July 2020), and is doing well. The visual acuity of her left eye at her most recent visit was 30/100.\n\nDiscussion and conclusions\n\nWe report a case of Fusarium infection complicating rheumatic keratitis in a patient receiving regular infusions of tocilizumab for rheumatoid arthritis; the infection took an atypical course and acutely progressed to endophthalmitis. To our knowledge, this is the first report of a case of Fusarium keratitis which acutely progressed to endophthalmitis during tocilizumab infusion.\n\nThe patient’s initial response to anti-fungal therapy was good; however, vitreous opacity rapidly emerged after the first tocilizumab infusion. Mild vitreous opacity also emerged after the second tocilizumab administration. Although we cannot draw any definitive conclusions, these observations suggest that tocilizumab may have been the aggravating factor for the fungal infection.\n\nAlthough progression of fungal keratitis is generally indolent, the inflammation in the present case progressed acutely. There are several case reports of Fusarium keratitis progressing to endophthalmitis, but few studies dealing with large populations. One study included 159 Fusarium keratitis patients [4], of whom 10 patients had infections that progressed to endophthalmitis. In those cases, hypopyon and endothelial plaques emerged 10 to 40 days after corneal infiltration. Compared with the previously published cases, the present case took an extremely acute course, as hypopyon emerged only two days after corneal infiltration appeared. Several factors—including epithelial defect due to rheumatoid arthritis-associated corneal ulceration, steroid administration, and susceptibility to infection arising from tocilizumab infusion—may explain these observations.\n\nOne might speculate that steroid discontinuation could be the cause of ocular inflammation worsening. However, ocular inflammation mainly aggravated five days before the admission to our department, when oral prednisolone was started and the administration frequency of topical steroids was increased. Moreover, it did not acutely aggravate after three days before the visit to our department, when oral prednisolone was withdrawn and the administration frequency of topical steroids was decreased. Additionally, ocular inflammation improved two days after the onset of anti-fungal therapy, when the topical steroid was changed to a milder type. These observations suggest that steroid withdrawal is at least not the main factor for ocular inflammation aggravation.\n\nThe present case was characterized by acute progression to ophthalmitis during tocilizumab administration. Tocilizumab is an anti-IL-6 receptor antibody used for the treatment of autoimmune diseases, including rheumatoid arthritis. It mediates anti-inflammatory effects by inhibiting the binding of IL-6 to its receptor. As it also has an immunosuppressive effect, complications associated with its use include pneumonia (including Pneumocystis pneumonia) and tuberculosis.\n\nFew studies have examined the relationship between fungal keratitis and IL-6. In a study which investigated the cytokine milieu in the tears of patients with fungal keratitis, higher levels of IL-6 were reported than in the tears of healthy individuals [6]. Application of inactivated Fusarium solani hyphae to cultured human corneal epithelial cells upregulated the secretion of IL-6 via activation of Toll-like receptors [7]. These studies indicate that IL-6 is upregulated in the anterior portion of the eye in response to fungal infection. However, IL-6 activity in this context is unknown. During infection with the bacterial pathogen Streptococcus aureus, application of IL-6 to the cornea of IL-6 knockout mice improved the symptoms of infection and reduced the number of bacteria to 1/3 the pre-treatment level [8]. Therefore, IL-6 may have anti-bacterial activity. IL-6 promotes elastase and free radical production by neutrophils, suggesting that it may inhibit bacterial infection via neutrophil activation. As neutrophils are the main cells that infiltrate the cornea in response to fungal infection, IL-6 inhibition by tocilizumab may aggravate inflammation through blockade of neutrophil activation.\n\nTo our knowledge, this is the first report of a case of fungal keratitis of which tocilizumab infusion was speculated to be an aggravating factor. There are some past studies describing tocilizumab as a risk factor for the onset and progression of systemic cryptococcosis and bacterial infection [9–11], so we speculate that progression of fungal keratitis is affected by tocilizumab infusion. However, the mechanisms of exacerbation and its incidence are not clear in the present case. Further study is needed to solve these problems.\n\nIn the present case, final visual acuity was relatively spared despite the acute course of the fungal infection. Past studies have indicated that Fusarium endophthalmitis developed from keratitis is associated with a poor prognosis, even after PKP. Therefore, early diagnosis and detection of endophthalmitis are needed, in combination with early surgical treatment to prevent the progression of endophthalmitis [4]. In the present case, culture of corneal scrapings and aqueous humor PCR were performed on the day of visit, which facilitated prompt diagnosis of Fusarium infection. PKP in combination with vitrectomy was performed at a relatively early stage, 10 days after vitreous opacity emerged on echography. We removed as much of the focus of infection as possible, using a temporary corneal prosthesis to improve visibility, before the infection progressed to the retina. In addition, intraocular drug migration was improved by vitreous removal. Our specific approach to treatment may be responsible for the recovery of the patient’s visual acuity.\n\nOne might say that a 10-day time-frame between Tocilizumab infusion and surgery is a considerable period of time for infection aggravation. We followed up this period by continuing conservative therapy, as the treatment seemed to be effective and fungal infection generally takes an indolent course. However, endophthalmitis worsened considerably at this relatively short period of time. The patient’s prognosis might have been better if the surgery had been performed as soon as possible, and this would be our future challenge.\n\nOur experience suggests that tocilizumab infusion may make patients more vulnerable to ocular infection. Therefore, patients should be closely monitored for signs of ocular inflammation during tocilizumab administration, especially as rapid detection and thorough treatment may contribute to the preservation or recovery of visual acuity.\n\nAbbreviations\n\nERG electroretinogram\n\nIL-6 interleukin 6\n\nIOL intraocular lens\n\nOCT optical coherence tomography\n\nPCR polymerase chain reaction\n\nPKP penetrating keratoplasty\n\nAcknowledgements\n\nNot applicable.\n\nAuthors’ contributions\n\nYM acquired the clinical information and drafted the manuscript. TS performed the surgery, acquired the clinical information, and reviewed the manuscript. KM performed the surgery. KN critically revised and corrected the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nThere are no sources of funding associated with this work.\n\nAvailability of data and materials\n\nAll data generated and analyzed during this study are included in this article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nThis study followed the tenets of the Declaration of Helsinki. Written informed consent was obtained from the participant.\n\nConsent for publication\n\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\n\nKM is a member of the editorial board of this journal.\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. Silva RA Sridhar J Miller D Wykoff CC Flynn HW Jr Exogenous fungal endophthalmitis: an analysis of isolates and susceptibilities to antifungal agents over a 20-year period (1990-2010) Am J Ophthalmol 2015 159 2 257 264 10.1016/j.ajo.2014.10.027 25449001\n2. Alfonso EC Cantu-Dibildox J Munir WM Miller D O’Brien TP Karp CL Insurgence of Fusarium keratitis associated with contact lens wear Arch Ophthalmol 2006 124 7 941 947 10.1001/archopht.124.7.ecs60039 16769827\n3. Klont RR Eggink CA Rijs AJMM Wesseling P, Verweij. Successful treatment of Fusarium keratitis with cornea transplantation and topical and systemic voriconazole Clin Infect Dis 2005 40 110 112 10.1086/430062\n4. Dursun D Fernandez V Miller D Alfonso EC Advanced fusarium keratitis progressing to endophthalmitis Cornea. 2003 22 4 300 303 10.1097/00003226-200305000-00004 12792470\n5. Rosenberg KD Flynn HW Jr Alfonso EC Miller D Fusarium endophthalmitis following keratitis associated with contact lenses Ophthalmic Surg Lasers Imaging 2006 37 4 310 313 10.3928/15428877-20060701-08 16898392\n6. Vasanthi M Prajna NV Lalitha P Mahadevan K Muthukkaruppan V A pilot study on the infiltrating cells and cytokine levels in the tear of fungal keratitis Indian J Ophthalmol 2007 55 1 27 31 10.4103/0301-4738.29491 17189883\n7. Jin X Qin Q Tu L Zhou X Lin Y Qu J Toll-like receptors (TLRs) expression and function in response to inactivate hyphae of Fusarium solani in immortalized human corneal epithelial cells Mol Vis 2007 13 1953 1961 17982419\n8. Hume EBH Cole N Garthwaite LL Khan S Willcox MDP A protective role for IL-6 in staphylococcal microbial keratitis Invest Ophthalmol Vis Sci 2006 47 11 4926 4930 10.1167/iovs.06-0340 17065508\n9. Nishioka H Takegawa H Kamei H Disseminated cryptococcosis in a patient taking tocilizumab for Castleman's disease J Infect Chemother 2018 24 2 138 141 10.1016/j.jiac.2017.09.009 29021093\n10. Nishimoto N Ito K Takagi N Safety and efficacy profiles of tocilizumab monotherapy in Japanese patients with rheumatoid arthritis: meta-analysis of six initial trials and five long-term extensions Mod Rheumatol 2010 20 3 222 232 10.3109/s10165-010-0279-5 20221663\n11. Koike T Harigai M Inokuma S Ishiguro N Ryu J Takeuchi T Takei S Tanaka Y Sano Y Yaguramaki H Yamanaka H Effectiveness and safety of tocilizumab: postmarketing surveillance of 7901 patients with rheumatoid arthritis in Japan J Rheumatol 2014 41 1 15 23 10.3899/jrheum.130466 24187110\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2415",
"issue": "21(1)",
"journal": "BMC ophthalmology",
"keywords": "Case report; Electroretinogram; Endophthalmitis; Fusarium keratitis; Tocilizumab",
"medline_ta": "BMC Ophthalmol",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000935:Antifungal Agents; D009877:Endophthalmitis; D015821:Eye Infections, Fungal; D005260:Female; D060585:Fusariosis; D006801:Humans; D007634:Keratitis",
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"references": "24187110;29021093;25449001;17065508;12792470;16898392;17982419;15909252;17189883;20221663;16769827",
"title": "Fusarium infection complicating rheumatic keratitis that acutely progressed to endophthalmitis during regular infusion of tocilizumab: a case report.",
"title_normalized": "fusarium infection complicating rheumatic keratitis that acutely progressed to endophthalmitis during regular infusion of tocilizumab a case report"
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"abstract": "Saprochaete capitata is a rare and emerging opportunistic fungus, involving immunocompromised hosts, in particular, neutropenic patients after chemotherapy. Case Report: We report a case of disseminated and cerebral infection by Saprochaete capitata, in a 68-year-old woman affected by acute myeloid leukemia that was successfully managed with liposomal amphotericin B and isavuconazole.\nThis case illustrates the feasibility of isavuconazole therapy in the treatment of a S. capitata infection when co-administered with midostaurin.",
"affiliations": "Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy.;Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy.;Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy.;Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy.;Department of Public Health and Infectious Diseases, Sapienza University, S.M. Goretti Hospital, Latina, Italy.;Hematology, Dipartimento Medicina Traslazionale e di Precisione, AOU Policlinico Umberto I, Sapienza University of Rome, Italy.;Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy.",
"authors": "Perrone|Salvatore|S|;Lisi|Chiara|C|;La Barbera|Elettra Ortu|EO|;Luise|Cristina|C|;Lichtner|Miriam|M|;Girmenia|Corrado|C|;Cimino|Giuseppe|G|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.4084/MJHID.2020.026",
"fulltext": "\n==== Front\nMediterr J Hematol Infect Dis\nMediterr J Hematol Infect Dis\nMediterranean Journal of Hematology and Infectious Diseases\nMediterranean Journal of Hematology and Infectious Diseases\n2035-3006 Università Cattolica del Sacro Cuore \n\n10.4084/MJHID.2020.026\nmjhid-12-1-e2020026\nCase Report\nIsavuconazole Therapy of Disseminated and Encephalic Saprochaete Capitata Infection in an Acute Myeloid Leukemia Patient Treated with Midostaurin\nPerrone Salvatore 1 Lisi Chiara 1 La Barbera Elettra Ortu 1 Luise Cristina 1 Lichtner Miriam 2 Girmenia Corrado 3 Cimino Giuseppe 14 \n1 Hematology, Polo Universitario Pontino, S.M. Goretti Hospital, Latina, Italy\n\n2 Department of Public Health and Infectious Diseases, Sapienza University, S.M. Goretti Hospital, Latina, Italy\n\n3 Hematology, Dipartimento Medicina Traslazionale e di Precisione, AOU Policlinico Umberto I, Sapienza University of Rome, Italy\n\n4 Department of Medical Oncology, Sapienza University of Rome, Medical and Surgical Sciences and Biotechnology, Rome, Italy\nCorrespondence to: Salvatore Perrone, M.D. Hematology, Polo Universitario Pontino, “Sapienza”. Via A. Canova S.M. Goretti Hospital, Latina, Italy. Tel: +3907736553126. E-mail: sperrone@hotmail.it\n2020 \n01 5 2020 \n12 1 e202002608 2 2020 05 4 2020 2020This is an Open Access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by-nc/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background\nSaprochaete capitata is a rare and emerging opportunistic fungus, involving immunocompromised hosts, in particular, neutropenic patients after chemotherapy. Case Report: We report a case of disseminated and cerebral infection by Saprochaete capitata, in a 68-year-old woman affected by acute myeloid leukemia that was successfully managed with liposomal amphotericin B and isavuconazole.\n\nConclusions\nThis case illustrates the feasibility of isavuconazole therapy in the treatment of a S. capitata infection when co-administered with midostaurin.\n\nSaprochaete capitataIsavuconazoleAcute myeloid leukemiaMidostaurinCNS\n==== Body\nIntroduction\nSaprochaete capitata (formerly known as Blastoschizomyces capitatus and Geotrichum capitatum) is a rare and emerging opportunistic fungus, involving immunocompromised hosts, in particular, neutropenic patients after chemotherapy, with crude mortality estimates as high as 60%.1,2 Herein we describe the first case, to our knowledge, of disseminated S. capitata infection successfully managed with isavuconazole.\n\nCase Report\nIn 2019, a 68-year-old woman presented with chest pain, dyspnoea, and gum pain lasting one week. Hyperleukocitosis (WBC 241×109/L) was sustained by monoblastic cells. Therefore, bone marrow aspiration was performed and confirmed an extensive infiltration (93% monocytic blasts) by acute myeloid leukemia (AML) with translocation t(9;11)(p21.3;q23.3) and Fms-related-tyrosine kinase 3 with a point mutation in the tyrosine kinase domain (FLT3-TKD) positivity. Therefore, she was treated with standard intensive chemotherapy ‘7+3’ (ARA-C 100mg/m2 ci. × 7 days and daunorubicin 60mg/m2 × 3) and midostaurin (50 mg bid, day 8 to 28), a recently approved FLT3 inhibitor metabolized to its active metabolites GGP6221 and CGP52421 via CYP3A4 in the liver.3,4 Due to the known interference of midostaurin with potent CYP3A4 inhibitors with the risk of side effects including QTc prolongation,5 as per protocol, we decided not to give the standard posaconazole antifungal prophylaxis, and we planned a preemptive antifungal approach with weekly serum galactomannan monitoring and precocious chest Computed Tomography (CT) in case of persisting neutropenic fever. On day +8, she developed neutropenic fever, and empirical anti-bacterial treatment with piperacillin/tazobactam and teicoplanin was started. After 48 hours, she was still febrile; therefore, she underwent a CT scan that revealed a 20 mm lung nodule, with halo-sign. Considering a possible invasive fungal infection (IFI) (serum galactomannan assay was negative), we started liposomal amphotericin B (3 mg/kg/day). Two days later, she was still febrile, and blood cultures showed S. capitata fungemia, galactomannan raised to 0.6 in two blood samples; therefore, liposomal amphotericin B dosage was increased to 5 mg/kg/day for 9 days, with defervescence within few days. Later, when neutropenia recovered, the CT-scan showed the evolution of the lung nodule into a cavitary lesion (Figure 1A), multiple liver abscesses (Figure 1B), and a single brain abscess in the left head of the caudate nucleus (Figure 1C–D). We then decided to discharge the patient and to shift antifungal treatment from intravenous liposomal amphotericin B to oral isavuconazole. We chose oral isavuconazole instead of oral voriconazole, which is a standard therapy of S. capitata infection6,7 because isavuconazole is a mild/moderate inhibitor while voriconazole is a potent inhibitor of CYP3A4.5 Isavuconazole was also chosen because of its in vitro activity against S.capitata8,9 and the favorable pharmacokinetic profile in the central nervous system (CNS) infections.10,11\n\nThe patient successfully underwent two courses of consolidation with high doses of cytarabine and midostaurin while under isavuconazole therapy without any midostaurin related toxicity (the patient was monitored biweekly for QTc prolongation on each ambulatory visit). During maintenance with midostaurin, we performed a therapeutic drug monitoring (TDM) of isavuconazole 5.2 μg/ml (normal range 2–5 μg/ml), no adjustment was undertaken. Eight months later, AML is in complete remission, and fungal infection is improving on isavuconazole (Figure 2), despite the prolonged neutropenia induced by the consolidation cycles.\n\nDiscussion\nThis case illustrates that isavuconazole may be an option in the treatment of S.capitata infections, and that may be a safe choice if a co-administration with midostaurin is required. A further case of safe isavuconazole and midostaurin therapy in an AML patient with a possible pulmonary fungal infection has been recently reported.12\n\nIndeed, our case raises the challenging question of the appropriateness of administering midostaurin concomitantly with a CYP3A4 inhibitor.\n\nPosaconazole and voriconazole are drugs of the first choice in the primary antifungal prophylaxis and therapy of invasive aspergillosis and other IFIs, respectively.13,14 However, in patients affected by FLT3 positive AML caution is requested when triazoles are administered concomitantly with midostaurin, given the possible toxicity related to the increased exposure to the FLT3 inhibitor, being posaconazole and voriconazole potent inhibitors of CYP3A4. Furthermore, an increased risk of QTc prolongation should be considered when patients receive midostaurin in association with other drugs that can prolong QTc, as the above triazoles.4,5\n\nThis limitation in the prevention and treatment of IFIs in FLT3 positive AML patients represents a challenging issue in the clinical practice, considering that IFIs significantly affect complete remission achievement and long-term survival of AML patients 15. Again, the protective effects of mold active antifungal prophylaxis during induction and salvage chemotherapy for AML may have long-lasting benefits that extend even after the allogeneic stem cell transplant procedure, which is indicated in FLT3 positive AML patients after the achievement of complete remission because of the high risk of leukemia relapse.16\n\nOn the other hand, the contraindication of the concomitant use of midostaurin and triazoles is controversial. Ouatas et al. analyzed data from the Ratify study focusing on the subset of patients with concomitant use of midostaurin and fluconazole, posaconazole, or voriconazole in prophylaxis.3,17 In that study, concomitant use of various CYP3A4 inhibitors and antifungals agents was permitted with caution but without any specific recommendation on how to perform dose adjustment. More than half of patients received posaconazole or voriconazole during induction, consolidation, or maintenance therapy. In those patients in which midostaurin plasma levels were measured, a 1.44-fold increase in midostaurin through levels was observed when the strong CYP3A4 inhibitors posaconazole or voriconazole were co-administered, and no increase of adverse events nor impact on efficacy outcomes were observed, therefore dose modification does not seem required.17 Isavuconazole is not in-label for IFI prophylaxis, but retrospective studies18,19 suggest it could be an interesting option to be investigated in settings similar to our case.\n\nInterestingly, few data exist about isavuconazole penetration in cerebral tissue, and experiences are mediated from mice models.20 In a patient with AML and cerebral aspergillosis, isavuconazole concentrations measured in the inflammatory brain tissue surrounding the abscess were similar to plasma, while the concentration in the liquid of the abscess was quasi-null.10 Two other patients with cerebral aspergillosis were treated with isavuconazole and required surgery for the progression of the infection. Bioptic samples showed increased drug concentration in the abscess and inflamed meninges compared to unaffected brain tissue.11 Differently from these cases, the outcome of our patient was favorable. Similarly, isavuconazole was also utilized with success to treat Rhino-Orbital-Cerebral Mucormycosis.23\n\nConclusions\nIn conclusion, our case illustrates the feasibility of isavuconazole therapy in the treatment of a S. capitata infection when co-administered with midostaurin. Considering that the warning about the risk of severe side effects of midostaurin treatment when administered concomitantly with potent CYP3A4 inhibitors, even if not confirmed, it can be speculated that the use of a mild/moderate CYP3A4 inhibitor, as isavuconazole, could be a safer choice particularly in an outpatient setting, when the strict monitoring of adverse events is less feasible. We think it could have clinical implications when treating patients with a rare yeast infection. However, prospective data in this setting would be helpful in the next future, also considering the emergence of S. capitata in central Europe.21,22\n\nCompeting interests: The authors declare no conflict of Interest.\n\nFigure 1 A) CT scan. In the left lung is present a 20 mm excavation filled with fluid: air-crescent sign. B) CT scan of the abdomen. Two hypodensae cystic hepatic lesions of 2 and 1.5 cm; other millimetric lesions can be seen (white arrows). C) Brain MRI: T2 weighted sequence. An 11 mm cystic lesion is present in the left head of the caudate nucleus, with compression of the left lateral ventricle. Mild peri-lesional edema is present. D) Brain MRI: T1 weighted gadolinium contrast-enhanced sequences. The same cystic lesion showing a concentric rim of contrast.\n\nFigure 2 CT scan after 8 months from S. capitata infection. A) In the left lung is present a 7 mm excavation scar (white arrow). B) CT scan of the abdomen. Shrunken hypodensae cystic hepatic lesion of 11 mm. C) Brain CT: A 9 mm cystic lesion surrounded by concentric rim is present in the left head of the caudate nucleus.\n==== Refs\nReferences\n1 Girmenia C Pagano L Martino B D’Antonio D Fanci R Specchia G Invasive infections caused by Trichosporon species and Geotrichum capitatum in patients with hematological malignancies: a retrospective multicenter study from Italy and review of the literature J Clin Microbiol 2005 43 4 1818 28 10.1128/JCM.43.4.1818-1828.2005 15815003 \n2 Mazzocato S Marchionni E Fothergill AW Sutton DA Staffolani S Gesuita R Epidemiology and outcome of systemic infections due to saprochaete capitata: case report and review of the literature Infection 2015 43 2 211 5 10.1007/s15010-014-0668-3 25078793 \n3 Stone RM Mandrekar SJ Sanford BL Laumann K Geyer S Bloomfield CD Midostaurin plus Chemotherapy for Acute Myeloid Leukemia with a FLT3 Mutation N Engl J Med 2017 377 5 454 464 10.1056/NEJMoa1614359 28644114 \n4 Abbas HA Alfayez M Kadia T Ravandi-Kashani F Daver N Midostaurin In Acute Myeloid Leukemia: An Evidence-Based Review And Patient Selection Cancer Manag Res 2019 11 8817 8828 10.2147/CMAR.S177894 31632141 \n5 Lindsay J Teh BW Micklethwaite K Slavin M Azole antifungals and new targeted therapies for hematological malignancy Curr Opin Infect Dis 2019 32 6 538 545 10.1097/QCO.0000000000000611 31688198 \n6 Girmenia C Pizzarelli G D’Antonio D Cristini F Martino P In vitro susceptibility testing of Geotrichum capitatum: comparison of the E-test, disk diffusion, and Sensititre colorimetric methods with the NCCLS M27-A2 broth microdilution reference method Antimicrob Agents Chemother 2003 47 12 3985 8 10.1128/AAC.47.12.3985-3988.2003 14638517 \n7 Cornely OA Cuenca-Estrella M Meis JF Ullmann AJ European Society of Clinical Microbiology and Infectious Diseases (ESCMID) Fungal Infection Study Group (EFISG) and European Confederation of Medical Mycology (ECMM) 2013 joint guidelines on diagnosis and management of rare and emerging fungal diseases Clin Microbiol Infect 2014 20 Suppl 3 1 4 10.1111/1469-0691.12569 24606200 \n8 Guinea J Recio S Escribano P Pelaez T Gama B Bouza E In vitro antifungal activities of isavuconazole and comparators against rare yeast pathogens Antimicrob Agents Chemother 2010 54 9 4012 5 10.1128/AAC.00685-10 20566770 \n9 Thompson GR 3rd Wiederhold NP Sutton DA Fothergill A Patterson TF In vitro activity of isavuconazole against Trichosporon, Rhodotorula, Geotrichum, Saccharomyces and Pichia species J Antimicrob Chemother 2009 64 1 79 83 10.1093/jac/dkp138 19406849 \n10 Lamoth F Mercier T Andre P Pagani JL Pantet O Maduri R Isavuconazole brain penetration in cerebral aspergillosis J Antimicrob Chemother 2019 74 6 1751 1753 10.1093/jac/dkz050 30753519 \n11 Rouzaud C Jullien V Herbrecht A Palmier B Lapusan S Morgand M Isavuconazole Diffusion in Infected Human Brain Antimicrob Agents Chemother 2019 63 10 10.1128/AAC.02474-18 31405852 \n12 Tollkuci E Isavuconazole therapy in an FLT3 mutated acute myeloid leukemia patient receiving midostaurin: A case report J Oncol Pharm Pract 2019 25 4 987 989 10.1177/1078155218764257 29558838 \n13 Maertens JA Girmenia C Bruggemann RJ Duarte RF Kibbler CC Ljungman P European guidelines for primary antifungal prophylaxis in adult haematology patients: summary of the updated recommendations from the European Conference on Infections in Leukaemia J Antimicrob Chemother 2018 73 12 3221 3230 10.1093/jac/dky286 30085172 \n14 Tissot F Agrawal S Pagano L Petrikkos G Groll AH Skiada A ECIL-6 guidelines for the treatment of invasive candidiasis, aspergillosis and mucormycosis in leukemia and hematopoietic stem cell transplant patients Haematologica 2017 102 3 433 444 10.3324/haematol.2016.152900 28011902 \n15 Girmenia C Micozzi A Piciocchi A Gentile G Di Caprio L Nasso D Invasive fungal diseases during first induction chemotherapy affect complete remission achievement and long-term survival of patients with acute myeloid leukemia Leuk Res 2014 38 4 469 74 10.1016/j.leukres.2014.01.007 24534569 \n16 Busca A Candoni A Audisio E Passera R Bruno B Monaco F Long-Lasting Protective Effect of Posaconazole Prophylaxis in Patients with Acute Myeloid Leukemia Receiving Allogeneic Hematopoietic Stem Cell Transplantation Biol Blood Marrow Transplant 2016 22 12 2214 2219 10.1016/j.bbmt.2016.09.019 27667012 \n17 Ouatas T Duval V Sinclair K Berkowitz N Concomitant use of midostaurin with strong CYP3A4 inhibitors: an analysis from the ratify trial Blood 2017 130 Supplement 1 3814 3814 \n18 Fontana L Perlin DS Zhao Y Noble BN Lewis JS Strasfeld L Isavuconazole Prophylaxis in Patients With Hematologic Malignancies and Hematopoietic Cell Transplant Recipients Clin Infect Dis 2020 70 5 723 730 10.1093/cid/ciz282 30958538 \n19 Bowen CD Tallman GB Hakki M Lewis JS Isavuconazole to prevent invasive fungal infection in immunocompromised adults: Initial experience at an academic medical centre Mycoses 2019 62 8 665 672 10.1111/myc.12924 31050373 \n20 Wiederhold NP Kovanda L Najvar LK Bocanegra R Olivo M Kirkpatrick WR Isavuconazole Is Effective for the Treatment of Experimental Cryptococcal Meningitis Antimicrob Agents Chemother 2016 60 9 5600 3 10.1128/AAC.00229-16 27324761 \n21 Tanuskova D Horakova J Svec P Bodova I Lengerova M Bezdicek M First case of invasive Magnusiomyces capitatus infection in Slovakia Med Mycol Case Rep 2017 16 12 15 10.1016/j.mmcr.2017.03.004 28409093 \n22 Birrenbach T Bertschy S Aebersold F Mueller NJ Achermann Y Muehlethaler K Emergence of Blastoschizomyces capitatus yeast infections, Central Europe Emerg Infect Dis 2012 18 1 98 101 10.3201/eid1801.111192 22261201 \n23 Andreani G Fadda GL Gned D Dragani M Cavallo G Monticone V Morotti A De Gobbi M Guerrasio A Barbui AM D’Avolio A Cilloni D Rhino-orbital-cerebral mucormycosis after allogeneic hematopoietic stem cell transplantation and isavuconazole therapeutic drug monitoring during intestinal graft versus host disease Mediterr J Hematol Infect Dis 2019 11 1 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"keywords": "Acute myeloid leukemia; CNS; Isavuconazole; Midostaurin; Saprochaete capitata",
"medline_ta": "Mediterr J Hematol Infect Dis",
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"title": "Isavuconazole Therapy of Disseminated and Encephalic Saprochaete Capitata Infection in an Acute Myeloid Leukemia Patient Treated with Midostaurin.",
"title_normalized": "isavuconazole therapy of disseminated and encephalic saprochaete capitata infection in an acute myeloid leukemia patient treated with midostaurin"
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"abstract": "BACKGROUND\nPost-transplant lymphoproliferative disease is a serious complication of renal transplantation. Major risk factors include Epstein-Barr virus (EBV) seronegativity and induction immunosuppression with lymphocyte-depleting agents.\n\n\nRESULTS\nWe present a case of a 50-year year-old woman with very early onset PTLD confined to the donor ureter. Phenotypic studies on the tumor material reveal that the lymphoma was most likely of donor origin. A complete staging workup including the kidney allograft was negative for any other sites of involvement.\n\n\nCONCLUSIONS\nThis case, which had a fatal outcome, emphasizes the risk of renal transplantation in BV-negative individuals when given induction with lymphocyte-depleting drugs.",
"affiliations": "Legacy Transplant Services, Legacy Good Samaritan Medical Center, Portland, Oregon, United States. Electronic address: bennettw@lhs.org.;Legacy Transplant Services, Legacy Good Samaritan Medical Center, Portland, Oregon, United States.;Legacy Transplant Services, Legacy Good Samaritan Medical Center, Portland, Oregon, United States.;Legacy Transplant Services, Legacy Good Samaritan Medical Center, Portland, Oregon, United States.;Legacy Pathology Services, Legacy Good Samaritan Medical Center, Portland, Oregon, United States.;Laboratory of Immunogenetics and Transplantation, Oregon Health & Science University, Portland, Oregon, United States.;Compass Oncology, Portland, Oregon, United States.",
"authors": "Bennett|W M|WM|;Batiuk|T D|TD|;McEvoy|K M|KM|;Douzdjian|V|V|;Hyde|J|J|;Shaut|C|C|;Segal|G M|GM|",
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"issn_linking": "0041-1345",
"issue": "47(7)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D005260:Female; D006801:Humans; D016030:Kidney Transplantation; D008232:Lymphoproliferative Disorders; D008875:Middle Aged; D013997:Time Factors; D014019:Tissue Donors; D014513:Ureter; D014515:Ureteral Diseases",
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"pubdate": "2015-09",
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"title": "Early Post-transplant Lymphoproliferative Disease in the Donor Ureter Without Systemic Involvement: A Case Report.",
"title_normalized": "early post transplant lymphoproliferative disease in the donor ureter without systemic involvement a case report"
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{
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{
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}
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{
"abstract": "Background: Autologous stem cell transplantation is considered a standard of care treatment in eligible patients with multiple myeloma, but puts the patient at high risk for infections and bleeding complications. Acquired von-Willebrand's disease (AVWD) and acquired platelet dysfunction are rare bleeding disorders that are associated with lymphoproliferative disorders such as multiple myeloma. Patients with acquired bleeding disorders who are planned for ASCT to treat the underlying condition are considered at highest risk for bleeding complications, and optimal treatment strategies are not known. Materials and Methods: We summarized the diagnostic and therapeutic approach to a patient affected by AVWD and acquired platelet disorder related to multiple myeloma. The patient who was planned for ASCT presented with moderate to severe bleeding symptoms. Results: Acute bleeding episodes were successfully controlled and prevented during induction and consolidation therapy with immunoglobulins, whereas replacement of plasma-derived VW factor showed no clinical improvement. High-dose melphalan-based consolidation therapy supported with autologous stem-cell transplantation led to an immediate and sustainable rise of von-Willebrand antigen and activity and a subsequent normalization of platelet aggregation activity. After a follow-up of 40 weeks, the patient maintained normalized VW levels and platelet aggregation capacity. There were no further signs or symptoms of bleeding. Conclusion: This case report highlights the necessity for combined supportive and causal treatment in patients with AVWD and paraproteinemic PD. High-dose melphalan with autologous stem cell support may function as a treatment option in patients with myeloma-related AVWD.",
"affiliations": "Department of Hemostaseology, Johann Wolfgang Goethe University of Frankfurt, Frankfurt am Main, Germany.;Department of Hemostaseology, Johann Wolfgang Goethe University of Frankfurt, Frankfurt am Main, Germany.;German Red Cross Blood Donor Department, Frankfurt am Main, Germany.;Department of Hematology and Oncology, Johann Wolfgang Goethe University of Frankfurt, Frankfurt am Main, Germany.;Department of Hemostaseology, Johann Wolfgang Goethe University of Frankfurt, Frankfurt am Main, Germany.",
"authors": "Stratmann|Jan|J|;Gundermann|Stefan|S|;Geisen|Christof|C|;Dukat|Alexandra|A|;Miesbach|Wolfgang|W|",
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"country": "Iran",
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"fulltext": "\n==== Front\nInt J Hematol Oncol Stem Cell ResInt J Hematol Oncol Stem Cell ResIJHOSCRInternational Journal of Hematology-Oncology and Stem Cell Research2008-30092008-2207Tehran University of Medical Sciences, Hematology-Oncology and Stem Cell Transplantation Research Center Tehran, Iran IJHOSCR-13-7Case ReportLong-Term Remission of Acquired Von-Willebrand's Disease and Platelet Dysfunction after High-Dose Melphalan in a Patient with Multiple Myeloma Stratmann Jan 1Gundermann Stefan 1Geisen Christof 2Dukat Alexandra 3Miesbach Wolfgang 1\n1 Department of Hemostaseology, Johann Wolfgang Goethe University of Frankfurt, Frankfurt am Main, Germany \n2 German Red Cross Blood Donor Department, Frankfurt am Main, Germany \n3 Department of Hematology and Oncology, Johann Wolfgang Goethe University of Frankfurt, Frankfurt am Main, Germany Corresponding Author: Jan Stratmann, Department of Hemostaseology, Johann Wolfgang Goethe University of Frankfurt, Frankfurt am Main, Germany. Tel.: 00496963015677. Fax: 00496963016089.E-mail: jan.stratmann@kgu.de1 1 2019 13 1 7 11 7 6 2018 18 11 2018 \nCopyright : © International Journal of Hematology-Oncology and Stem Cell Research & Tehran University of Medical Sciences\nThis is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nBackground: Autologous stem cell transplantation is considered a standard of care treatment in eligible patients with multiple myeloma, but puts the patient at high risk for infections and bleeding complications. Acquired von-Willebrand's disease (AVWD) and acquired platelet dysfunction are rare bleeding disorders that are associated with lymphoproliferative disorders such as multiple myeloma. Patients with acquired bleeding disorders who are planned for ASCT to treat the underlying condition are considered at highest risk for bleeding complications, and optimal treatment strategies are not known. \n\n\nMaterials and Methods: We summarized the diagnostic and therapeutic approach to a patient affected by AVWD and acquired platelet disorder related to multiple myeloma. The patient who was planned for ASCT presented with moderate to severe bleeding symptoms. \n\n\nResults: Acute bleeding episodes were successfully controlled and prevented during induction and consolidation therapy with immunoglobulins, whereas replacement of plasma-derived VW factor showed no clinical improvement. High-dose melphalan-based consolidation therapy supported with autologous stem-cell transplantation led to an immediate and sustainable rise of von-Willebrand antigen and activity and a subsequent normalization of platelet aggregation activity. After a follow-up of 40 weeks, the patient maintained normalized VW levels and platelet aggregation capacity. There were no further signs or symptoms of bleeding. \n\n\nConclusion: This case report highlights the necessity for combined supportive and causal treatment in patients with AVWD and paraproteinemic PD. High-dose melphalan with autologous stem cell support may function as a treatment option in patients with myeloma-related AVWD. \n\nKey Words\nAcquired von-Willebrand's diseaseMultiple myelomaAutologous stem cell transplantationPlatelet dysfunctionImmunoglobulin\n==== Body\nIntroduction\n Multiple myeloma (MM) is a malignant plasma-cell disorder whose clinical features include lytic bone lesions, anemia, kidney failure and hypercalcemia. The initial therapy of symptomatic MM varies depending on risk stratification and fitness of the patient; however, international guidelines recommend high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in eligible patients to improve survival1. Patients who undergo ASCT are at high risk for infections and bleeding complications due to transient severe pancytopenia and prophylactic measures, including the use of broad spectrum antibiotics and transfusion of platelet and blood products2,3. \n\nAcquired von-Willebrand disease (AVWD) and acquired platelet dysfunction (APD) are rare bleeding disorders that are associated with lymphoproliferative disorders such as MM. Clinical features involve mucocutaneous bleeding, menorrhagia and prolonged bleeding from minor bruises or dental procedures, thus resembling the inherited VWD and inherited PD in clinical findings 4. \n\nPatients with acquired bleeding disorders who are planned for ASCT to treat the underlying condition are considered at high risk for bleeding complications. Optimal treatment strategies have not been established due to the limited number of affected patients and multiple pathophysiologic mechanisms of these acquired bleeding disorders5. In general, causal treatment of the underlying condition is considered crucial for sustainable response and supportive treatment (such as the administration of desmopressin, replacement of VWF, immunoglobulins, plasmapheresis and antifibrinolytics) aiming to control and prevent severe bleeding episodes6.\n\nIn the following case report, we describe a patient affected by AVWD and APD related to MM. We review our diagnostic workup and treatment approach to control acute bleeding events, prevent bleeding in high-risk situations and obtain long-term remission. Written informed consent was provided by the patient.\n\nCase presentation\nA 62-year-old male patient with MM IgG kappa, ISS 17, anemia (10.3g/dl [normal range 13.5 – 17-5g/dl]) and two isolated bone lesions in the spine was referred to the cancer center for treatment initiation (laboratory findings [standard values in parentheses]: β2-microglobulin, 3.2mg/l [0.8 – 2.4mg/l]; M-gradient, 0.26g/dl, 4% [0g/dl, 0%]; 90% bone marrow infiltration with plasmatic cells [0.5 – 3.0%]; serum free light chain ratio, 8.72 [0.26-1.65]; body weight: 65 kilogram). \n\nHis medical history involved diabetes mellitus, atopic dermatitis and Bechterew´s disease with severe arthrosis of the right hip causing a wheelchair-dependency most time of the day. A noticeable bleeding history was documented: the patient suffered from nose bleeding since he was a child as well as intermittent severe gastrointestinal bleeding episodes due to angiodysplasia in the jejunum and ileum, which were controlled by local endoscopic interventions at accessible sites. However, an open appendectomy as a child and inguinal hernia repair two years ago were performed without major bleeding events. The family history for bleeding disorders was negative. There were no specific findings in the full body examination. \n\nThe patient was referred to our department of hemostaseology for further diagnostic workup of the reported bleeding episodes in advance of the planned induction therapy for the MM. The coagulation tests showed VWF: Ag 12% [60 – 150%], VWF: Act < 4% [47,8 - 173,2%], VIII:C 13.6% [68 - 133%], aPTT 51s [25-37sec], bleeding time epinephrin>220sec [84 – 160sec], bleeding time ADP > 227sec [68-121sec]), a reduced platelet aggregation induced by ristocetin of 9% [89-100%] and ADP of 63% [88-100%] and normal levels of coagulation factor IX and XIII. Multimer analysis revealed absence of all proportions of VWF, compatible with type 3 VWD. Administration of VWF concentrate in combination with antifibrinolytics was recommended in case of acute bleeding. Presence of an inhibiting autoantibody against VWF was excluded in our and a reference laboratory. \n\nThe patient was treated with four induction cycles of VCD (Bortezomib 1,3mg/m2 d1,4,8,11; Cyclophosphamid 900mg/m2 d1; Dexamethason 40mg d1-12) 8 and one cycle of CAD (cyclophosphamide 1g/m2 d1; adriamycin 15g/m2 d1-4; dexamethasone 40mg d1-4)9 for stem-cell mobilization, accompanied by standard of care supportive therapy. The patient suffered from two self-limiting mild bleeding events and low-grade polyneuropathy. A cumulative dose of 18250 units (95IE/kg bodyweight per day) of a plasma-derived FVIII/VWF combination concentrate (Haemate P) was administered on three consecutive days for continuous central-line insertion-site bleeding during stem cell collection. The patient achieved a stable disease after completion of the induction therapy.\n\nThe patient was re-referred to our department in advance of the planned consolidation therapy for nose bleeding that was not manageable with local compression for more than 24hours. We administered an initial dose of 6000 units (92 units/kg bodyweight) of Haemate P, but low concurrent recovery values with less than 10% VWF: Act three hours after VWF administration (see Figure 1B) indicated a rapid clearance of VWF. We hypothesized a MM associated AVWD and administered immunoglobulines (IVIg) 1g per kg bodyweight for four consecutive days. A rapid recovery of VWF and reoccurrence of all proportions of VW multimers could be documented on day 2 after one dose of 60g IVIg. In line with the laboratory findings, the formerly uncontrolled nose bleeding stopped after the first IVIg dose. Administration was repeated once (60g IVIg) to maintain normal VWF levels throughout the consolidation therapy (Figure 1A). Impairment of platelet aggregation, however, was not ameliorated by IVIg administration. \n\nFig. 1 (A) Development of coagulation factors and platelets during treatment: VWF:Act, von Willebrand factor activity; VIII:C, factor VIII activity; IVIg, immunoglobulin; ASCT, d0 of consolidation therapy: autologous stem cell transplantation; (B) recovery of VWF:Ag, VWF:Act and VIII:C after administration of 92 units/kg bodyweight Haemate P (plasma-derived VWF / FVIII concentrate)\n\n Consolidation was performed with high-dose melphalan at a dose of 200 mg per square meter of body-surface area supported with autologous stem cell transplantation (ASCT) using 2.57 x 106 CD34+ cells per kilogram bodyweight (melphalan 100mg/m2 d-3, d-2; stem cell support d0)3. The patient suffering from neutropenic fever was successfully treated with antibiotics and no bleeding events were identified. An immediate and sustainable rise of VWF and FVIII after ASCT was documented (Figure 1A). In addition, ristocetin-induced thrombocyte aggregation and in-vitro bleeding time normalized 5 weeks after ASCT. The patient achieved a partial remission according to the international response criteria evaluated 9 weeks after consolidation therapy10. Coagulation factors were normal at last follow-up, 40 weeks after ASCT. There were no clinical signs or symptoms of bleeding. \n\nDiscussion\n To our knowledge, this is the first report on a long-term remission of a patient diagnosed with AVWD and PD as a complication of MM after administration of high-dose melphalan supported with ASCT.\n\nDistinguishing acquired from inherited VWD is challenging and anamnestic findings play a major role in making the diagnosis. In our case, the personal history including childhood bleeding events but negative family history was inconclusive, leading to the initial assumption of inherited VWD. In the course of disease, rapid clearance of plasma-derived VWF gave rise to the correct diagnosis. Repeatedly, autoantibodies against VWF could be excluded. The general frequency of inhibiting autoantibodies in AVWD is low, and therefore does not provide enough sensitivity for the diagnosis of AVWD4. \n\nTreatment of AVWD is challenging and aims to control acute bleeding events, prevent bleeding in high-risk situations like chemotherapy-induced pancytopenia and obtain long-term remission. Immunoglobulins are a reasonable therapy option for lymphoproliferative-related AVWD, especially in IgG-restricted MM11. All proportions of VW multimers could already be detected after the first IVIg administration of 60g (0.92g per kg bodyweight), leading to a prolongation of the VWF half-life from less than one hour (Fig. 1B) to a few days (Fig. 1A). \n\nLong-term remissions of AVWD using immunomodulatory drugs (e.g. thalidomide) and proteasome inhibitors (e.g. bortezomib) have been described12,13, but time to treatment response ranged between weeks and months in these cases, providing limited usefulness in patients with high clinical burden of AVWD. This is however the first case of a long-term remission of AVWD achieved by high-dose melphalan supported with ASCT. A sustainable rise of VWF could be documented from day one after reconstitution with autologous stem cells that reached a maximum VWF activity within 2 weeks after ASCT, a critical phase where therapy-related thrombocytopenia causes a high risk for spontaneous bleeding events (Fig. 1A). Rise of VWF was accompanied by a significant reduction of paraproteinemia, albeit level of paraprotein does not necessarily correlate with clinical AVWD severity or laboratory findings14. \n\nOf interest, IVIg was not able to restore platelet function, indicating a non-immunogenic impairment of ristocetin-induced platelet aggregation. In accordance to Djunic et al. who performed systematic mixing studies and showed that adding IVIg to the reaction mixture was not able to restore platelet activity in vitro15, we have provided the first corresponding clinical evidence that IVIg fails to significantly change platelet aggregation capacity in paraproteinemic impairment. Platelet function and in-vitro bleeding time however subsequently normalized after high-dose melphalan therapy, presumably due to the general reduction of paraprotein burden.\n\nIn summary, this case report highlights the necessity for close anamnestic review of the patient´s history as well as the need for combined supportive and causal treatment in patients with AVWD and paraproteinemic APD. Close monitoring and an interdisciplinary approach involving hematologists and hemostaseologists are of great importance to manage patients with these rare acquired bleeding disorders. Immunoglobulins provide short-term usefulness to bridge patients who are at high-risk for bleeding complications. High-dose chemotherapy followed by ASCT can be considered as a salvage treatment option for patients suffering from these rare bleeding disorders. \n\nCONFLICTS OF INTEREST\nThe authors declare no conflicts of interest or financial relationships related to this research.\n==== Refs\nReferences\n1 Moreau P San Miguel J Ludwig H Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol. 2013 24 Suppl 6 vi133 7 23956208 \n2 Fermand JP Ravaud P Chevret S High-Dose Therapy and Autologous Peripheral Blood Stem Cell Transplantation in Multiple Myeloma: Up-front or Rescue Treatment? Results of a Multicenter Sequential Randomized Clinical Trial Blood 1998 92 9 3131 6 9787148 \n3 Palumbo A Cavallo F Gay F Autologous transplantation and maintenance therapy in multiple myeloma N Engl J Med. 2014 371 895 905 25184862 \n4 Tiede A Priesack J Werwitzke S Diagnostic workup of patients with acquired von Willebrand syndrome: a retrospective single-centre cohort study J Thromb Haemost 2008 6 4 569 76 18208537 \n5 Tiede A Rand JH Budde U How I treat the acquired von Willebrand syndrome Blood 2011 117 25 6777 6785 21540459 \n6 Callaghan MU Wong TE Federici AB Treatment of acquired von Willebrand syndrome in childhood Blood 2013 122 120 2019 22 23878141 \n7 Greipp PR San Miguel J Durie BG International staging system for multiple myeloma J Clin Oncol 2005 23 15 3412 20 15809451 \n8 Einsele H Engelhardt M Tapprich C Phase II study of bortezomib, cyclophosphamide and dexamethasone as induction therapy in multiple myeloma: DSMM XI trial Br J Haematol 2017 179 4 586 597 28961309 \n9 Fruehauf S Klaus J Huesing J Efficient mobilization of peripheral blood stem cells following CAD chemotherapy and a single dose of pegylated G-CSF in patients with multiple myeloma Bone Marrow Transplant 2007 39 12 743 50 17450182 \n10 Durie BGM Harousseau JL Miguel JS International uniform response criteria for multiple myeloma Leukemia 2006 20 9 1467 73 16855634 \n11 Federici AB Stabile F Castaman G Treatment of acquired von Willebrand syndrome in patients with monoclonal gammopathy of uncertain significance: comparison of three different therapeutic approaches Blood 1998 92 8 2707 11 9763553 \n12 Katagiri S Akahane D Amano K Long-term remission of acquired von Willebrand syndrome associated with multiple myeloma using bortezomib and dexamethasone therapy Haemophilia 2016 22 6 e557 e559 27641423 \n13 Engelen ET van Galen KPM Schutgens RE Thalidomide for treatment of gastrointestinal bleedings due to angiodysplasia: A case report in acquired von Willebrand syndrome and review of the literature Haemophilia 2015 21 4 419 29 25929157 \n14 Lavin M Brophy TM Rawley O Lenalidomide as a novel treatment for refractory acquired von Willebrand syndrome associated with monoclonal gammopathy J Thromb Haemost 2016 14 6 1200 5 26991062 \n15 Djunic I Elezovic I Ilic V The effect of paraprotein on platelet aggregation J Clin Lab Anal 2014 28 2 141 6 24395751\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2008-2207",
"issue": "13(1)",
"journal": "International journal of hematology-oncology and stem cell research",
"keywords": "Acquired von-Willebrand's disease; Autologous stem cell transplantation; Immunoglobulin; Multiple myeloma; Platelet dysfunction",
"medline_ta": "Int J Hematol Oncol Stem Cell Res",
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"pages": "7-11",
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"references": "15809451;16855634;17450182;18208537;21540459;23878141;23956208;24395751;25184862;25929157;26991062;27641423;28961309;9763553;9787148",
"title": "Long-Term Remission of Acquired Von-Willebrand's Disease and Platelet Dysfunction after High-Dose Melphalan in a Patient with Multiple Myeloma.",
"title_normalized": "long term remission of acquired von willebrand s disease and platelet dysfunction after high dose melphalan in a patient with multiple myeloma"
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{
"abstract": "Paclitaxel-induced photodermatitis is extremely rare despite the frequent use of paclitaxel-trastuzumab combination chemotherapy. A 70-year-old woman with infiltrating intraductal breast cancer developed photodermatitis after ten treatment courses of weekly paclitaxel-trastuzumab combination chemotherapy. Withdrawal of paclitaxel and sun avoidance led to its resolution. A combined effect of solar radiation and enhanced porphyrin synthesis is speculated for photodermatitis in paclitaxel. However, the issue of aberrant porphyrin biosynthesis being causal or an epiphenomenon remains unsettled as elevated porphyrins synthesis does not necessarily cause photosensitivity in all treated cases. The relevant literature on paclitaxel-induced photodermatitis and pathomechanism involved is reviewed.",
"affiliations": "Department of Dermatology, Venereology and Leprosy, Dr. Rajendra Prasad Government Medical College, Kangra (Tanda), Himachal Pradesh, India.;Department of Dermatology, Venereology and Leprosy, Dr. Rajendra Prasad Government Medical College, Kangra (Tanda), Himachal Pradesh, India.;Department of Dermatology, Venereology and Leprosy, Dr. Rajendra Prasad Government Medical College, Kangra (Tanda), Himachal Pradesh, India.",
"authors": "Mahajan|Vikram K|VK|;Sharma|Vikas|V|;Wadhwa|Dhaarna|D|",
"chemical_list": "D000068878:Trastuzumab; D017239:Paclitaxel",
"country": "India",
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"doi": "10.4103/ijp.IJP_337_17",
"fulltext": "\n==== Front\nIndian J Pharmacol\nIndian J Pharmacol\nIJPharm\nIndian Journal of Pharmacology\n0253-7613\n1998-3751\nWolters Kluwer - Medknow India\n\n33283775\nIJPharm-52-430\n10.4103/ijp.IJP_337_17\nDrug Watch\nPhotodermatitis in a woman with infiltrating intraductal breast carcinoma: An uncommon adverse cutaneous drug reaction of paclitaxel revisited\nMahajan Vikram K.\nSharma Vikas\nWadhwa Dhaarna\nDepartment of Dermatology, Venereology and Leprosy, Dr. Rajendra Prasad Government Medical College, Kangra (Tanda), Himachal Pradesh, India\nAddress for correspondence: Dr. Vikram K. Mahajan, Department of Dermatology, Venereology and Leprosy, Dr. Rajendra Prasad. Govt. Medical College, Kangra (Tanda) - 176 001, Himachal Pradesh, India. E-mail: vkm1@rediffmail.com\nSep-Oct 2020\n05 12 2020\n52 5 430434\n19 6 2017\n18 6 2019\n05 10 2020\nCopyright: © 2020 Indian Journal of Pharmacology\n2020\nThis 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.\nPaclitaxel-induced photodermatitis is extremely rare despite the frequent use of paclitaxel-trastuzumab combination chemotherapy. A 70-year-old woman with infiltrating intraductal breast cancer developed photodermatitis after ten treatment courses of weekly paclitaxel-trastuzumab combination chemotherapy. Withdrawal of paclitaxel and sun avoidance led to its resolution. A combined effect of solar radiation and enhanced porphyrin synthesis is speculated for photodermatitis in paclitaxel. However, the issue of aberrant porphyrin biosynthesis being causal or an epiphenomenon remains unsettled as elevated porphyrins synthesis does not necessarily cause photosensitivity in all treated cases. The relevant literature on paclitaxel-induced photodermatitis and pathomechanism involved is reviewed.\n\nActinic dermatitis\nadverse cutaneous drug reactions\nbreast cancer\ndocetaxel\nnab-paclitaxel\nphotosensitivity\ntaxanes\n==== Body\nIntroduction\n\nDrug-induced photosensitivity is the third-most common adverse cutaneous reaction and accounts for approximately 2%–15% of patients in tertiary referral. They usually follow the administration of a drug with photosensitizing potential and exposure to ultraviolet (UV) or visible light for a sufficient period. In most instances, UV-A having long-wavelength with the ability to penetrate into the dermis is implicated, whereas UV-B and visible light might elicit such reactions infrequently. Tetracyclines, fluoroquinolones (sparfloxacin, pefloxacin, and ofloxacin), non-steroidal anti-inflammatory drugs (naproxen and ketoprofen), diuretics (furosemide and thiazides), antifungals (griseofulvin and voriconazole), phenothiazines (chlorpromazine, trifluoperazine, and prochlorperazine), amiodarone, sulfonylureas, and dapsone are common photosensitizing drugs. An uncommon case of paclitaxel-induced photodermatitis is presented here and relevant literature is also reviewed.\n\nCase Report\n\nA 70-year-old woman presented with acrofacial erythematous lesions. Historically, she had a radical mastectomy 6 months back for intraductal carcinoma (grade 2) of the right breast infiltrating overlying skin, nipple, and axillary lymph nodes (pT2N3aM0). Immunohistochemistry was negative for estrogen/progesterone receptor (ER-/PR-) and cytogenetic studies showed positive human epidermal growth factor receptor 2/neu (HER 2/NEU) gene amplification. She had received 12 chemotherapy courses each comprising paclitaxel (130 mg/week) and trastuzumab (270 mg/week for three courses followed by 135 mg/week). Ten weeks (ten treatment courses) after initiating chemotherapy, she developed pruritus, burning, diffuse dusky erythema, and minimal edema in a photo distribution pattern involving the face, front of the neck, distal forearms, dorsa of the hands and feet [Figure 1]. However, the chemotherapy was continued for another 2 weeks while her symptoms persisted with daily exacerbations on sun exposure while oral cetirizine 10 mg/d provided temporary relief in itching. She also had diffuse thinning of scalp hair. Other systemic examination and review of recent laboratory reports (hemogram and serum biochemistry) showed no abnormality. She did not consent for skin biopsy, photopatch testing, and assessment for urinary porphyrins despite counseling. Suspecting paclitaxel-induced photodermatitis, its immediate withdrawal was advised. She was prescribed twice daily application of betamethasone dipropionate (0.05%) cream, physical sunscreen containing 7.5% micronized zinc oxide (Sunstop-19®, Ajanta Pharma, India), and desloratadine 5 mg/d per oral. A follow-up 3 weeks later showed complete clearance of photodermatitis. The patient was still receiving maintenance trastuzumab (135 mg/week) and oncologists did not support paclitaxel re-challenge in view of chemotherapy completion.\n\nFigure 1 Photodermatitis; diffuse dusky erythema and minimal edema of photo exposed distal forearms and dorsal hands. Note sharp demarcation of photolocalized erythema. Similar changes of mild intensity were present over the forehead, cheeks, V area of the neck, and dorsal feet\n\nDiscussion\n\nTrastuzumab is a recombinant DNA-derived humanized anti-p185-HER2 monoclonal antibody that binds to the extracellular domain of the HER2 receptor. For its antiproliferative action on tumor cells and is used for chemotherapy-resistant metastatic breast cancer with HER2 protein overexpression. It is considered safe except for occasional reports of urticaria, angioedema, and fatal anaphylaxis following intravenous administration. As it enhances the antitumor effect of paclitaxel/docetaxel, both are usually combined for the treatment of chemotherapy-resistant metastatic breast carcinoma wherein severe onychopathy/nail dystrophy or hand and foot syndrome have been reported in such a scenario.[1] Paclitaxel and docetaxel (taxanes), originally extracted from yew tree (Taxus brevifolia/T. bactata) bark, are potent chemotherapeutic agents for treating the metastatic ovarian, breast, head and neck, gastrointestinal, and lung cancers.[2] Nab-paclitaxel is a solvent-free, albumin-bound nanoparticle paclitaxel without associated issues of poor solubility and hypersensitivity. They inhibit mitosis and cell division by binding to ß–tubulin of the mitotic spindle that arrest cell cycle in G2-M phase junction, and cause direct apoptosis by bcl-2 phosphorylation.[2] Paclitaxel-induced adverse cutaneous drug reactions are uncommon and include injection site reactions (erythema, tenderness, discoloration and swelling) among others [Table 1]. Although paclitaxel reportedly can trigger photosensitive dermatoses such as photodistributed erythema multiforme, photo-recall phenomenon, photoonycholysis, lupus erythematosus (LE), or subacute cutaneous LE, photodermatitis per se appears rare in reviewed reports which may develop after any time or any number of treatment courses [Table 2].[23456] Cohen et al.[2] reported a case of breast cancer with metastasis to lungs having paclitaxel-induced photodermatitis after 4 weeks of weekly paclitaxel and trastuzumab. The photodermatitis resolved after discontinuation of paclitaxel while trastuzumab was continued. Our patient developed characteristic photodermatitis after 10 weeks of combination chemotherapy that resolved following paclitaxel withdrawal in a similar manner. Although we could not perform drug rechallenge, paclitaxel could be implicated for the onset of photodermatitis following its administration (temporal correlation) and resolution of rash and no more recurrence after its discontinuation (de-challenge) as per the World Health Organization Uppsala Monitoring Center causality scale.\n\nTable 1 Reported adverse effects of paclitaxel and trastuzumab\n\nType of adverse effects\tPaclitaxel\tTrastuzumab\t\nHypersensitivity reactions\tAngioedema\tAngioedema\t\n\tUrticaria\tUrticaria\t\n\tAnaphylaxis\tAnaphylaxis\t\n\tFlushing/pruritus\tMorbilliform rash\t\n\tMorbilliform rash\t\t\nCutaneous adverse effects\tHand and foot syndrome\tHand and foot syndrome (in combination with paclitaxel)\t\n\tPATEO syndrome\t\t\n\tIntertriginous drug rash\t\t\n\tMaculopapular drug rash\t\t\n\tPhotodistributed EM\t\t\n\tPhotodermatitis\t\t\n\tAGEP\t\t\n\tFlagellate and reticulate pigmentation\t\t\n\tDrug-induced LE/SCLE\t\t\n\tSclerodermatus skin changes\t\t\n\tRecall (radiation/UV) dermatitis\t\t\n\tInflammation of actinic keratoses\t\t\n\tSJS/TEN\t\t\nAdverse effects affecting hair and nails\tAlopecia - reversible/persistent\tOnychoytrophy/onychopathy (in combination with docetaxel)\t\n\tOnycholysis/photo onycholysis\t\t\n\tOnychopathy\t\t\n\tOnychomadesis, Beau’s lines\t\t\n\tMelanonychia/leukonychia\t\t\n\tParonychia\t\t\n\tOnychorrhexis\t\t\nAdverse effects affecting mucosal surfaces\tMucositis\t-\t\n\tDysgeusia\t\t\n\tTongue pigmentation\t\t\nMiscellaneous\tFixed drug eruptions\t-\t\n\tHot flashes\t\t\n\tInflammation in actinic keratosis\t\t\n\tXerosis\t\t\nMost of these adverse effects are documented in literature as case reports, small case series, or in postmarketing surveys. AGEP=Acute generalized exanthematous pustulosis, PATEO=Periarticular thenar erythema with onycholysis, EM=Erythema multiforme, LE=Lupus erythematosus, SJS=Stevens-Johnson syndrome, TEN=Toxic epidermal necrolysis, SCLE=Subacute cutaneous lupus erythematosus, UV=Ultraviolet\n\nTable 2 Characteristics of patients with paclitaxel-induced photodermatitis\n\nReference number\tCase number\tAge in years/gender\tPrimary diagnosis\tChemotherapy schedule\tNumber of chemotherapy courses (duration) before the onset of rash\tRemarks\t\nCohen et al. 2009[1]\t1\t40/female\tBreast cancer with metastasis to lungs\tPaclitaxel (160 mg/week) + Trastuzumab 225 mg/week followed by 110 mg/week for 3 m\t4 treatment courses (4 weeks)\tHad earlier received docetaxel without response\t\n\t\t\t\t\t\tLesional biopsy showed vacuolar degeneration of basal cells, sparse necrotic keratinocytes, papillary dermal edema, perivascular mononuclear cell infiltrate\t\n\t\t\t\t\t\tIncreased urinary porphyrins (ALA, PBG, PBGD)\t\nFerreira et al. 2010[3]\t2\t60/male\tNonsmall cell lung cancer with bone metastasis\tDocetaxel + local radiotherapy\t2 treatment courses\n(2 weeks)\tTreated earlier with left pneumonectomy + carboplatin and vinorelbine\t\n\t\t\t\t\t\tDose and schedule of docetaxel administration not mentioned\t\n\t\t\t\t\t\tOnycholysis was present\t\nBeutler et al. 2015[4]\t3\t69/female\tNonsmall cell lung cancer (stage-IV) with bone metastasis\tNab-paclitaxel 100 mg/m2 (185 mg)/week\t4 treatment courses\n(4 weeks)\tLesional biopsy showed hyperkeratosis, mild spongiosis, scattered dyskeratotic cells, sparse interface dermatitis, mild melanin incontinence, and increased mucin\t\n\t\t\t\t\t\tNormal CK, aldolase, LDH, AST, and ALT. ANA +\t\n\t\t\t\t\t\tNegative autoantibodies for dsDNA, RO, LA, Smith, RNP, SCl-70, Jo-1, and histone\t\nAkay et al. 2010[5]\t4\t63/female\tMetastatic breast carcinoma\tDocetaxel 75 mg/m2 + Trastuzumab 8 mg/kg followed by 6 mg/kg, at every 3 weeks\tTwo treatment courses (2 weeks)\tLesional biopsy showed lymphocytic cell infiltrate\t\n\t\t\t\t\t\tIncreased total urinary porphyrins, UP, PCP, CP\t\n\t\t\t\t\t\tNormal ALA, PBG\t\n\t\t\t\t\t\tNormal C3/C4, and liver enzymes. Negative HBsAg, Hepatitis C, and autoantibodies (ANA, anti ds DNA, anti-Ro, anti-SS-A/SS-B, anti-histone, anti-Smith)\t\nTokunaga et al. 2013[6]\t5\tMale (age not stated)\tScalp angiosarcoma\tDocetaxel (dosing schedule not provided)\t3 m after initiating docetaxel\tReviewed other five patients with photosensitivity from 2 to 22 courses of docetaxel/paclitaxel treatment courses\t\n\t\t\t\t\t\tAll showed increased erythrocyte protoporphyrin\t\n\t\t\t\t\t\tAll shoed sensitivity to UV-B light on photo testing\t\n\t\t\t\t\t\tRash resolved with topical steroid ointment\t\nPresent case\t6\t70/female\tIntraductal breast carcinoma with metastasis to lymph nodes\tPaclitaxel (130 mg/week) + Trastuzumab (270 mg/week followed by 135 mg/week)\t10 treatment courses (10 weeks)\tRadical mastectomy performed prior to chemotherapy\t\n\t\t\t\t\t\tSkin biopsy or estimation of urinary porphyrins not performed for want of consent/in house facility\t\n\t\t\t\t\t\tBlood biochemistry, hemogram was normal\t\n\t\t\t\t\t\tPhoto dermatitis resolved after withdrawal of paclitaxel\t\nANA=Antinuclear antibody, ALA=Aminolevulinic acid, CK=Creatine kinase, PBG=Porphobilinogen, PBGD=Porphobilinogen deaminase, UP=Uroporphyrin, PCP=Pentacarboxyporphyrin, CP=Coproporphyrin-I and III, LDH=Lactate dehydrogenase, AST=Aspartate aminotransferase, ALT=Alanine aminotransferase, HBsAg=Hepatitis B virus surface antigen, UVB=Ultraviolet-B\n\nAlthough pathomechanism of paclitaxel-induced photodermatitis is poorly understood for its rarity, nab-paclitaxel, and more frequently, docetaxel as monotherapy or in combination with trastuzumab have caused photodermatitis after 2–4 weekly treatments.[3456] It has been usually imputed to nonspecific increased porphyrin synthesis as evidenced from increased urinary porphyrins, erythrocyte porphyrins or their precursors (aminolevulinic acid and porphobilinogen), and porphobilinogen deaminase activity among paclitaxel and trastuzumab treated patients.[1] Further, phototesting showed sensitivity to UVB and not to UVA or visible light in a patient on treatment with docetaxel alone for scalp angiosarcoma.[6] Besides, porphyrinogenic effect of paclitaxel has been demonstrated experimentally in primary neural tissue cell cultures. On the other hand, trastuzumab, although, known to increase sensitization of cancer cells for ionizing radiation therapy usually involving 4–6 MV X-ray photons or other electromagnetic rays, it is not implicated for photodermatitis despite combined administration of both drugs is known to elevate serum concentrations of trastuzumab by nearly 1.5 times.[1] It seems plausible as electromagnetic rays used for radiation therapy lie beyond the UVA (320–400 nm), UVB (290–320 nm) or visible light (400–760 nm) spectrum responsible for most photobiologic reactions whereas UVC (200–290 nm) is absorbed in the atmosphere before reaching the earth.\n\nIn view of the foregoing, it is possible that solar radiation combined with enhanced porphyrin synthesis from paclitaxel caused an interaction that is perhaps responsible, may be partially, for the increased likelihood of photodermatitis in our patient as well. However, whether this aberrant porphyrin biosynthesis in these patients is causal or just an epiphenomenon remains unclear currently since elevated porphyrins synthesis does not necessarily cause photosensitivity in all treated cases.[6] In addition, paclitaxel-induced photosensitivity is reportedly not an absolute contraindication for its further use since many patients tolerated subsequent additional therapy with concurrent use of photoprotection. Nevertheless, dermatologists need to be aware of the possibility of paclitaxel-induced photodermatitis as additional cases may be seen in future, especially due to the potential usefulness of paclitaxel in psoriasis management.\n\nStatement of ethics\n\nInformed consent was obtained from the patient wherein she has given her consent for her images and other clinical information to be reported in scientific journal without disclosing her identity, name, initials, or personal information knowing fully that anonymity may not be guaranteed despite all efforts made. All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2013. The patient was provided standard medical treatment and counseling.\n\nDeclaration of patient consent\n\nThe authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.\n\nFinancial support and sponsorship\n\nNil.\n\nConflicts of interest\n\nThere are no conflicts of interest.\n\nAcknowledgments\n\nThe authors sincerely thank the patient for her consent.\n==== Refs\n1 Merimsky O Inbar MJ Herceptin-taxol related hand and foot syndrome Isr Med Assoc J 2000 2 786 11344738\n2 Cohen AD Mermershtain W Geffen DB Schoenfeld N Mamet R Cagnano E Cutaneous photosensitivity induced by paclitaxel and trastuzumab therapy associated with aberrations in the biosynthesis of porphyrins J Dermatolog Treat 2005 16 19 21 15897162\n3 Ferreira O Baudrier T Mota A Duarte AF Azevedo F Docetaxel-induced acral erythema and nail changes distributed to photoexposed areas Cutan Ocul Toxicol 2010 29 296 9 20608863\n4 Beutler BD Cohen PR Nab-paclitaxel-associated photosensitivity: Report in a woman with non-small cell lung cancer and review of taxane-related photodermatoses Dermatol Pract Concept 2015 5 121 4 26114068\n5 Akay BN Unlu E Buyukcelik A Akyol A Photosensitive rash in association with porphyrin biosynthesis possibly induced by docetaxel and trastuzumab therapy in a patient with metastatic breast carcinoma Jpn J Clin Oncol 2010 40 989 91 20522447\n6 Tokunaga M Iga N Endo Y Fujisawa A Tanioka M Kabashima K Elevated protoporphyrin in patients with skin cancer receiving taxane chemotherapy Eur J Dermatol 2013 23 826 9 24480579\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0253-7613",
"issue": "52(5)",
"journal": "Indian journal of pharmacology",
"keywords": "Actinic dermatitis; adverse cutaneous drug reactions; breast cancer; docetaxel; nab-paclitaxel; photosensitivity; taxanes",
"medline_ta": "Indian J Pharmacol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D001943:Breast Neoplasms; D018270:Carcinoma, Ductal, Breast; D005260:Female; D006801:Humans; D017239:Paclitaxel; D010787:Photosensitivity Disorders; D000068878:Trastuzumab",
"nlm_unique_id": "7902477",
"other_id": null,
"pages": "430-434",
"pmc": null,
"pmid": "33283775",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "26114068;20608863;20522447;24480579;15897162;11344738",
"title": "Photodermatitis in a woman with infiltrating intraductal breast carcinoma: An uncommon adverse cutaneous drug reaction of paclitaxel revisited.",
"title_normalized": "photodermatitis in a woman with infiltrating intraductal breast carcinoma an uncommon adverse cutaneous drug reaction of paclitaxel revisited"
} | [
{
"companynumb": "IN-FRESENIUS KABI-FK202014117",
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{
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"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "MAHAJAN V, SHARMA V, WADHWA D. PHOTODERMATITIS IN A WOMAN WITH INFILTRATING INTRADUCTAL BREAST CARCINOMA: AN UNCOMMON ADVERSE CUTANEOUS DRUG REACTION OF PACLITAXEL REVISITED. INDIAN JOURNAL OF PHARMACOLOGY. 2020 SEP?52: NO.5:430?434.",
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}
] |
{
"abstract": "The coinfection of Hepatitis B virus (HBV) and human immunodeficiency virus (HIV) has been associated with increased death rates. However, the relevant research has mostly relied on serologic HBV testing [HBV surface antigen (HBsAg)]. The aim of this work was to explore the relationship of HBV viraemia with overall mortality among HIV/HBV coinfected individuals. The analysis included 1,609 HIV seropositives of a previously described cohort (1984-2003) with limited exposure to tenofovir (12%) and a median follow-up of approximately 5 years. Those with persistent expression of HBsAg were further tested for HBV-DNA. The data were analyzed using Poisson regression models. Totally, 101 participants were chronic carriers of HBsAg (6.28%). Of these, 81 were tested for HBV-DNA. The median HBV-DNA levels were 3.81 log (base-10) International Units (IU)/ml. A third (31%) of those tested for HBV-DNA had received tenofovir. Before developing acquired immune deficiency syndrome (AIDS), the adjusted incidence rate ratio (IRR) for all-cause mortality of coinfected patients with HBV viraemia above the median value versus the HIV monoinfected group was 3.44 [95% confidence interval (CI): 1.05-11.27]. Multivariable regressions in the coinfected group only (n = 81) showed that one log-10 increase in HBV-DNA levels was associated with an elevated risk for death (IRR: 1.24, 95%CI: 1.03-1.49). HBV-DNA levels predict overall mortality in the setting of HIV/HBV coinfection, especially during the period before developing AIDS, and could thus help prioritize needs and determine the frequency of medical monitoring.",
"affiliations": "Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece.;Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece.;First Department of Propaedeutic Medicine, Laiko General Hospital, Medical School, University of Athens, Athens, Greece.;Department of Hygiene, Epidemiology and Medical Statistics, Medical School, University of Athens, Athens, Greece.",
"authors": "Nikolopoulos|Georgios K|GK|;Paraskevis|Dimitrios|D|;Psichogiou|Mina|M|;Hatzakis|Angelos|A|",
"chemical_list": "D004279:DNA, Viral; D006514:Hepatitis B Surface Antigens",
"country": "United States",
"delete": false,
"doi": "10.1002/jmv.24357",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-6615",
"issue": "88(3)",
"journal": "Journal of medical virology",
"keywords": "HBV; HBV-DNA; HIV; coinfection; mortality",
"medline_ta": "J Med Virol",
"mesh_terms": "D018791:CD4 Lymphocyte Count; D060085:Coinfection; D004279:DNA, Viral; D005260:Female; D005500:Follow-Up Studies; D015658:HIV Infections; D015497:HIV-1; D006509:Hepatitis B; D006514:Hepatitis B Surface Antigens; D006515:Hepatitis B virus; D006801:Humans; D008297:Male; D008875:Middle Aged; D016012:Poisson Distribution; D019562:Viral Load; D014766:Viremia",
"nlm_unique_id": "7705876",
"other_id": null,
"pages": "466-73",
"pmc": null,
"pmid": "26288334",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "HBV-DNA levels predict overall mortality in HIV/HBV coinfected individuals.",
"title_normalized": "hbv dna levels predict overall mortality in hiv hbv coinfected individuals"
} | [
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"activesubstancename": "TENOFOVIR DISOPROXIL FUMARATE"
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"medicinalproduct": "TENOFOVIR DISOPROXIL FUMARATE."
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"activesubstancename": "LAMIVUDINE"
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"drugindication": "HIV INFECTION",
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"medicinalproduct": "LAMIVUDINE."
}
],
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"reaction": [
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}
],
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"literaturereference_normalized": "hbv dna levels predict overall mortality in hiv hbv coinfected individuals",
"qualification": "3",
"reportercountry": "GR"
},
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"receiptdate": "20150908",
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},
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},
"serious": 1,
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"transmissiondate": "20151125"
},
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{
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},
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"drugindication": "HEPATITIS B",
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"medicinalproduct": "LAMIVUDINE."
},
{
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},
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"medicinalproduct": "LAMIVUDINE."
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"medicinalproduct": "TENOFOVIR DISOFOXIL FUMARATE"
}
],
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}
],
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"qualification": "3",
"reportercountry": "GR"
},
"primarysourcecountry": "GR",
"receiptdate": "20150908",
"receivedate": "20150908",
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"receivertype": "6"
},
"reporttype": "1",
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
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}
] |
{
"abstract": "Gamma-hydroxybutyrate (GHB) is a synthetic drug increasingly used by consumers of psychoactive substances. The sought after psychoactive effects of GHB have resulted in an increase in recreational use in Europe. GHB is considered to have a high dependence potential, and abrupt discontinuation after long-term use can result in a severe withdrawal syndrome. Despite a large number of publications related to GHB withdrawal and detoxification, to date, no evidence-based protocol or consensual international therapeutic guidelines are available (over and above the administration of benzodiazepines). We hereby present a day-to-day description of inpatient GHB detoxification management, from admission to discharge.\n\n\n\nThis case report pertains to a 47-year-old patient hospitalized for a severe GHB use disorder. The patient had independently made several unsuccessful attempts to stop GHB use. Following to these failures, the patient was oriented to our addiction department for inpatient detoxification. Withdrawal symptoms appeared 4 hours after the last dose of GHB, and consisted of diaphoresis, coenesthetic hallucinations, tremors, motor instability, tachycardia, and a hypertensive peak. Symptoms were successfully managed with diazepam titration and nonpharmacological treatment. The duration of hospitalization was 13 days. At discharge, detoxification was complete and the patient was engaged in relapse prevention therapy. Three months after discharge, the patient had maintained abstinence.\n\n\n\nGHB withdrawal, which can be severe, is better prevented or attenuated by daily medical monitoring and adjustment of treatment dosage. Failure of outpatient detoxification should be included in the indication criteria in the guidelines for inpatient detoxification.",
"affiliations": "Addictology and Psychiatry Department, Nantes University Hospital, France (LvT, MR, JC, HD, MGB); Centre for Evaluation and Information on Pharmacodependence, Clinical Pharmacology Department, Nantes University Hospital, France (MR, CVV); EA 4275, Biostatistics, Pharmacoepidemiology and Subjective Measures in Health Sciences, Nantes University, France (MR, JC, CVV, MGB); Poison Control Center, University Hospital, Angers, France (DB).",
"authors": "von Theobald|Louis|L|;Rousselet|Morgane|M|;Cholet|Jennyfer|J|;Debar|Hélène|H|;Boels|David|D|;Victorri-Vigneau|Caroline|C|;Grall-Bronnec|Marie|M|",
"chemical_list": "D012978:Sodium Oxybate",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000294",
"fulltext": "\n==== Front\nJ Addict MedJ Addict MedADMJournal of Addiction Medicine1932-06201935-3227Lippincott Williams & Wilkins JAM-D-16-0013710.1097/ADM.000000000000029400011Case ReportsInpatient Gamma-Hydroxybutyrate Detoxification: A Case Report Describing Day-to-day Therapeutic Management von Theobald Louis MDRousselet Morgane MScCholet Jennyfer MDDebar Hélène MScBoels David PharmDVictorri-Vigneau Caroline PharmD, PhDGrall-Bronnec Marie MD, PhDAddictology and Psychiatry Department, Nantes University Hospital, France (LvT, MR, JC, HD, MGB); Centre for Evaluation and Information on Pharmacodependence, Clinical Pharmacology Department, Nantes University Hospital, France (MR, CVV); EA 4275, Biostatistics, Pharmacoepidemiology and Subjective Measures in Health Sciences, Nantes University, France (MR, JC, CVV, MGB); Poison Control Center, University Hospital, Angers, France (DB).Send correspondence and reprint requests to Morgane Rousselet, MSc, Addictology and Psychiatry Department, University Hospital, Hôpital Saint Jacques, 85, rue Saint Jacques, 44093 Nantes cedex 1, France. E-mail: morgane.rousselet@chu-nantes.fr5 2017 25 1 2017 11 3 231 234 4 8 2016 21 12 2016 Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Addiction Medicine.2017This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. http://creativecommons.org/licenses/by-nc-nd/4.0Background:\nGamma-hydroxybutyrate (GHB) is a synthetic drug increasingly used by consumers of psychoactive substances. The sought after psychoactive effects of GHB have resulted in an increase in recreational use in Europe. GHB is considered to have a high dependence potential, and abrupt discontinuation after long-term use can result in a severe withdrawal syndrome. Despite a large number of publications related to GHB withdrawal and detoxification, to date, no evidence-based protocol or consensual international therapeutic guidelines are available (over and above the administration of benzodiazepines). We hereby present a day-to-day description of inpatient GHB detoxification management, from admission to discharge.\n\nCase Summary:\nThis case report pertains to a 47-year-old patient hospitalized for a severe GHB use disorder. The patient had independently made several unsuccessful attempts to stop GHB use. Following to these failures, the patient was oriented to our addiction department for inpatient detoxification. Withdrawal symptoms appeared 4 hours after the last dose of GHB, and consisted of diaphoresis, coenesthetic hallucinations, tremors, motor instability, tachycardia, and a hypertensive peak. Symptoms were successfully managed with diazepam titration and nonpharmacological treatment. The duration of hospitalization was 13 days. At discharge, detoxification was complete and the patient was engaged in relapse prevention therapy. Three months after discharge, the patient had maintained abstinence.\n\nConclusions:\nGHB withdrawal, which can be severe, is better prevented or attenuated by daily medical monitoring and adjustment of treatment dosage. Failure of outpatient detoxification should be included in the indication criteria in the guidelines for inpatient detoxification.\n\nKeywords\ncase reportgamma-hydroxybutyratesubstance use disordertherapeutic managementwithdrawalOPEN-ACCESSTRUE\n==== Body\nGamma-hydroxybutyrate (GHB) is an endogenous compound both precursor to and metabolite of gamma aminobutyric acid (GABA). GHB is found in the hippocampus, cortex, thalamus, and amygdala where it binds to GHB receptors (White, 2017). Exogenous GHB is absorbed through the digestive system and easily crosses the blood-brain barrier. Exogenous administration of GHB results in the activation of the GABA-B receptor. GHB has a high affinity to GABA-B receptors and to a lesser extent to subtypes of GABA-A receptors (Kamal et al., 2015). In addition to interacting with GABA and GHB receptors, GHB has been shown to produce effects linked to other neurotransmitters, in particular dopamine, serotonin, acetylcholine, and norepinephrine (Wong et al., 2004). The effects of GHB on the central nervous system are 2-fold; GHB initially acts as an inhibitor of dopamine release, before secondly increasing dopamine concentrations. Furthermore, small increases in central nervous system serotonin and norepinephrine concentrations also occur. GHB produces a mix of stimulant-sedative subjective effects (Busardo and Jones, 2015). The dose-effect curve for GHB is steep, this means that small increases in dosage result in disproportionately large increases in effects and toxicity. Lower doses are sufficient to induce euphoria and well-being, whereas larger doses result in drowsiness and effects on both speech and motor coordination (Wood et al., 2011). GHB is approved as a treatment option for cataplexy in narcolepsy (the exact mechanism has not been elucidated, although a mechanism via the stimulation of inhibitory extrasynaptic GABA receptors has recently been proposed [White, 2017]). GHB is also used illicitly. Recreational users seek GHB-induced euphoria, anxiolysis, and positive effect on libido. These effects explain the increase of the recreational use of GHB, during the last decades, in Europe (Corkery et al., 2015). Moreover, GHB has been incriminated in sexual assaults. Cases of sexual assault may be underreported as victims may be, due to the administration of GHB, heavily sedated or comatose. GHB-induced amnesia can also add further difficulty in the recollection of facts. This leads to a delay before care. When finally admitted for care, a victims’ plasma or urine GHB concentrations may be too low to detect. Due to the potent depressant effect on the central nervous system, high GHB concentrations in plasma might cause death from cardiorespiratory depression (Busardo and Jones, 2015). Furthermore, GHB is considered to have a high dependence potential, and abrupt discontinuation after long-term use can result in a severe withdrawal syndrome (Kamal et al., 2016c). Despite a large number of publications related to GHB withdrawal and detoxification (eg, de Jong et al., 2012; Ghio et al., 2014; Kamal et al., 2014; Kamal et al., 2016a, 2016b, 2016c), to date, no evidence-based protocol or consensual international guidelines are available—over and above the administration of benzodiazepines (de Jong et al., 2013; McDonough et al., 2004; Busardo and Jones, 2015; Kamal et al., 2016c).\n\nIn the following sections, we discuss the clinical presentation and therapeutic implications relative to a 47-year-old patient hospitalized for GHB detoxification. To our knowledge, this is among the first detailed day-to-day descriptions of the management of inpatient GHB detoxification, from admission to discharge.\n\nCASE PRESENTATION\nMr X is a 47-year-old patient with a medical history characterized by Peyronie disease, treated with several surgical interventions. He also reported chronic use of cocaine.\n\nMr X began using GHB in a social context, at a swingers’ party when he was 37 years old. The substance allowed him to improve his sexual ability and to decrease his performance anxiety, with entactogenic and anxiolytic effects persisting for a few hours. Progressively (for several years), these effects became shorter and less potent, indicating a pronounced phenomenon of tolerance. Mr Xs use of GHB gradually became daily, and then increased to multiple uses per day (a total of 15–20 g of GHB a day, split into doses taken every 3 hours). Mr X described strong craving with a loss of control over his use, leading to a reduction of his social and recreational activities. Seven years after his first encounter with the drug, Mr X began to synthesize GHB at home. The precursors gamma butyrolactone and sodium hydroxide were ordered over the Internet. The chronic use of GHB resulted in a psychomotor retardation, an attention deficit disorder and alexithymia. Although, he was aware of the negative consequences of his consumption, Mr X was unable to stop. Indeed, he had made several attempts at detoxification, independently of any medical support. Each attempt was marked by the following symptoms: sweating, shaking, palpitations, motor instability, increased anxiety, and increased craving.\n\nFollowing to these failures, the patient was referred to our addiction center by his general practitioner. A severe GHB use disorder according to the Diagnostic and Statistical Manual of Mental Health Disorders 5th edition (American Psychiatric Association, 2013) was diagnosed, and medical detoxification was programmed in our inpatient detoxification unit. A multidisciplinary approach is provided, combining physical, psychological and social interventions, and a medication protocol. The GHB inpatient detoxification time line is presented in Figure 1.\n\nFIGURE 1 Time line of the reported GHB inpatient detoxification and benzodiazepine protocol. D, days; GHB, gamma hydroxy butyrate; H, hours.\n\nFollowing the admission, withdrawal symptoms appeared 4 hours after the last dose of GHB with diaphoresis, tremors, motor instability, tachycardia, and hypertensive peaks (systolic blood pressure 190 mm Hg). The patient also reported coenesthetic hallucinations of the trunk and limbs, accompanied by a painful feeling of “sweating flames” and “burning skin.” Mr X recognized the hallucinatory nature of these sensations and was able to critically analyze them. A chromatographic assay found a urinary level of GHB of 3160 mg/L. Screening of urine sample for other substances (cocaine, opiates, methadone, buprenorphine, and tetrahydrocannabinol) was also done by immuno-fixation. Only benzodiazepines prescribed by the patient's general practitioner for anxiety were detected. A complete blood cell count showed hyperleukocytosis 12,900/mm3 with normal C-reactive protein, liver function tests indicated minimal cytolysis of 1.5N. No hydroelectrolytic disorders or rhabdomyolysis was found.\n\nTo reduce withdrawal symptoms, Mr X was treated with diazepam. Dosage, of up to 60 mg/d, was adjusted daily. No adverse effects were observed during treatment. Nondrug measures included the development of outdoor activities (walking alone or with a nurse) and cold showers aimed at soothing the coenesthetic sensations. Symptoms persisted for 48 hours in paroxysmal fashion before gradually subsiding on day 8, allowing for the rapid reduction in diazepam dosage (as shown in Fig. 1). The Cushman score (Cushman et al., 1985) was recorded during day 1 through day 4 to assess the severity of the GHB withdrawal symptoms. The Cushman score, usually used for alcohol withdrawal management, is calculated from the clinical data of blood pressure, heart rate, breathing rate as well as the presence of tremors, sweating, agitation, and sensory symptoms. In the absence of a specific GHB withdrawal management tool, we decided to use the Cushman score as GHB withdrawal presents symptomatic similarities with alcohol withdrawal. GHB urine concentration was zero on day 4 and withdrawal symptoms present at admission completely regressed after day 8. After discharge, relapse prevention therapy was continued. Three months after discharge Mr X was still abstinent.\n\nDISCUSSION\nThis case report pertains to a patient who successfully completed inpatient GHB detoxification, after several unsuccessful detoxification attempts without any medical support. We are reminded of the existence of severe GHB use disorders and this case also confirms existing data on withdrawal modes: the rapid onset of symptoms (Wojtowicz et al., 2008), clinical symptoms similar to those of GABAergic withdrawal (Miotto et al., 2001), the frequency of hallucinatory symptoms (Hernandez et al., 1998), and the effectiveness of long half-life benzodiazepine therapy—including diazepam as a first intention therapeutic option to endure withdrawal symptoms (McDonough et al., 2004). In this case report, withdrawal symptoms lasted 8 days, which can be considered as a long time in light of the period of elimination of GHB. Withdrawal symptoms beginning within 1 to 12 hours after the last dose (4 hours for our patient) and which may continue for 3 to 21 days were reported in literature (Wojtowicz et al., 2008). Although it is known that GHB increases the intracellular level of dopamine in both the mesolimbic system and the nigrostriatal pathway, the translation to the clinical symptoms observed during withdrawal is unclear. The sustained modifications within the central nervous system (Nicholson and Balster, 2001), persisting even after stopping GHB, could explain the kinetics and the complex forms of the withdrawal syndrome (agitation, anxiety, hallucinations). Treatment with typical or atypical antipsychotics has been necessary in some cases (McDonough et al., 2004), although not for the patient in this case report. This suggests that scheduled inpatient detoxification, with daily supervision and medication dosage adjustments, could help patients cope with the severity of withdrawal syndrome and prevent complications. Recently, Kamal et al. (2014) have developed decision guidelines to determine whether an outpatient or inpatient setting should be chosen. Surprisingly, they do not consider a history of unsuccessful outpatient detoxification as a criterion for the indication of inpatient detoxification. In this context, it is important to establish consensual international guidelines. Furthermore, using an established tool for the management of GHB withdrawal syndrome symptoms could provide a basis for improved adaptation of medication dosage to the specific needs of patients.\n\nOne must also keep in mind that the best treatment remains prevention. To achieve this, 2 barriers must be prioritized. First, medical use of GHB should be limited, because of its potential for misuse, to a few indications under strict medical supervision. Caution is particularly required when a history of substance use disorder (Caputo et al., 2009) or borderline personality disorder (Keating, 2014) is reported. Secondly, prohibiting the selling of GHB precursors (gamma butyrolactone and 1,4-butanediol) to the public, as decided by some governments (eg, the French Ministry of Health's decision on September 2, 2011). These measures aim to minimize the availability GHB and the associated risks of intoxication and dependence.\n\nCONCLUSIONS\nThe example of Mr X highlights the value of case reports and the insight that they can provide in establishing specific consensus on the management of GHB use disorder. Indeed, GHB withdrawal, which can be severe, is better prevented or attenuated by daily medical monitoring and adjustment of treatment dosage. Failure of outpatient detoxification should be included in the indication criteria in the guidelines for inpatient detoxification.\n\nAcknowledgments\nThe authors thank Mr X.\n\nWritten consent for the publication in medical literature was obtained from the patient.\n\nLVT, JC, and HB were involved in the care and the treatment of the patient. CVV, DB, MR, and MGB participated in the interpretation of data. LVT wrote the first draft of the manuscript. MR, MGB, and CVV revised the manuscript. All authors approved the final version of the article to be published.\n\nThe authors report no conflicts of interest.\n==== Refs\nREFERENCES\nAmerican Psychiatric Association . Diagnostic and Statistical Manual of Mental Health Disorders: DSM-5 . 5th ed. Arlington, VA : American Psychiatric Publishing Inc ; 2013 .\nBusardo FP Jones AW \nGHB pharmacology and toxicology: acute intoxication, concentrations in blood and urine in forensic cases and treatment of the withdrawal syndrome . Curr Neuropharmacol \n2015 ; 13 :47 –70 .26074743 \nCaputo F Francini S Stoppo M \nIncidence of craving for and abuse of gamma-hydroxybutyric acid (GHB) in different populations of treated alcoholics: an open comparative study . J Psychopharmacol \n2009 ; 23 :883 –890 .18635689 \nCorkery JM Loi B Claridge H \nGamma hydroxybutyrate (GHB), gamma butyrolactone (GBL) and 1,4-butanediol (1,4-BD; BDO): a literature review with a focus on UK fatalities related to non-medical use . Neurosci Biobehav Rev \n2015 ; 53 :52 –78 .25843781 \nCushman P JrForbes R Lerner W \nAlcohol withdrawal syndromes: clinical management with lofexidine . Alcohol Clin Exp Res \n1985 ; 9 :103 –108 .3890587 \nde Jong CA Kamal R Dijkstra BA \nGamma-hydroxybutyrate detoxification by titration and tapering . Eur Addict Res \n2012 ; 18 :40 –45 .22142784 \nde Jong CA Kamal R van Noorden M \nTreatment of GHB withdrawal syndrome: catch 22 or challenge for addiction medicine? \nAddiction \n2013 ; 108 :1686 .23718746 \nGhio L Cervetti A Respino M \nManagement and treatment of gamma butyrolactone withdrawal syndrome: a case report and review . J Psychiatr Pract \n2014 ; 20 :294 –300 .25036586 \nHernandez M McDaniel CH Costanza CD \nGHB-induced delirium: a case report and review of the literature of gamma hydroxybutyric acid . Am J Drug Alcohol Abuse \n1998 ; 24 :179 –183 .9513637 \nKamal RM Dijkstra BA de Weert-van Oene GH \nPsychiatric comorbidity, psychological distress, and quality of life in gamma-hydroxybutyrate-dependent patients . J Addict Dis \n2016 ; 35 :1 –8 .26789434 \nKamal RM Dijkstra BA Loonen AJ \nThe effect of co-occurring substance use on gamma-hydroxybutyric acid withdrawal syndrome . J Addict Med \n2016 ; 10 :229 –235 .27310146 \nKamal RM Schellekens A De Jong CA \nBaclofen as relapse prevention in the treatment of gamma-hydroxybutyrate (GHB) dependence: an open label study . BMC Psychiatry \n2015 ; 15 :91 .25927622 \nKamal RM van Iwaarden S Dijkstra BA \nDecision rules for GHB (gamma-hydroxybutyric acid) detoxification: a vignette study . Drug Alcohol Depend \n2014 ; 135 :146 –151 .24380737 \nKamal RM van Noorden MS Franzek E \nThe neurobiological mechanisms of gamma-hydroxybutyrate dependence and withdrawal and their clinical relevance: a review . Neuropsychobiology \n2016 ; 73 :65 –80 .27003176 \nKeating GM \nSodium oxybate: a review of its use in alcohol withdrawal syndrome and in the maintenance of abstinence in alcohol dependence . Clin Drug Investig \n2014 ; 34 :63 –80 .\nMcDonough M Kennedy N Glasper A \nClinical features and management of gamma-hydroxybutyrate (GHB) withdrawal: a review . Drug Alcohol Depend \n2004 ; 75 :3 –9 .15225884 \nMiotto K Darakjian J Basch J \nGamma-hydroxybutyric acid: patterns of use, effects and withdrawal . Am J Addict \n2001 ; 10 :232 –241 .11579621 \nNicholson KL Balster RL \nGHB: a new and novel drug of abuse . Drug Alcohol Depend \n2001 ; 63 :1 –22 .11297827 \nWhite CM \nPharmacologic, pharmacokinetic, and clinical assessment of illicitly used gamma-hydroxybutyrate . J Clin Pharmacol \n2017 ; 57 :33 –39 .27198055 \nWojtowicz JM Yarema MC Wax PM \nWithdrawal from gamma-hydroxybutyrate, 1,4-butanediol and gamma-butyrolactone: a case report and systematic review . CJEM \n2008 ; 10 :69 –74 .18226321 \nWong CG Gibson KM Snead OC 3rd \nFrom the street to the brain: neurobiology of the recreational drug gamma-hydroxybutyric acid . Trends Pharmacol Sci \n2004 ; 25 :29 –34 .14723976 \nWood DM Brailsford AD Dargan PI \nAcute toxicity and withdrawal syndromes related to gamma-hydroxybutyrate (GHB) and its analogues gamma-butyrolactone (GBL) and 1,4-butanediol (1,4-BD) . Drug Test Anal \n2011 ; 3 :417 –425 .21548140\n\n",
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"abstract": "BACKGROUND\nCurrent data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer.\n\n\nMETHODS\nPatients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0-2 were treated with panitumumab 6 mg kg(-1), GEM 1000 mg m(-2) (10 mg m(-2) min(-1)) and OX 85 mg m(-2) on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival.\n\n\nRESULTS\nThirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5-24 months) and median overall survival 20.3 months (95% CI 9-25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%.\n\n\nCONCLUSIONS\nThe combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.",
"affiliations": "Division of Hematology/Oncology, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY, USA.;Division of Hematology/Oncology, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY, USA.;Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.;Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.;Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.;Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.;Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.;Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.;Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA.;Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, USA.;Division of Hematology/Oncology, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY, USA.;Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA.;Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA.;Department of Public Health Sciences, University of Rochester Medical Center, Rochester, NY, USA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.;Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.;Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.;Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.;Department of Pathology, Massachusetts General Hospital, Boston, MA, USA.;Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.;Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.;Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA.",
"authors": "Hezel|A F|AF|;Noel|M S|MS|;Allen|J N|JN|;Abrams|T A|TA|;Yurgelun|M|M|;Faris|J E|JE|;Goyal|L|L|;Clark|J W|JW|;Blaszkowsky|L S|LS|;Murphy|J E|JE|;Zheng|H|H|;Khorana|A A|AA|;Connolly|G C|GC|;Hyrien|O|O|;Baran|A|A|;Herr|M|M|;Ng|K|K|;Sheehan|S|S|;Harris|D J|DJ|;Regan|E|E|;Borger|D R|DR|;Iafrate|A J|AJ|;Fuchs|C|C|;Ryan|D P|DP|;Zhu|A X|AX|",
"chemical_list": "D000911:Antibodies, Monoclonal; C117307:KRAS protein, human; D009944:Organoplatinum Compounds; D011518:Proto-Oncogene Proteins; D000077150:Oxaliplatin; D003841:Deoxycytidine; D000077544:Panitumumab; C056507:gemcitabine; D016283:Proto-Oncogene Proteins p21(ras); D018631:ras Proteins",
"country": "England",
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"doi": "10.1038/bjc.2014.343",
"fulltext": "\n==== Front\nBr J CancerBr. J. CancerBritish Journal of Cancer0007-09201532-1827Nature Publishing Group bjc201434310.1038/bjc.2014.34324960403Clinical StudyPhase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer Phase II study of gemcitabine and oxaliplatinHezel A F 1*Noel M S 19Allen J N 2Abrams T A 3Yurgelun M 3Faris J E 2Goyal L 2Clark J W 2Blaszkowsky L S 2Murphy J E 2Zheng H 4Khorana A A 5Connolly G C 1Hyrien O 6Baran A 6Herr M 7Ng K 3Sheehan S 2Harris D J 2Regan E 3Borger D R 8Iafrate A J 8Fuchs C 3Ryan D P 2Zhu A X 2*1 Division of Hematology/Oncology, James P. Wilmot Cancer Center, University of Rochester, Rochester, NY, USA2 Division of Hematology/Oncology, Massachusetts General Hospital, Boston, MA, USA3 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA4 Biostatistics Center, Massachusetts General Hospital, Boston, MA, USA5 Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, OH, USA6 Department of Biostatistics and Computational Biology, University of Rochester Medical Center, Rochester, NY, USA7 Department of Public Health Sciences, University of Rochester Medical Center, Rochester, NY, USA8 Department of Pathology, Massachusetts General Hospital, Boston, MA, USA* E-mail: aram_hezel@urmc.rochester.edu or E-mail: azhu@partners.org9 Co-first author.\n\n29 07 2014 24 06 2014 111 3 430 436 30 01 2014 30 04 2014 12 05 2014 Copyright © 2014 Cancer Research UK2014Cancer Research UKFrom twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/3.0/Background:\nCurrent data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer.\n\nMethods:\nPatients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0–2 were treated with panitumumab 6 mg kg−1, GEM 1000 mg m−2 (10 mg m−2 min−1) and OX 85 mg m−2 on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival.\n\nResults:\nThirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5–24 months) and median overall survival 20.3 months (95% CI 9–25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%.\n\nConclusions:\nThe combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.\n\nbiliary tract cancercholangiocarcinomaepidermal growth factor receptor EGFRKRASpanitumumab\n==== Body\nBiliary tract cancer (BTC) encompasses both intra- and extrahepatic cholangiocarcinomas and gallbladder carcinoma. The annual incidence is >12 000 cases (Siegel et al, 2013) in the United States with a rising number of intrahepatic cholangiocarcinomas (Patel, 2001). Curative therapy for BTC is surgical resection, however, over 80% of patients present with metastatic disease, for whom treatment options are palliative. Based on the ABC-02 trial, the standard of care for advanced BTC is cisplatin and gemcitabine, which demonstrated significant improvement in median overall survival (OS) of 11.7 months compared to 8.3 months with gemcitabine alone (Valle et al, 2010). Additional trials have evaluated gemcitabine in combination with oxaliplatin with response rates in excess of 30% and favourable toxicity profile, providing another option for first-line therapy (Andre et al, 2004, Pracht et al, 2012).\n\nThe epidermal growth factor receptor (EGFR) is broadly expressed in BTC and in vitro studies have suggested the potential efficacy of inhibitors of this pathway (Harder et al, 2009). It has been further suggested that tumour genetics may influence the impact of EGFR inhibition. Preclinical data has demonstrated KRAS wild-type (KRAS WT) human cholangiocarcinoma cell lines show increased sensitivity to cetuximab when compared to KRAS mutant cell lines (Xu et al, 2010). In another study vandetanib, a partial EGFR inhibitor, suppressed growth of TKKK (KRAS WT) BTC cell line, while HuCCT (KRAS mutant) required 10 times the amount of drug for similar effect (Yoshikawa et al, 2009). KRAS mutations are found in 3–50% of tumours depending on tumour location and methodology used to evaluate for mutations in different studies (Suto et al, 2000; Rashid et al, 2002; Ong et al, 2012). The most recent report suggests that KRAS mutations are most common in extrahepatic tumours and that rates for intrahepatic cancers are on the lower end of this spectrum at 9–22% (Voss et al, 2013). Early phase trials evaluating EGFR inhibition in BTC demonstrated clinical activity with observed responses (Philip et al, 2006; Lubner et al, 2010). These early trials, however, were not guided by tumour genetics and the pattern of responses was variable with no clear anatomic or pathologic corollaries identified. Given this, and the paradigm of sensitivity to EGFR blocking antibodies as established in colon cancer (Douillard et al, 2010), we undertook a molecularly driven approach evaluating panitumumab, a fully human EGFR blocking monoclonal, in combination with gemcitabine and oxaliplatin (GEMOX) in KRAS WT BTC.\n\nMaterials and Methods\nThis phase II clinical trial was reviewed and approved by the institutional review boards at the Wilmot Cancer Center, University of Rochester (Rochester, NY, USA) and the Dana-Farber/Harvard Cancer Center (Boston, MA, USA).\n\nAll patients provided written informed consent before participation in accordance with institutional and federal guidelines.\n\nAt the University of Rochester tumour-derived DNA (isolated from FFPE biopsy material) was assessed for KRAS mutations in codons 12 and 13 via PCR using Roche Light Cycler. At Massachusetts General Hospital Cancer Center, total nucleic acids were extracted from FFPE diagnostic tumour tissue and mutational profiling was performed using a custom modified ABI PRISM SNaPshot Multiplex System on an ABI PRISM 3730 DNA-Analyzer (Life Technologies/Applied Biosystems, Grand Island, NY, USA), as previously described (Dias-Santagata et al, 2010).\n\nEligibility criteria\nEligibility included histological confirmation metastatic or unresectable KRAS WT biliary tract adenocarcinoma (bile ducts, hepatic duct, cystic duct, common bile duct, ampulla of Vater or gallbladder adenocarcinoma) with measurable disease defined as at least one lesion >2 cm that can be accurately measured with standard imaging techniques. Participants were 18 years of age or older with no history of chemotherapy or anti-EGFR therapy for biliary tract or gallbladder cancer. Eligible patients required an ECOG performance status of 0 or 1, adequate hepatic, renal and haematologic function (serum bilirubin <2.5 mg dl−1, aspartate aminotransferase and alanine aminotransferase <2.5 × institutional upper limit of normal, serum creatinine below upper institutional limits or creatinine clearance >60 ml min−1 per 1.73 m−2, absolute neutrophil count (ANC) >1500 mcl−1, platelet count >100 000 mcl−1 and a life expectancy >3 months. Patients with concurrent malignancies were excluded unless they were treated with curative intent with no known active disease for 3 years prior to enrolment and these include adequately treated non-melanomatous skin cancer or lentigo maligna, treated cervical carcinoma in situ without evidence of disease, prostatic intraepithelial neoplasia without evidence of disease or DCIS without evidence of invasive breast cancer. Patients with known brain metastasis were also excluded. Patients with pre-existing grade 2 or higher peripheral neuropathy were excluded. Prior chemoembolization or radiation to the liver was allowed as long as there was measurable disease outside the radiation area and at least 4 weeks had lapsed since therapy. Women of childbearing potential and men were required to agree to the use adequate contraception and pregnant women were excluded.\n\nStudy design and treatment\nThe trial was designed as an open-label, single-arm phase II study. Eligible patients were treated first with panitumumab at 6 mg kg−1 over 1 h, followed by gemcitabine at 1000 mg m−2 as dose rate infusion at 10 mg m−2 min−1, and then with oxaliplatin at 85 mg m−2 over 2 h, on days 1 and 15 of every 28-day cycle. Patients were screened with computed tomography (CT) scans of the chest, abdomen and pelvis, physical examination, blood chemistries and KRAS evaluation. During treatment patients were assessed prior to therapy on days 1 and 15 of each cycle; CT scans and CA19-9 levels were performed every 8 weeks.\n\nToxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment was discontinued in the event of disease progression, performance status of ⩾3, or participant withdrawal. Panitumumab was held for symptomatic skin or nail-related toxicity or any clinically related ⩾ grade 3 toxicity. When panitumumab was withheld due to skin or nail toxicity the administration of GEMOX was left to the clinical discretion of the treating physician. Gemcitabine and oxaliplatin were held for ANC <1000 mcl−1 or platelet count <75 000 mcl−1, or other ⩾ grade 3 non-haematologic toxicities. Treatment could be delayed for up to 3 weeks to allow for recovery from toxicity, if the patient did not meet re-treatment criteria after a 3-week delay, then the patient will be removed from the study. Antibiotics and steroids were permitted for panitumumab-related rash at the discretion of the treating physician.\n\nThe trial was registered at Clinical Trials.gov with the identifier NCT01308840.\n\nStatistical analysis\nThe primary endpoint was the radiographic response rate by RECIST criteria to GEMOX+panitumumab and secondary endpoints included progression-free survival (PFS), OS and toxicity. A sample size of 30 patients was selected to achieve a power of 80% to detect an absolute difference in response rate of 20% (50% vs 30%) using a one-sided binomial test with a type 1 error set at 0.10. Adverse events and response data were presented as frequencies and percentages. Associated two-sided 95% confidence intervals (CIs) were constructed. Progression-free survival was defined as the time from study enrolment to date of cancer progression or death, whichever occurred first, and OS was defined as the time of enrolment in the study until the date of death from any cause. The distributions of PFS and OS were estimated using the method of Kaplan–Meier. The analysis was performed using intent-to-treat (ITT) principles. All analyses were conducted using SAS software (version 9.3; SAS Institute, Cary, NC, USA).\n\nResults\nPatient characteristics\nBetween 2010 and 2012, 38 patients were enrolled in the trial; of these, 28 were evaluable for efficacy and 31 for toxicity (Figures 1 and 2). Baseline characteristics are shown in Table 1. Three patients were excluded due to having a KRAS mutation and two due to having insufficient tissue for KRAS testing. Of note, a number of patients were selected based on known KRAS status established by clinical broad-based institutional tumour genotyping efforts independent of this trial. Thirty-three patients were allocated to receive treatment but 2 patients did not receive treatment as they were removed from the study due to rapidly progressing symptoms while awaiting KRAS testing. Of the 31 patients who received at least one dose of study drug, 28 patients were evaluable for response because 3 patients did not undergo initial restaging CT evaluation. Reasons for not receiving a second CT evaluation included one patient whose performance status declined rapidly, one patient who was hospitalised during the first cycle followed by an extended treatment delay and then requested to withdraw from the study, and a third patient who developed grade 3 anaemia, hyponatremia, and hyperbilirubinemia and was not able to tolerate additional chemotherapy. Of the included 31 patients, 17 were male and 14 female, the median age was 61 (36–74), 29 patients with metastatic disease and, 2 with locally advanced disease. Baseline characteristics are shown in (Table 1).\n\nDose intensity\nThe median number of completed treatment cycles was 6 (range 2–24). The most common indication for dose reductions of gemcitabine was thrombocytopenia and occurred in 32% of patients. Oxaliplatin was dose reduced in 42% of patients secondary to neuropathy. In the 11 patients who completed 10 or more cycles of chemotherapy, 7 patients had to permanently discontinue oxaliplatin for the remainder of their treatment. Patients with preserved performance status of ⩽2 were allowed to remain on gemcitabine and panitumumab after discontinuation of oxaliplatin as long as they maintained clinical benefit (stable disease or objective response). Dose adjustments for panitumumab were infrequent, it was held for one patient who had a grade 3 finger fissures and dose reduced in another patient due to rash.\n\nEfficacy\nOf the 31 patients who received treatment, 14 patients had a confirmed partial response resulting in an objective response rate of 45% (95% CI 27–64) in the ITT population (Table 2). Of the 28 patients who had a post treatment follow-up scan, the response rate was 50%. Median OS was 20.3 months (95% CI 9–25 months; Figure 3) and median PFS was 10.6 months (95% CI 5–24 months; Figure 4) in the ITT population.\n\nToxicity\nThirty-one patients received at least one treatment cycle and were eligible for toxicity assessment. In general, the combination of GEMOX and panitumumab was tolerated reasonably well. Table 3 highlights grade 3 and 4 toxicities. Grade 3 fatigue, anaemia, neuropathy, and electrolyte changes were fairly common; there were no grade 3 or 4 cases of motor toxicity. Patients were not prophylactically treated for EGFR-related rash.\n\nCorrelative analysis\nEGFR-related rash was seen in 20 patients and hypomagnesemia in 21 patients, there was no statistical correlation between the presence of rash/hypomagnesemia and response.\n\nDiscussion\nThis open-label phase II trial was designed to evaluate the efficacy of the addition of the EGFR inhibitor panitumumab to standard systemic therapy among selected patients with a KRAS WT allele. The chemotherapeutic backbone of GEMOX was chosen given the favourable side-effect profile, convenient schedule (once every 2 weeks) and similar efficacy when compared to gemcitabine and cisplatin (Harder et al, 2006; Verderame et al, 2006; Andre et al, 2008). We found a response rate of 50%, in evaluable patients and 45% in patients who received at least one dose of study drug. The median PFS was 10.6 months and median OS 20.3 months. Furthermore, the combination of gemcitabine, oxaliplatin and panitumumab was well tolerated with manageable grade 3 and 4 toxicities.\n\nThere are three randomised trials evaluating targeted EGFR inhibition in BTC and these have offered limited understanding on the impact of KRAS in response to EGFR therapy. BTC is a heterogeneous group of tumours with varying genetic drivers based on geographic region, which may contribute to variable responses to systemic therapy. Such disease heterogeneity makes comparison of trials between geographic regions and with differing composition of diseases (gallbladder, intra- and extrahepatic tumours) challenging. A phase III trial evaluating anti-EGFR therapy among unselected populations assessed the combination of GEMOX with either erlotinib or placebo, the response rate with erlotinib was 30% compared to 16% in the placebo arm, but failed to show a significant increase in PFS or OS (Lee et al, 2012). Only 6 out of 60 patients with evaluable tissue were found to harbour a KRAS mutation limiting any conclusions about the impact of mutations on clinical efficacy. The largest randomised II trial with an EGFR monocloncal antibody (BINGO) enrolled 150 patients to cetuximab and GEMOX vs GEMOX alone, the addition of cetuximab failed to show a statistically significant increase in PFS (Malka et al, 2012). The response rate in the cetuximab–GEMOX arm was 23%, compared to 29% in the GEMOX arm with a trend towards increased OS (12.4 vs 11 months) in the GEMOX arm. Although not statistically significant, there was a trend towards increased PFS in the cetuximab arm, 6 vs 5.3 months. Tumour samples were available for genetic analysis in 50% of patients, KRAS mutations were found in 19% of patients tested, and there was no prognostic or predictive impact based on genetic characterisation identified among this cohort. A third more recent randomised phase II experience with GEMOX and cetuximab found a trend towards increased progression-free and OS in KRAS mutant patients who received cetuximab compared to those who received GEMOX (Chen et al, 2013). This is a surprising finding given the understanding of the molecular biology of mutant RAS signalling as well as paradigms in other tumour types where RAS mutations are predictive of EGFR insensitivity.\n\nIn the other phase II marker-driven trial of panitumumab in BTC the response rate was 33% and median PFS 8.3 months (Jensen et al, 2012). In comparison to that trial rates of toxicity with GEMOX and panitumumab were similar; however, we found a lower incidence of rash possibly due to the fact that we did not include capecitabine. The most recent trial evaluating panitumumab in BTC used the chemotherapeutic backbone of gemcitabine and irinotecan resulting in a response rate of 31% with median PFS 9.7 months and OS 12.9 months (Sohal et al, 2013). This study did not exclude patients who were KRAS mutant, and among 17 patients with adequate samples, 7 harboured KRAS mutations.\n\nA summary of published EGFR trials in BTC is outlined in Table 4 (Gruenberger et al, 2010; Rubovszky et al, 2013).\n\nThe PFS of 10.6 months and mOS of 20.3 months were the longest among anti-EGFR trials reported to date. The response rate in the intrahepatic cholangiocarcinoma subset (25 pts) was 48%, among the non-intrahepatic cholangiocarcinoma patients there were two responses, one patient with extrahepatic cholangiocarcinoma, and one patient with gallbladder carcinoma. A notable difference in our trial compared to other GEMOX anti-EGFR combinations is that we allowed patients to remain on study receiving gemcitabine and panitumumab even after discontinuation of oxaliplatin secondary to neurotoxicity. Oxaliplatin was discontinued in 25% of patients, who then continued to receive gemcitabine and panitumumab, and it is possible that such an approach, utilising the two agents with little accumulated toxicity as maintenance therapy enabled a relatively long PFS. Given the single-arm design, it is unknown whether the favourable OS outcomes were contributed by including patients with only the KRAS WT signature.\n\nThe recent uncovering of the genetic landscape of BTC demonstrates this to be a heterogeneous disease influenced by both anatomic location within the biliary system and on geographic region (Hezel et al, 2010). This will not only make clinical study increasingly challenging, but also much more likely successful, as we should aim to parse out subgroups of patients from each other to test the impact of the new and promising therapeutic targets that have emerged in BTC.\n\nPredicting response to treatment stratified by genetic subtype may spare patients unlikely to respond to targeted therapy unnecessary toxicity, and it may result in cost saving for the healthcare system. At this time the role of anti-EGFR therapy in BTC is modest, with variable results and negative, though relatively small, unselected randomised trials. The prognostic or therapeutic significance of KRAS testing in BTC is unknown highlighting the importance of continued analysis with subsequent trial design. We realise that limitations of our study include single-arm phase II design, which may lead to selection bias and presently survival data is not yet mature. The single group nature of our phase II design precludes definitive conclusions on the added efficacy of panitumumab when added to GEMOX. Nonetheless, here we report the combination of GEMOX and panitumumab with a response rate of 45% in evaluable patients was well tolerated and led to a relatively favourable mPFS and OS. Although further randomised trials excluding KRAS mutant patients may demonstrate a benefit, this would need to be balanced against using efforts and resources in evaluating other new promising targeted agents in BTC and ongoing efforts at genetic stratification to better guide therapeutic approaches.\n\nThis work was funded by a research grant to AFH and AXZ (as the primary investigators) from Amgen, Inc., Thousand Oaks, CA, USA.\n\nThis work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3.0 Unported License.\n\nAFH has served as a consultant to Bayer and Novartis and has received speaking honoraria from Celgene, Bayer, and Novartis. MSN has served as a consultant for Bayer. DRB is a consultant for Bio-Reference Laboratories. CF has served as a consultant for Amgen, Takeda, Metamark, Genetics, Genentech, Acceleron and Momenta Pharmaceuticals. AXZ has served as a consultant for Acceleron Pharmaceuticals, Sanofi-aventis, Exelixis, Daiichi Sankyo, Eisai, Celgene and Jennerex. The remaining authors declare no conflict of interest.\n\nFigure 1 Study flow diagram depicts all patients assessed for eligibility and enrolled in the study.\n\nFigure 2 Waterfall plot of percentage of tumour change from baseline in 28 evaluable patients.\n\nFigure 3 Kaplan–Meier curve of overall survival (OS).\n\nFigure 4 Kaplan–Meier curve of progression-free survival (PFS).\n\nTable 1 Baseline characteristics\nCharacteristics\tNo. of patients 31\t%\t\nSex\t\nMale\t17\t54.8\t\nFemale\t14\t45.2\t\nMedian age, years (range)\t61 (36–74)\t \t\nECOG performance status\t\n0\t10\t32.3\t\n1\t21\t67.7\t\nExtent of disease\t\nLocally advanced\t2\t6.5\t\nMetastatic\t29\t93.5\t\nPrimary tumour site\t\nIntrahepatic cholangiocarcinoma\t25\t80.6\t\nGallbladder\t3\t9.7\t\nExtrahepatic cholangiocarcinoma\t3\t9.7\t\nMetastases\t\nLymph nodes\t24\t77.4\t\nLung\t8\t25.8\t\nBone\t4\t12.9\t\nOmentum/peritoneal\t4\t12.9\t\nAdrenal\t3\t9.7\t\nPelvic soft tissue\t1\t3.2\t\nAbbreviation: ECOG=Eastern Cooperative Oncology Group.\n\nTable 2 Efficacy estimates\n \tNumber (% 95% CI)\t\n \t(n=31)\t\nBest response\t \t\n Complete response\t0 (0)\t\n Partial response\t14 (45; 27.3–64.0)\t\n Stable disease\t14 (45; 27.3–64.0)\t\n Progressive disease\t3 (9.7; 2.0–25.8)\t\n Overall response rate\t14 (45; 27.3–64.0)\t\n Disease control rate\t28 (90; 79.4–100)\t\nMedian PFS\t10.6 Months (4.8–24.2)\t\nMedian OS\t20.3 Months (9.1–25.1)\t\nAbbreviations: CI=confidence interval; OS=overall survival; PFS=progression-free survival.\n\nTable 3 Adverse events\n \tGrade 1,\nn\n(%)\tGrade 2,\nn\n(%)\tGrade 3,\nn\n(%)\tGrade 4,\nn\n(%)\t\nAnaemia\t10 (32)\t8 (26)\t7 (23)\t1 (3)\t\nNeutropenia\t2 (6)\t3 (10)\t2 (6)\t0\t\nLeukopenia\t4 (13)\t8 (26)\t4 (13)\t3 (10)\t\nThrombocytopenia\t10 (32)\t12 (39)\t2 (6)\t0\t\nFatigue\t13 (42)\t5 (16)\t7 (23)\t0\t\nNausea\t15 (48)\t4 (13)\t4 (13)\t0\t\nAbdominal pain\t5 (16)\t1 (3)\t3 (10)\t0\t\nDiarrhoea\t7 (23)\t5 (16)\t2 (6)\t0\t\nInfection\t0\t0\t4 (13)\t0\t\nNeuropathy\t10 (32)\t5 (16)\t6 (19)\t0\t\nEGFR-related rash\t12 (39)\t6 (19)\t2 (6)\t0\t\nElevated alkaline phosphatase\t12 (39)\t6 (19)\t2 (6)\t0\t\nHypomagnesemia\t10 (32)\t9 (29)\t2 (6)\t0\t\nAbbreviation: EGFR=epidermal growth factor receptor.\n\nTable 4 Completed EGFR inhibitor trials in BTC/GEMOX\nTreatment\tPhase\tNo. of subjects\tORR\tmPFS\n(m)\tmOS (m)\tReference\t\nGEMOX\nGEMOX+erlotinib\tIII\t268\t16% 30%\t4.2\n5.8\t9.5\n9.5\tLee et al, 2012\t\nGEMOX\nGEMOX+\ncetuximab\tII\t150\t29% 23%\t5.5\n6.1\t12.4\n11\tMalka et al, 2012\t\nGEMOX\nGEMOX+\ncetuximab\tII\t122\t17% 27%\t4.1\n6.7\t9.8\n10.6\tChen et al, 2013\t\nGEMOX\nPanitumumab\tII\t31\t45%\t10.6\t20.3\tHezel et al, 2010\t\nGEMOX\nCetuximab\tII\t30\t63%\t8.8\t15.2\tGruenberger et al, 2010\t\nGemcitabine\nCapecitabine\nCetuximab\tII\t34\t18%\t7.8\t14.5\tRubovszky et al, 2013\t\nGEMOX\nCapecitabine\nPanitumumab\tII\t46\t33%\t8.3\t10\tJensen et al, 2012\t\nGemcitabine\nIrinotecan\nPanitumumab\tII\t31\t31%\t9.7\t12.7\tSohal et al, 2013\t\nErlotinib (2nd line)\tII\t42\t8%\t2.6\t7.5\tPhilip et al, 2006\t\nAbbreviations: BTC=biliary tract cancer; EGFR=epidermal growth factor receptor; GEMOX=in combination with gemcitabine and oxaliplatin; mOS=median overall survival; mPFS=median progression free survival; ORR=objective response rate.\n==== Refs\nAndre T Reyes-Vidal JM Fartoux L Ross P Leslie M Rosmorduc O Clemens MR Louvet C Perez N Mehmud F Scheithauer W 2008 Gemcitabine and oxaliplatin in advanced biliary tract carcinoma: a phase II study Br J Cancer 99 862 867 19238628 \nAndre T Tournigand C Rosmorduc O Provent S Maindrault-Goebel F Avenin D Selle F Paye F Hannoun L Houry S Gayet B Lotz JP de Gramont A Louvet C 2004 Gemcitabine combined with oxaliplatin (GEMOX) in advanced biliary tract adenocarcinoma: a GERCOR study Ann Oncol 15 1339 1343 15319238 \nChen LCJ Chao Y Tsai C Shan Y Hsu C Huang S Tsou H Lee K Chiu C Rau K Ho C Yu M 2013 KRAS mutation status-stratified randomized phase II trial of GEMOX with and without cetuximab in advanced biliary tract cancer (ABTC): The TCOG T1210 trial 2013 ASCO Annual MeetingJ Clin Oncol (suppl; abstr 4018).\nDias-Santagata D Akhavanfard S David SS Vernovsky K Kuhlmann G Boisvert SL Stubbs H Mcdermott U Settleman J Kwak EL Clark JW Isakoff SJ Sequist LV Engelman JA Lynch TJ Haber DA Louis DN Ellisen LW Borger DR Iafrate AJ 2010 Rapid targeted mutational analysis of human tumours: a clinical platform to guide personalized cancer medicine EMBO Mol Med 2 146 158 20432502 \nDouillard JY Siena S Cassidy J Tabernero J Burkes R Barugel M Humblet Y Bodoky G Cunningham D Jassem J Rivera F Kocakova I Ruff P Blasinska-Morawiec M Smakal M Canon JL Rother M Oliner KS Wolf M Gansert J 2010 Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study J Clin Oncol 28 4697 4705 20921465 \nGruenberger B Schueller J Heubrandtner U Wrba F Tamandl D Kaczirek K Roka R Freimann-Pircher S Gruenberger T 2010 Cetuximab, gemcitabine, and oxaliplatin in patients with unresectable advanced or metastatic biliary tract cancer: a phase 2 study Lancet Oncol 11 1142 1148 21071270 \nHarder J Riecken B Kummer O Lohrmann C Otto F Usadel H Geissler M Opitz O Henss H 2006 Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer Br J Cancer 95 848 852 16969352 \nHarder J Waiz O Otto F Geissler M Olschewski M Weinhold B Blum HE Schmitt-Graeff A Opitz OG 2009 EGFR and HER2 expression in advanced biliary tract cancer World J Gastroenterol 15 4511 4517 19777609 \nHezel AF Deshpande V Zhu AX 2010 Genetics of biliary tract cancers and emerging targeted therapies J Clin Oncol 28 3531 3540 20547994 \nJensen LH Lindebjerg J Ploen J Hansen TF Jakobsen A 2012 Phase II marker-driven trial of panitumumab and chemotherapy in KRAS wild-type biliary tract cancer Ann Oncol 23 2341 2346 22367707 \nLee J Park SH Chang HM Kim JS Choi HJ Lee MA Jang JS Jeung HC Kang JH Lee HW Shin DB Kang HJ Sun JM Park JO Park YS Kang WK Lim HY 2012 Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study Lancet Oncol 13 181 188 22192731 \nLubner SJ Mahoney MR Kolesar JL Loconte NK Kim GP Pitot HC Philip PA Picus J Yong WP Horvath L van Hazel G Erlichman CE Holen KD 2010 Report of a multicenter phase II trial testing a combination of biweekly bevacizumab and daily erlotinib in patients with unresectable biliary cancer: a phase II Consortium study J Clin Oncol 28 3491 3497 20530271 \nMalka D Fartoux L Rousseau V Trarbach T Boucher E de la Fouchardiere C Faivre SJ Viret F Blanc J-F Assenat E Hammel P Louvet C von Wichert G Ducreux M Rosmorduc O Pignon J-P Greten TF 2012 Gemcitabine and oxaliplatin (GEMOX) alone or in combination with cetuximab as first-line treatment for advanced biliary cancer: Final analysis of a randomized phase II trial (BINGO) ASCO Meeting AbstractsJ Clin Oncol (suppl; abstr 4032).\nOng CK Subimerb C Pairojkul C Wongkham S Cutcutache I Yu W Mcpherson JR Allen GE Ng CC Wong BH Myint SS Rajasegaran V Heng HL Gan A Zang ZJ Wu Y Wu J Lee MH Huang D Ong P Chan-on W Cao Y Qian CN Lim KH Ooi A Dykema K Furge K Kukongviriyapan V Sripa B Wongkham C Yongvanit P Futreal PA Bhudhisawasdi V Rozen S Tan P Teh BT 2012 Exome sequencing of liver fluke-associated cholangiocarcinoma Nat Genet 44 690 693 22561520 \nPatel T 2001 Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States Hepatology 33 1353 1357 11391522 \nPhilip PA Mahoney MR Allmer C Thomas J Pitot HC Kim G Donehower RC Fitch T Picus J Erlichman C 2006 Phase II study of erlotinib in patients with advanced biliary cancer J Clin Oncol 24 3069 3074 16809731 \nPracht M Le Roux G Sulpice L Mesbah H Manfredi S Audrain O Boudjema K Raoul JL Boucher E 2012 Chemotherapy for inoperable advanced or metastatic cholangiocarcinoma: retrospective analysis of 78 cases in a single center over four years Chemotherapy 58 134 141 22572213 \nRashid A Ueki T Gao YT Houlihan PS Wallace C Wang BS Shen MC Deng J Hsing AW 2002 K-ras mutation, p53 overexpression, and microsatellite instability in biliary tract cancers: a population-based study in China Clin Cancer Res 8 3156 3163 12374683 \nRubovszky G1 Láng I Ganofszky E Horváth Z Juhos E Nagy T Szabó E Szentirmay Z Budai B Hitre E 2013 Cetuximab, gemcitabine and capecitabine in patients with inoperable biliary tract cancer: a phase 2 study Eur J Cancer 49 3806 3812 24007821 \nSiegel R Naishadham D Jemal A 2013 Cancer statistics, 2013 CA Cancer J Clin 63 11 30 23335087 \nSohal DP Mykulowycz K Uehara T Teitelbaum UR Damjanov N Giantonio BJ Carberry M Wissel P Jacobs-Small M O'dwyer PJ Sepulveda A Sun W 2013 A phase II trial of gemcitabine, irinotecan and panitumumab in advanced cholangiocarcinoma Ann Oncol 24 3061 3065 24146220 \nSuto T Habano W Sugai T Uesugi N Funato O Kanno S Saito K Nakamura S 2000 Aberrations of the K-ras, p53, and APC genes in extrahepatic bile duct cancer J Surg Oncol 73 158 163 10738270 \nValle J Wasan H Palmer DH Cunningham D Anthoney A Maraveyas A Madhusudan S Iveson T Hughes S Pereira SP Roughton M Bridgewater J Investigators ABCT 2010 Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer N Engl J Med 362 1273 1281 20375404 \nVerderame F Russo A di Leo R Badalamenti G Santangelo D Cicero G Valerio MR Gulotta G Tomasello G Gebbia N Fulfaro F 2006 Gemcitabine and oxaliplatin combination chemotherapy in advanced biliary tract cancers Ann Oncol 17 (Suppl 7vii68 vii72 16760298 \nVoss JS Holtegaard LM Kerr SE Fritcher EG Roberts LR Gores GJ Zhang J Highsmith WE Halling KC Kipp BR 2013 Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions Hum Pathol 44 1216 1222 23391413 \nXu L Hausmann M Dietmaier W Kellermeier S Pesch T Stieber-Gunckel M Lippert E Klebl F Rogler G 2010 Expression of growth factor receptors and targeting of EGFR in cholangiocarcinoma cell lines BMC Cancer 10 302 20565817 \nYoshikawa D Ojima H Kokubu A Ochiya T Kasai S Hirohashi S Shibata T 2009 Vandetanib (ZD6474), an inhibitor of VEGFR and EGFR signalling, as a novel molecular-targeted therapy against cholangiocarcinoma Br J Cancer 100 1257 1266 19319137\n\n",
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"title": "Phase II study of gemcitabine, oxaliplatin in combination with panitumumab in KRAS wild-type unresectable or metastatic biliary tract and gallbladder cancer.",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "OXALIPLATIN."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "078759",
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"drugcharacterization": "1",
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"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": null,
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"drugenddateformat": null,
"drugindication": "GALLBLADDER CANCER",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"medicinalproduct": "GEMCITABINE"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PANITUMUMAB"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": null,
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"drugindication": "GALLBLADDER CANCER",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"medicinalproduct": "PANITUMUMAB"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "GEMCITABINE\\GEMCITABINE HYDROCHLORIDE"
},
"drugadditional": null,
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"drugauthorizationnumb": "078759",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": "1000 MG/M2 ON DAY 1 AND DAY 15 OF EACH 28-DAY CYCLE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BILE DUCT CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "GEMCITABINE"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
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"drugenddateformat": null,
"drugindication": "GALLBLADDER CANCER",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "OXALIPLATIN."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PANITUMUMAB"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "6 MG/KG ON DAY 1 AND DAY 15 OF EACH 28-DAY CYCLE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BILE DUCT CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PANITUMUMAB"
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Anaemia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hyponatraemia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hyperbilirubinaemia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HEZEL A.F., NOEL M.S., ALLEN J.N., ABRAMS T.A., YURGELUN M, FARIS J.E. ET.AL.. PHASE II STUDY OF GEMCITABINE, OXALIPLATIN IN COMBINATION WITH PANITUMUMAB IN KRAS WILD-TYPE UNRESECTABLE OR METASTATIC BILIARY TRACT AND GALLBLADDER CANCER. BRITISH JOURNAL OF CANCER. 2014;1-7",
"literaturereference_normalized": "phase ii study of gemcitabine oxaliplatin in combination with panitumumab in kras wild type unresectable or metastatic biliary tract and gallbladder cancer",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20141020",
"receivedate": "20141020",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10527002,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150528"
}
] |
{
"abstract": "BACKGROUND\nThe incidence and mortality rates of cancer in patients with Bipolar Disorder (BD) is higher compared with the general population. The role of Lithium (Li) in cancer proliferation/inhibition is still a controversial issue in the literature.\n\n\nOBJECTIVE\nBased on a clinical case with lithium intake and development of a renal tumor, we aimed to explore the relationship between Li use and tumor proliferation, with regard to the mechanism of action of Li.\n\n\nMETHODS\nWe present evidence of a female patient with bipolar disorder I, who had been on Li for several years, either as monotherapy or in combination with Valproate (VPA). While on Li monotherapy, the patient had undergone unilateral nephrectomy due to a chromophobe cell renal tumor. A literature search was performed using keywords bipolar disorder, medical comorbidity, cancer, renal tumor, lithium, mood stabilizers, valproate and mechanism of action.\n\n\nRESULTS\nThe limited data on the relationship between Li and cancer proliferation in clinical populations support neither a positive relationship between long-term Li use and increased urinary tract cancers nor an overall cancer risk. Growing evidence identifies effects of Li on cancer proliferation through inhibition of glycogen synthase kinase-3β (GSK-3β), modulations of redox status, inflammatory changes, pro-/anti-apoptotic mechanisms, and mitochondrial function changes.\n\n\nCONCLUSIONS\nDespite the presence of contradictory data, a substantial body of evidence mainly from molecular studies points to Li's anti-carcinogenic effects. However, the underlying mechanistic pathways remain unclear. Mitochondrial dysfunction and redox modulations are potential areas for research on the relationship between Li and cancer proliferation.",
"affiliations": "Department of Psychiatry, School of Medicine, Dokuz Eylul University, Izmir, Turkey.;Department of Neuroscience, Health Sciences Institute, Dokuz Eylul University, Izmir, Turkey.;Department of Psychiatry, School of Medicine, Dokuz Eylul University, Izmir, Turkey.",
"authors": "Ozerdem|Aysegul|A|;Ceylan|Deniz|D|;Targıtay|Bilge|B|",
"chemical_list": "D018692:Antimanic Agents; D018020:Lithium Compounds; D014635:Valproic Acid; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta",
"country": "Netherlands",
"delete": false,
"doi": "10.2174/1389200219666180430095933",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1389-2002",
"issue": "19(8)",
"journal": "Current drug metabolism",
"keywords": "GSK-3; Lithium; cancer proliferation; mitochondrial damage; redox modulations; tumor; urinary tract cancer.",
"medline_ta": "Curr Drug Metab",
"mesh_terms": "D018207:Angiomyolipoma; D018692:Antimanic Agents; D017209:Apoptosis; D001714:Bipolar Disorder; D002292:Carcinoma, Renal Cell; D049109:Cell Proliferation; D004359:Drug Therapy, Combination; D005260:Female; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D015994:Incidence; D007680:Kidney Neoplasms; D018020:Lithium Compounds; D008875:Middle Aged; D008928:Mitochondria; D009392:Nephrectomy; D010084:Oxidation-Reduction; D015996:Survival Rate; D014635:Valproic Acid",
"nlm_unique_id": "100960533",
"other_id": null,
"pages": "653-662",
"pmc": null,
"pmid": "29708074",
"pubdate": "2018",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "The Relationship Between Lithium and Cancer Proliferation: A Case-Based Review of the Literature.",
"title_normalized": "the relationship between lithium and cancer proliferation a case based review of the literature"
} | [
{
"companynumb": "PHHY2018TR075541",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "78679",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "(300?600) MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": "2006",
"drugstartdateformat": "602",
"drugstructuredosagenumb": "600",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "QUETIAPINE."
},
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "VALPROATE SODIUM"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "DEPRESSION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "VALPROATE SODIUM."
},
{
"actiondrug": "3",
"activesubstance": {
"activesubstancename": "QUETIAPINE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "78679",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "200 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "DEPRESSION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": "2006",
"drugstartdateformat": "602",
"drugstructuredosagenumb": "200",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "QUETIAPINE."
}
],
"patientagegroup": null,
"patientonsetage": "46",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Depression",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Suicide attempt",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "OZERDEM A, CEYLAN D, TARGITAY B. THE RELATIONSHIP BETWEEN LITHIUM AND CANCER PROLIFERATION: A CASE?BASED REVIEW OF THE LITERATURE.. CURRENT DRUG METABOLISM. 2018?19(8):653?62",
"literaturereference_normalized": "the relationship between lithium and cancer proliferation a case based review of the literature",
"qualification": "3",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20180823",
"receivedate": "20180823",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15312920,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20181010"
}
] |
{
"abstract": "BACKGROUND\nThe incidence of drug-induced pancreatitis is rare. There have been no prior definite cases reported of ibuprofen-induced pancreatitis.\n\n\nMETHODS\nWe present a case of a young man with acute pancreatitis probably secondary to an ibuprofen overdose. Immediately preceding the onset of the attack he took a 51 mg/kg dose of ibuprofen. He had other causes of acute pancreatitis excluded by clinical history, serum toxicology and abdominal imaging.\n\n\nCONCLUSIONS\nIn the absence of re-challenge we believe it is probable that ibuprofen has a causative link with acute pancreatitis.",
"affiliations": "Department of General and Vascular Surgery, Trinity College Dublin, Adelaide Meath and National Childrens Hospital, Tallaght, Ireland. paulmagill8@hotmail.com",
"authors": "Magill|Paul|P|;Ridgway|Paul French|PF|;Conlon|Kevin Christopher|KC|;Neary|Paul|P|",
"chemical_list": "D007052:Ibuprofen",
"country": "Italy",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1590-8577",
"issue": "7(3)",
"journal": "JOP : Journal of the pancreas",
"keywords": null,
"medline_ta": "JOP",
"mesh_terms": "D000208:Acute Disease; D000293:Adolescent; D062787:Drug Overdose; D006801:Humans; D007052:Ibuprofen; D008297:Male; D010195:Pancreatitis",
"nlm_unique_id": "101091810",
"other_id": null,
"pages": "311-4",
"pmc": null,
"pmid": "16685113",
"pubdate": "2006-05-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of probable ibuprofen-induced acute pancreatitis.",
"title_normalized": "a case of probable ibuprofen induced acute pancreatitis"
} | [
{
"companynumb": "IE-JNJFOC-20060601641",
"fulfillexpeditecriteria": "1",
"occurcountry": "IE",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "1",
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLETS",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BACK PAIN",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "2",
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "1600",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "IBUPROFEN 400 MG"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "1",
"drugadministrationroute": "048",
"drugauthorizationnumb": "017463",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLETS",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BACK PAIN",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "2",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "2800",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "IBUPROFEN 400 MG"
}
],
"patientagegroup": "4",
"patientonsetage": "18",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pancreatitis acute",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Intentional self-injury",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Intentional product misuse",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MAGILL P, RIDGWAY PF, CONLON KC, NEARY P. A CASE OF PROBABLE IBUPROFEN-INDUCED ACUTE PANCREATITIS. JOURNAL OF THE PANCREAS MAY-2006?7(3):311-4.",
"literaturereference_normalized": "a case of probable ibuprofen induced acute pancreatitis",
"qualification": "3",
"reportercountry": "IE"
},
"primarysourcecountry": "IE",
"receiptdate": "20190208",
"receivedate": "20060613",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 6064170,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190418"
}
] |
{
"abstract": "BACKGROUND\nRetrospective studies have suggested that phosphatase and tensin homolog (PTEN) expression might predict the efficacy of cetuximab in patients with KRAS wild-type metastatic colorectal cancer (mCRC). The present study was designed to prospectively evaluate the efficacy of first-line irinotecan, fluorouracil, and folinate (FOLFIRI) plus cetuximab every second week according to PTEN expression.\n\n\nMETHODS\nOriginally, patients with KRAS wild-type mCRC were randomly assigned to receive either FOLFIRI or cetuximab plus FOLFIRI (FOLFIRI-C). After a protocol amendment, the FOLFIRI arm was discontinued, and additional patients received FOLFIRI-C. Cox proportional hazard models were used to investigate the effect of PTEN and MET expression and BRAF and phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit α mutations on progression-free survival (PFS) and overall survival (OS).\n\n\nRESULTS\nA total of 35 and 54 patients received FOLFIRI and FOLFIRI-C, respectively. For the patients assigned to FOLFIRI and FOLFIRI-C, the median OS was 17.7 and 23.3 months and the median PFS was 8.2 and 6.6 months, respectively. For patients receiving FOLFIRI-C, the loss of PTEN expression did not affect PFS or OS. Significant interactions for PFS were detected between the MET expression levels (P = .047) and BRAF mutation (P = .018) and treatment. On univariate analysis, BRAF mutation was significantly associated with shorter OS for patients receiving either FOLFIRI-C (P = .016) or FOLFIRI (P = .035). Multivariate analysis confirmed the independent prognostic value of BRAF mutation on OS and that of MET expression levels on PFS (P = .025) and OS (P = .028) but only in the patients receiving FOLFIRI alone. Adverse events with FOLFIRI-C were consistent with those expected from FOLFIRI plus weekly cetuximab.\n\n\nCONCLUSIONS\nAlthough prospective analysis of PTEN did not allow a validation of the prognostic value of this biomarker, an every second week cetuximab schedule, in addition to first-line FOLFIRI, was effective and well tolerated. The possible predictive value of MET expression levels warrants additional investigation.",
"affiliations": "Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy; Department of Medical Biotechnology and Translational Medicine, University of Milano, Milano, Italy. Electronic address: nic_personeni@hotmail.com.;Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.;Medical Oncology Unit, A.O. Busto Arsizio, P.O. Saronno, Saronno, Italy.;Oncology Department, Medical Oncology Unit, Azienda Ospedaliera Treviglio, Treviglio, Italy.;Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.;Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.;Department of Oncology, Ospedale San Raffaele, Milan, Italy.;Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.;Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.;Department of Oncology, Laboratory of Clinical Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.;Department of Oncology, Laboratory of Clinical Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.;Department of Oncology, Laboratory of Clinical Research, IRCCS-Istituto di Ricerche Farmacologiche Mario Negri, Milano, Italy.;Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Italy.;Department of Pathology, Humanitas Clinical and Research Center, Rozzano, Italy.;Ospedale Papa Giovanni XXIII, Bergamo, Italy.;Humanitas Cancer Center, Humanitas Clinical and Research Center, Rozzano, Italy.",
"authors": "Personeni|Nicola|N|;Rimassa|Lorenza|L|;Verusio|Claudio|C|;Barni|Sandro|S|;Rubino|Luca|L|;Bozzarelli|Silvia|S|;Villa|Eugenio|E|;Carnaghi|Carlo|C|;Tronconi|Maria Chiara|MC|;Gerardi|Chiara|C|;Galli|Francesca|F|;Floriani|Irene|I|;Destro|Annarita|A|;Raschioni|Carlotta|C|;Labianca|Roberto|R|;Santoro|Armando|A|",
"chemical_list": "C117307:KRAS protein, human; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; D016283:Proto-Oncogene Proteins p21(ras); D000068818:Cetuximab; D002955:Leucovorin; D005472:Fluorouracil; D002166:Camptothecin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1533-0028",
"issue": "14(3)",
"journal": "Clinical colorectal cancer",
"keywords": "Anti-EGFR antibody; BRAF; MET; PIK3CA; Phosphatase and tensin homolog",
"medline_ta": "Clin Colorectal Cancer",
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"pubdate": "2015-09",
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{
"abstract": "Endometrial cancer presenting with peritoneal metastases carries a poor prognosis. The addition of hyperthermic intraperitoneal chemotherapy (HIPEC) to the surgical management of these patients has been studied in recent years, but only with cisplatin.\n\n\n\nThis is a series of 3 patients presenting with endometrial cancer and synchronous peritoneal metastases who underwent cytoreductive surgery and carboplatin HIPEC as primary treatment. Complete cytoreductive surgery was achieved for each patient. No grade 3-5 complications were observed. Two patients died at 12 and 18 months, respectively, and 1 patient was alive with disease at 29 months.\n\n\n\nThis case series suggests that the addition of carboplatin HIPEC to the surgical management of peritoneal metastases from endometrial cancer is safe as primary treatment. However, long-term survival remains poor.",
"affiliations": "Division of Surgical Oncology, Maisonneuve-Rosemont Hospital, Montréal, QC. Electronic address: alexandre.brindamour.1@ulaval.ca.;Department of Obstetrics & Gynecology, University of Montréal, Montréal, QC.;Division of Surgical Oncology, Maisonneuve-Rosemont Hospital, Montréal, QC; Department of Obstetrics & Gynecology, University of Montréal, Montréal, QC.;Division of Gynecologic Oncology, Maisonneuve-Rosemont Hospital, Montréal, QC; Department of Obstetrics & Gynecology, University of Montréal, Montréal, QC.;Division of Gynecologic Oncology, Maisonneuve-Rosemont Hospital, Montréal, QC; Department of Obstetrics & Gynecology, University of Montréal, Montréal, QC.;Division of Surgical Oncology, Maisonneuve-Rosemont Hospital, Montréal, QC; Department of Obstetrics & Gynecology, University of Montréal, Montréal, QC.;Division of Gynecologic Oncology, Maisonneuve-Rosemont Hospital, Montréal, QC; Department of Obstetrics & Gynecology, University of Montréal, Montréal, QC.",
"authors": "Brind'Amour|Alexandre|A|;Brault|Claudèle|C|;Sidéris|Lucas|L|;De Guerke|Lara|L|;Auclair|Marie-Hélène|MH|;Dubé|Pierre|P|;Fortin|Suzanne|S|",
"chemical_list": "D016190:Carboplatin",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jogc.2020.07.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1701-2163",
"issue": "43(2)",
"journal": "Journal of obstetrics and gynaecology Canada : JOGC = Journal d'obstetrique et gynecologie du Canada : JOGC",
"keywords": "cytoreductive surgery; endometrial neoplasms; gynecologic surgery; hyperthermic itraperitoneal chemotherapy; peritoneal carcinomatosis",
"medline_ta": "J Obstet Gynaecol Can",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D003131:Combined Modality Therapy; D065426:Cytoreduction Surgical Procedures; D016889:Endometrial Neoplasms; D005260:Female; D006801:Humans; D000084262:Hyperthermic Intraperitoneal Chemotherapy; D008875:Middle Aged; D009367:Neoplasm Staging; D010534:Peritoneal Neoplasms; D016896:Treatment Outcome",
"nlm_unique_id": "101126664",
"other_id": null,
"pages": "247-250",
"pmc": null,
"pmid": "33039314",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Carboplatin Hyperthermic Intraperitoneal Chemotherapy in the Management of Primary Stage IVB Endometrial Cancer.",
"title_normalized": "carboplatin hyperthermic intraperitoneal chemotherapy in the management of primary stage ivb endometrial cancer"
} | [
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"abstract": "This case report aimed to describe cyclic patterns of residual mood symptoms in partially remitted bipolar I patient. In a 24-year-old woman with bipolar I disorder, residual mood symptoms measured by self-rated daily mood chart for 18 months were analyzed using wavelet analysis. A 146-day periodicity was prominent for the first 100 days after discharge. Between 100-200 days, 146-day periodicity was progressively diminished and 21- and 8-day periodicity was prominent. Between 200-516 days, 21-day periodicity was diminished and 85-day periodicity became prominent. This case suggest that bipolar patients might have cyclic residual symptoms with specific frequencies.",
"affiliations": "Department of Psychiatry, Dongrae Hospital, Busan, Republic of Korea.;Department of Psychiatry, Pusan National University Hospital, Busan, Republic of Korea.;Department of Psychiatry, Pusan National University Hospital, Busan, Republic of Korea.;Department of Psychiatry, Pusan National University Hospital, Busan, Republic of Korea.;Department of Psychiatry, Pusan National University Hospital, Busan, Republic of Korea.;Department of Psychiatry, Pusan National University Hospital, Busan, Republic of Korea.;Department of Psychiatry, Pusan National University Hospital, Busan, Republic of Korea.;Department of Psychiatry, Pusan National University Hospital, Busan, Republic of Korea.;Department of Psychiatry, Pusan National University Hospital, Busan, Republic of Korea.",
"authors": "Cheon|YongJun|Y|;Moon|Eunsoo|E|;Park|Je-Min|JM|;Lee|Byung-Dae|BD|;Lee|Young-Min|YM|;Jeong|Hee-Jeong|HJ|;Kang|Tae-Uk|TU|;Park|Jeonghyun|J|;Choi|Yoonmi|Y|",
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"fulltext": "\n==== Front\nPsychiatry InvestigPsychiatry InvestigPIPsychiatry Investigation1738-36841976-3026Korean Neuropsychiatric Association 10.30773/pi.2017.08.23pi-2017-08-23Case ReportCan Residual Symptoms During Inter-Episode Period after Partial Remission in Bipolar I Disorder Have Cyclic Patterns with Specific Frequencies? Cheon YongJun 1Moon Eunsoo 23Park Je-Min 23Lee Byung-Dae 23Lee Young-Min 23Jeong Hee-Jeong 2Kang Tae-Uk 2Park Jeonghyun 2Choi Yoonmi 2\n1 Department of Psychiatry, Dongrae Hospital, Busan, Republic of Korea\n2 Department of Psychiatry, Pusan National University Hospital, Busan, Republic of Korea\n3 Department of Psychiatry, Pusan National University School of Medicine, Busan, Republic of KoreaCorrespondence: Eunsoo Moon, MD, PhD Department of Psychiatry, Pusan National University Hospital, Pusan National University School of Medicine, 179 Gudeok-ro, Seo-gu, Busan 49241, Republic of Korea Tel: +82-51-240-7303, Fax: +82-51-248-3648, E-mail: esmun@hanmail.net3 2018 28 2 2018 15 3 330 334 26 5 2017 18 8 2017 23 8 2017 Copyright © 2018 Korean Neuropsychiatric Association2018This 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 unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.This case report aimed to describe cyclic patterns of residual mood symptoms in partially remitted bipolar I patient. In a 24-year-old woman with bipolar I disorder, residual mood symptoms measured by self-rated daily mood chart for 18 months were analyzed using wavelet analysis. A 146-day periodicity was prominent for the first 100 days after discharge. Between 100–200 days, 146-day periodicity was progressively diminished and 21- and 8-day periodicity was prominent. Between 200–516 days, 21-day periodicity was diminished and 85-day periodicity became prominent. This case suggest that bipolar patients might have cyclic residual symptoms with specific frequencies.\n\nBipolar disorderRapid cyclingCyclicityResidual symptomWavelet analysis\n==== Body\nINTRODUCTION\nBipolar disorder is a recurrent and chronic disease that has wax and wane in the long-term course [1]. Longitudinal course of bipolar disorder is known to have various patterns, in some cases, consisting of completely subsided and partially remitted having residual symptoms during inter-episode [2]. Residual symptoms can be highly associated with relapse and recurrences of mood episode [3]. These residual symptoms impose a negative impact on cognitive functions and functional status, and clinical importance is increasing [2,4]. Patterns of residual symptoms have sometimes mild depressive symptoms with relatively long period, and have alternative course between mild depressive and hypomanic symptoms, and enhanced positive and negative emotional reaction according to life events [4,5]. However, there is no study about the cyclicity of residual mood fluctuation yet. Most studies analyzed the patterns and instability of mood changes for several months. Only one study examined mood states for 2 years, however, that study measured monthly mood state, and did not analyze the cyclicity of residual mood symptoms. Therefore, we postulated that inter-episode mood changes in some bipolar patients might have some specific cyclicity, and the changes over the time. Fortunately, we observed the cyclic patterns of mood fluctuation for 18 months in partially remitted bipolar I patients. We report our single case report about analyzing the cyclicity of residual mood changes using wavelet analysis.\n\nCase\nMs. A is a 24-year old college student with a psychiatric history of DSM-5 defined bipolar I disorder. She was admitted for 2 months in psychiatric ward with her first manic episode on euphoric mood, mood fluctuation, hyperactivity, talkativeness, decrease need for sleep, grandiose delusion, and auditory hallucination when she was 16 years old. At first admission, she was taking lithium 900 mg, valproate 750 mg, olanzapine 5 mg. After discharge, she undergo three additional admissions due to recurrences of three manic episodes with psychotic features at age 19, 21, and 22, because she did not taking medication regularly. At 4th admission, she showed treatment-resistant severe manic symptoms with mood fluctuations. After admission for 85 days, she was partially remitted on taking combination of medications showing partial response, such as lithium 900 mg (blood level: 0.67–0.82 mmol/L), valporate 1,000 mg (blood level: 93.01–106.90 ug/mL), risperidone 5 mg, quetiapine 100 mg, propranolol 40 mg, benztropine 1 mg.\n\nAfter discharge, she exhibited residual mood fluctuation and the changes of mood-related behaviors such as social withdrawal, excessive dancing, excessive exercise over followup in the outpatient clinic. After temporary exacerbation, she became recovered, through mood fluctuation, gradually, she was improved. However, she did complaints of adverse effects of medications such as alopecia, rigidity, drooling, gait disturbance, dizziness, binge eating, daytime somnolence. Her medications were gradually reduced and changed into lithium 300 mg, valproate 500 mg, risperidone 3.5 mg, ziprasidone 20 mg, propranolol 40 mg bid, benztropine 1 mg. She had obsessive compulsive personality, and recorded daily mood rating, sleep duration, weight and menstrual period using mood and sleep chart. Her mood fluctuation was various and complex. It was difficult to analyze the pattern of mood changes with the naked eyes. Therefore, we analyzed the pattern of changes as well as the existence of rhythmicity in mood and sleep records using wavelet transform. Various extrinsic and intrinsic factors can influence biological process, thus biological signals such as mood and sleep records are non-stationary. And wavelet transform is known to be powerful for obtaining amplitudes at multiple time scales from these data. Continuous wavelet transform was performed on her self-reported mood chart and sleep time using Morlet wavelet (Figure 1) as mother wavelet on Matlab R2013b.\n\nMeanwhile, changes in dominant frequencies had some relevance with the change of clinical symptoms. For example, at Period A (between 0–100 days), wavelet analysis showed dominance of 146-day periodicity and patient showed great fluctuations of residual symptoms right after discharge. At period B (between 100–200 days), 146-day periodicity was progressively diminished and 21- and 8-day periodicity was prominent. At that time, patient showed mixed symptoms (CGI-BP-M ≥3 at 126, 130th day and CGI-BP-D ≥4 at 134, 148, 195, and 202th day). Finally, at period C (between 200–516 days), when patient gradually recovered and became stable, 21-day periodicity was diminished and 85-day periodicity became prominent.\n\nDiscussion\nThis case showed that a bipolar patient has cyclic components of daily mood chart recording during inter-episode period. These findings suggest that residual mood symptoms of longitudinal course in patients with bipolar disorder might have cyclic patterns with specific frequency. Cyclic patterns might be composed of several components with specific frequency, such as several months (around 146 days and 85 days), about 1 months (around 21 days), about 1 weeks (around 8 days). We adopted wavelet analysis methodology to analyze periodicity of bipolar patient’s subject mood score. To demonstrate its implication more clearly, we modeled four kinds of sine waves with different frequencies (146–, 85–, 21–, and 8 days) and conducted wavelet analysis on combination of these sine waves (Figure 2). Consequent scalogram showed similar periodicity of patient’s mood analysis, except there was modest wax and wane pattern on periodicity of patient’s scalogram. It could be the reflection of the wax and wane pattern of patient’s residual symptom.\n\nAnd we could observe CGI-BP score was estimated as 4 for five times around 100–230 days. This could be interpreted as an emergence of new mood episode. But according to patient’s history, period of elevated or depressed mood which was enough to be CGI-BP score 4 was no more than 1–2 days, which could not meet diagnostic criteria of mood episode.\n\nIn this single case report, we do not conclude the clinical meaning of these specifc frequencies. However, we can speculate that frequency around several months seems to be rapid cycling and/or seasonal patterns [6]. Also, frequency around 1 month (21 days in our case) might be the reflection of menstrual cycle observed in the female patient [7,8]. In addition, frequency around 8 days may be the cyclothymic component [9,10]. And, these frequencies might be influenced by mood state, and gradually subsided over time by the long-term effect of mood stabilizers, though, in the acute stage, they did not show the full efficacy.\n\nIn this case report, we could observe the correlation between clinical presentation and periodicities in scalogram. Generally, as the severity and variability of residual symptoms diminished, dominant frequency of scalogram increased. Interestingly, when patient was at mixed state, low frequency component (145-day) became less dominant and high frequency component (21- and 8-day) became more dominant. There may be reciprocal inhibition between low-frequency and high-frequency components.\n\nBipolar disorder is known to show circadian rhythm abnormality. There are several kinds of biological oscillators in the brain. And they are interconnected and regulate each other, so whole brain system exhibits limited, regulated biological rhythms. But, in the state of disease, these interconnections might be out of control. Each oscillator affects mood more directly, so stability of whole brain system decreases and mood variability may be greatly increased. This case suggests that regulated biological rhythms in healthy state might be dyscontrolled and expressed in disease state. Extreme type of these dyscontrolled biological rhythms might be mood episode. In clinical situation, dyscontrolled rhythms can be different according to the type of vulnerability, therefore, there might be the various patterns of residual symptoms. These cyclic mood changes can show the self-limited course according to own frequency of mood rhythm. Mood stabilizer can reduce the amplitude of these cyclic mood swings, and improve the ability of controlling the several mood components. And these states may be reflected in changes of number of periodicities in mood scalogram.\n\nThis case report has some limitations. These findings in single case report have some problems to be generalized to bipolar patients. In addition, this case report is based on a subjective self-report of mood state in a bipolar patient, not on objective biological rhythms. Further analysis of cyclic patterns using wavelet analysis is needed to be applicable to other biological rhythm using a larger sample of bipolar patient and objective biological data obtained from wearable devices. However, this case suggests that some bipolar patients might have cyclic residual symptoms, and have several cyclic components with specific frequencies. Therefore, analysis of the cyclic components of residual mood symptoms can be needed to study the longitudinal course of bipolar disorder. Furthermore, the changes in the periodicity of cyclic components for long-term treatment might be used as a state marker reflecting the longitudinal treatment response of bipolar disorder in clinical settings.\n\nFigure 1. Continuous wavelet transform scalogram on patient’s self mood rating. Horizontal axis represents time in days. Vertical axis represents scale factors of the wavelet, which is converted to period of mood cycle. Color of the scalogram represents intensity of the corresponding wavelet coefficient (blue: low, red: high). As noted, four kinds of high intensity bands can be identified (cycles with period of 146, 85, 21, and 8 days). Red dot: CGI-BP-M (Score 1–4), Yellow dot: CGI-BP-D scores (score 1–4). CGI-BP-M: Clinical Global Impression Bipolar Version-Mania, CGI-BP-D: Clinical Global Impression Bipolar Version-Depression.\n\nFigure 2. (A) Dampened sinusoidal wave with period of 146 days. (B) Dampened sinusoidal wave with period of 85 days. (C) Sinusoidal wave with period of 21 days. (D) Sinusoidal wave with period of 8 days. (E) Sum of A–D. (F) Wavelet scalogram on E. Wavelet scalogram of sum of four sinusoidal waves with different period shows four different intensity bands, and signal intensity (=color) on the scalogram correlates to amplitude of corresponding waves. Similarities between Figures 1 and 2F visualizes implication of wavelet scalogram of patient’s mood rating scales.\n==== Refs\nREFERENCES\n1 Judd LL Akiskal HS Schettler PJ Endicott J Maser J Solomon DA The long-term natural history of the weekly symptomatic status of bipolar I disorder Arch Gen Psychiatry 2002 59 530 537 12044195 \n2 Judd LL Akiskal HS Schettler PJ Endicott J Leon AC Solomon DA Psychosocial disability in the course of bipolar I and II disorders: a prospective, comparative, longitudinal study Arch Gen Psychiatry 2005 62 1322 1330 16330720 \n3 Judd LL Schettler PJ Akiskal HS Coryell W Leon AC Maser JD Residual symptom recovery from major affective episodes in bipolar disorders and rapid episode relapse/recurrence Arch Gen Psychiatry 2008 65 386 394 18391127 \n4 Gershon A Eidelman P Inter-episode affective intensity and instability: predictors of depression and functional impairment in bipolar disorder J Behav Ther Exp Psychiatry 2015 46 14 18 25164093 \n5 Koenders MA Giltay EJ Hoencamp E Elzinga BM Spinhoven P Spijker AT The bidirectional impact of perceived and enacted support on mood in bipolar outpatients: a two-year prospective study Compr Psychiatry 2015 60 59 67 25935461 \n6 Geoffroy PA Bellivier F Scott J Etain B Seasonality and bipolar disorder: a systematic review, from admission rates to seasonality of symptoms J Affect Disord 2014 168 210 223 25063960 \n7 Endicott J The menstrual cycle and mood disorders J Affect Disord 1993 29 193 200 8300978 \n8 Parry BL Newton RP Chronobiological basis of female-specific mood disorders Neuropsychopharmacology 2001 25 5 Suppl S102 S108 11682284 \n9 Akiskal HS Hantouche EG Allilaire JF Bipolar II with and without cyclothymic temperament: “dark” and “sunny” expressions of soft bipolarity J Affect Disord 2003 73 49 57 12507737 \n10 Van Meter AR Youngstrom EA Findling RL Cyclothymic disorder: a critical review Clin Psychol Rev 2012 32 229 243 22459786\n\n",
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"abstract": "OBJECTIVE\nTo confirm the efficacy and safety of bevacizumab/XELOX combination for the treatment of locally advanced or metastatic colorectal cancer (CRC) in Italy.\n\n\nMETHODS\nThis multicentric, prospective, open-label study included patients with CRC previously untreated with chemotherapy. Patients were administered bevacizumab in combination with XELOX. The primary efficacy end-point was progression-free survival (PFS). Secondary end-points included time to overall response (TOR), duration of response (DOR), time to treatment failure (TTF) and overall survival (OS). The incidence and type of adverse events AEs and severe AEs were evaluated. Also, the mutational status of BRAF and KRAS was assessed by high resolution melting and direct sequencing, and quality of life (QoL) was measured by the EuroQoL EQ-5D questionnaire at baseline and at the last visit.\n\n\nRESULTS\nThe intention-to-treat population included 197 patients (mean age: 62.3 ± 9.9 years, 56.4% males). At baseline, 16/34 evaluable subjects (47.1%) harbored a KRAS and/or a BRAF mutation; the mean QoL index was 80.2 ± 14.3. First-line therapy was given for 223.7 ± 175.9 d, and after a mean follow-up of 387.7 ± 238.8 d all patients discontinued from the study mainly for disease progression (PD, 45.4%) and AEs (25.4%). Median PFS was 9.7 mo (95%CI: 8.4-10.5) and the median values for secondary end-points were: TOR = 3.9 mo (95%CI: 2.6-4.7), DOR = 8.5 mo (95%CI: 7.3-10.3), TTF = 6.7 mo (95%CI: 6.0-7.7) and OS = 23.2 mo (95%CI: 20.1-27.2). Patients carrying at least one lesion had a lower overall response rate (66.7% vs 88.9%) and a lower probability of achieving complete or partial response than those without mutations, but the difference in relative risk was not statistically significant (P = 0.2). Mean EQ-5D-3L raw index score significantly decreased to 74.9 ± 19.1 at the last visit (signed-rank test, P = 0.0076), but in general the evaluation on QoL perceived by patients was good.\n\n\nCONCLUSIONS\nThe efficacy of bevacizumab in combination with XELOX in terms of PFS in patients with aCRC or mCRC in Italy was confirmed, with acceptable toxicity.",
"affiliations": "Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.;Lorenzo Antonuzzo, Elisa Giommoni, Francesco Di Costanzo, Medical Oncology, Azienda Ospedaliero-Universitaria Careggi, 50139 Florence, Italy.",
"authors": "Antonuzzo|Lorenzo|L|;Giommoni|Elisa|E|;Pastorelli|Davide|D|;Latiano|Tiziana|T|;Pavese|Ida|I|;Azzarello|Domenico|D|;Aieta|Michele|M|;Pastina|Ilaria|I|;Di Fabio|Francesca|F|;Bertolini|Alessandro|A|;Corsi|Domenico Cristiano|DC|;Mogavero|Selene|S|;Angelini|Valentina|V|;Pazzagli|Mario|M|;Di Costanzo|Francesco|F|",
"chemical_list": "D020533:Angiogenesis Inhibitors; C117307:KRAS protein, human; D010071:Oxaloacetates; D003841:Deoxycytidine; D000068258:Bevacizumab; D000069287:Capecitabine; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D005472:Fluorouracil",
"country": "United States",
"delete": false,
"doi": "10.3748/wjg.v21.i23.7281",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1007-9327",
"issue": "21(23)",
"journal": "World journal of gastroenterology",
"keywords": "Bevacizumab; Chemotherapy; Colorectal neoplasms; XELOX; anti-Vascular endothelial growth factor",
"medline_ta": "World J Gastroenterol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D000069287:Capecitabine; D015179:Colorectal Neoplasms; D004252:DNA Mutational Analysis; D003841:Deoxycytidine; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D005472:Fluorouracil; D006801:Humans; D057194:Intention to Treat Analysis; D007558:Italy; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009362:Neoplasm Metastasis; D010071:Oxaloacetates; D011446:Prospective Studies; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D011788:Quality of Life; D012307:Risk Factors; D011795:Surveys and Questionnaires; D013997:Time Factors; D016896:Treatment Outcome",
"nlm_unique_id": "100883448",
"other_id": null,
"pages": "7281-8",
"pmc": null,
"pmid": "26109816",
"pubdate": "2015-06-21",
"publication_types": "D017428:Clinical Trial, Phase III; D016428:Journal Article; D016448:Multicenter Study",
"references": "17442997;10109801;18421054;18640933;18854571;19097774;19339720;19406901;20921465;21646616;23168366;23100174;23441760;10623704;11006366;11886010;15175435;18421053",
"title": "Bevacizumab plus XELOX as first-line treatment of metastatic colorectal cancer: The OBELIX study.",
"title_normalized": "bevacizumab plus xelox as first line treatment of metastatic colorectal cancer the obelix study"
} | [
{
"companynumb": "IT-SA-2015SA120979",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "OXALIPLATIN"
},
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"drugadministrationroute": "042",
"drugauthorizationnumb": "021759",
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"drugdosagetext": "130 MG/M2,Q3W",
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"drugindication": "COLORECTAL CANCER",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "3",
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"drugseparatedosagenumb": "1",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "OXALIPLATIN."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BEVACIZUMAB"
},
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": "7.5 MG/KG,Q3W",
"drugenddate": null,
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"drugindication": "COLORECTAL CANCER",
"drugintervaldosagedefinition": "803",
"drugintervaldosageunitnumb": "3",
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"drugseparatedosagenumb": "1",
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"drugstructuredosagenumb": "7.5",
"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "BEVACIZUMAB."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CAPECITABINE"
},
"drugadditional": "3",
"drugadministrationroute": "048",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNK",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "FILM-COATED TABLET",
"drugdosagetext": "1000 MG/M2,BID",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "COLORECTAL CANCER",
"drugintervaldosagedefinition": "805",
"drugintervaldosageunitnumb": "12",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
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"drugstructuredosagenumb": "1000",
"drugstructuredosageunit": "009",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "CAPECITABINE."
}
],
"patientagegroup": "5",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cardio-respiratory arrest",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ANTONUZZO L, GIOMMONI E, PASTORELLI D, LATIANO T, PAVESE I, AZZARELLO D, ET AL.. BEVACIZUMAB PLUS XELOX AS FIRST?LINE TREATMENT OF METASTATIC COLORECTAL CANCER: THE OBELIX STUDY.. WORLD J GASTROENTEROL.. 2015?21(23):7281?8",
"literaturereference_normalized": "bevacizumab plus xelox as first line treatment of metastatic colorectal cancer the obelix study",
"qualification": "1",
"reportercountry": "IT"
},
"primarysourcecountry": "IT",
"receiptdate": "20210325",
"receivedate": "20150814",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "2",
"safetyreportid": 11381371,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210419"
}
] |
{
"abstract": "METHODS\nTwo patients, 68 and 72 years old, were admitted with fever whilst under treatment with ruxolitinib for myelofibrosis. They had not been screened for latent tuberculosis infection (LTBI) and extensive tuberculosis was found in both patients. They died within weeks from complications of fulminant disease.\n\n\nCONCLUSIONS\nDoctors who prescribe ruxolitinib should be aware of the increased risk of infectious diseases like tuberculosis. Under immune suppression, tuberculosis often runs a disseminated course. The constitutional symptoms of myelofibrosis strongly resemble those of tuberculosis and the latter diagnosis should always be considered. Active and latent tuberculosis should be excluded and treated, if necessary, before giving ruxolitinib.",
"affiliations": "Gemeentelijke Gezondheidsdienst Amsterdam, afd. Tuberculosebestrijding, Amsterdam.",
"authors": "Keizer|Sytze|S|;Gerritsen|Roald|R|;Jauw|Yvonne|Y|;Janssen|Jeroen|J|;Koopman|Bart|B|;Bresser|Paul|P|",
"chemical_list": "D000995:Antitubercular Agents; D009570:Nitriles; D011720:Pyrazoles; D011743:Pyrimidines; C540383:ruxolitinib",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0028-2162",
"issue": "159()",
"journal": "Nederlands tijdschrift voor geneeskunde",
"keywords": null,
"medline_ta": "Ned Tijdschr Geneeskd",
"mesh_terms": "D000368:Aged; D000995:Antitubercular Agents; D017809:Fatal Outcome; D006801:Humans; D055985:Latent Tuberculosis; D008297:Male; D009570:Nitriles; D055728:Primary Myelofibrosis; D011720:Pyrazoles; D011743:Pyrimidines",
"nlm_unique_id": "0400770",
"other_id": null,
"pages": "A8650",
"pmc": null,
"pmid": "25990328",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Fatal tuberculosis during treatment with ruxolitinib.",
"title_normalized": "fatal tuberculosis during treatment with ruxolitinib"
} | [
{
"companynumb": "NL-INCYTE CORPORATION-2015IN002904",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RUXOLITINIB"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "202192",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLET",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MYELOFIBROSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "INC424"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HYDROXYUREA"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MYELOFIBROSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "HYDROXYUREA."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
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"drugenddate": null,
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"drugindication": "MYELOFIBROSIS",
"drugintervaldosagedefinition": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
}
],
"patientagegroup": null,
"patientonsetage": "68",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Multi-organ failure",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Respiratory failure",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pancytopenia",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pulmonary tuberculosis",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Pseudomonas infection",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KEIZER S, GERRITSEN R, JAUW Y, JANSSEN J, KOOPMAN B, BRESSER P. FATAL TUBERCULOSIS DURING TREATMENT WITH RUXOLITINIB. NETHERLANDS JOURNAL OF MEDICINE. 2015;159:1-4",
"literaturereference_normalized": "fatal tuberculosis during treatment with ruxolitinib",
"qualification": "3",
"reportercountry": "NL"
},
"primarysourcecountry": "NL",
"receiptdate": "20150709",
"receivedate": "20150626",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11221456,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20151125"
},
{
"companynumb": "NL-INCYTE CORPORATION-2015IN002892",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MYELOFIBROSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "RUXOLITINIB"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "202192",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosageform": "TABLET",
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MYELOFIBROSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "INC424"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "THALIDOMIDE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MYELOFIBROSIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "THALIDOMIDE"
}
],
"patientagegroup": null,
"patientonsetage": "72",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Peritonitis",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pulmonary tuberculosis",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Duodenal ulcer perforation",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Septic shock",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KEIZER S, GERRITSEN R, JAUW Y, JANSSEN J, KOOPMAN B, BRESSER P. FATAL TUBERCULOSIS DURING TREATMENT WITH RUXOLITINIB. NETH JOURN MED. 2015;159:1-4",
"literaturereference_normalized": "fatal tuberculosis during treatment with ruxolitinib",
"qualification": "3",
"reportercountry": "NL"
},
"primarysourcecountry": "NL",
"receiptdate": "20150709",
"receivedate": "20150625",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11219152,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20151125"
}
] |
{
"abstract": "BACKGROUND\nInterstitial lung disease in rheumatoid arthritis (RA-ILD) is an extra-articular involvement that impairs the prognosis and for which there is still no well-coded treatment. The aim of this study was to evaluate abatacept (ABA) effectiveness and safety in patients with RA-ILD.\n\n\nMETHODS\nRA-ILD patients who started ABA treatment were consecutively enrolled. Chest high-resolution computed tomography (HRCT), clinical, laboratory and respiratory function variables were collected at baseline and after 18 months of ABA treatment. HRCT abnormalities were evaluated using a computer-aided method (CaM). ABA response was established based on the change in the percentage of fibrosis evaluated at HRCT-CaM, dividing patients into \"worsened\" (progression ≥ 15%), \"improved\" (reduction ≥ 15%), and \"stable\" (changes within the 15% range). The multivariate regression model was used to assess the associations between RA characteristics and ABA response.\n\n\nRESULTS\nForty-four patients (81% women, mean age 59.1 ± 8.0, mean disease duration of 7.5 ± 3.1 years) were studied. Five patients (11.4%) showed RA-ILD progression, 32 patients (72.6%) were considered stable, and 7 patients (16.0%) showed an RA-ILD improvement. The proportion of current smokers was significantly different between \"worsened\" patients, respect to those defined as \"improved/stable\" (p = 0.01). Current smoking habit (p = 0.005) and concomitant methotrexate treatment (p = 0.0078) were the two variables related to RA-ILD progression in multivariate regression analysis.\n\n\nCONCLUSIONS\nTreatment with ABA is associated with a RA-ILD stability or improvement in the 88.6% of patients. Current smoking habit and concomitant treatment with methotrexate are the modifiable factors associated with RA-ILD worsening. Key Points • Abatacept plays a favourable role in the control of RA-ILD, with a significant worsening in only 11.4% of patients during a 18-month follow-up period. • The predictive variables related to RA-ILD progression during abatacept therapy are the concomitant treatment with methotrexate and current smoking habit.",
"affiliations": "Rheumatology Clinic, Università Politecnica Delle Marche, Via Aldo Moro, 25 - 60035 - Jesi, Ancona, Italy. marikatardella@gmail.com.;Rheumatology Clinic, Università Politecnica Delle Marche, Via Aldo Moro, 25 - 60035 - Jesi, Ancona, Italy.;Department of Radiology, Ospedali Riuniti, Università Politecnica Delle Marche, Ancona, Italy.;Department of Radiology, Ospedali Riuniti, Università Politecnica Delle Marche, Ancona, Italy.;Rheumatology Clinic, Università Politecnica Delle Marche, Via Aldo Moro, 25 - 60035 - Jesi, Ancona, Italy.",
"authors": "Tardella|Marika|M|http://orcid.org/0000-0003-4764-7197;Di Carlo|Marco|M|http://orcid.org/0000-0002-0906-4647;Carotti|Marina|M|http://orcid.org/0000-0001-6562-180X;Giovagnoni|Andrea|A|http://orcid.org/0000-0002-5264-652X;Salaffi|Fausto|F|http://orcid.org/0000-0002-3794-6831",
"chemical_list": "D018501:Antirheumatic Agents; D000069594:Abatacept; D008727:Methotrexate",
"country": "Germany",
"delete": false,
"doi": "10.1007/s10067-021-05854-w",
"fulltext": "\n==== Front\nClin Rheumatol\nClin Rheumatol\nClinical Rheumatology\n0770-3198\n1434-9949\nSpringer International Publishing Cham\n\n34313866\n5854\n10.1007/s10067-021-05854-w\nOriginal Article\nAbatacept in rheumatoid arthritis-associated interstitial lung disease: short-term outcomes and predictors of progression\nhttp://orcid.org/0000-0003-4764-7197\nTardella Marika marikatardella@gmail.com\n\n1\nhttp://orcid.org/0000-0002-0906-4647\nDi Carlo Marco dica.marco@yahoo.it\n\n1\nhttp://orcid.org/0000-0001-6562-180X\nCarotti Marina marina.carotti@gmail.com\n\n2\nhttp://orcid.org/0000-0002-5264-652X\nGiovagnoni Andrea a.giovagnoni@univpm.it\n\n2\nhttp://orcid.org/0000-0002-3794-6831\nSalaffi Fausto fausto.salaffi@gmail.com\n\n1\n1 grid.7010.6 0000 0001 1017 3210 Rheumatology Clinic, Università Politecnica Delle Marche, Via Aldo Moro, 25 - 60035 – Jesi, Ancona, Italy\n2 grid.7010.6 0000 0001 1017 3210 Department of Radiology, Ospedali Riuniti, Università Politecnica Delle Marche, Ancona, Italy\n27 7 2021\n27 7 2021\n2021\n40 12 48614867\n25 4 2021\n27 6 2021\n30 6 2021\n© The Author(s) 2021\nhttps://creativecommons.org/licenses/by/4.0/ Open AccessThis 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/.\nIntroduction\n\nInterstitial lung disease in rheumatoid arthritis (RA-ILD) is an extra-articular involvement that impairs the prognosis and for which there is still no well-coded treatment. The aim of this study was to evaluate abatacept (ABA) effectiveness and safety in patients with RA-ILD.\n\nMethods\n\nRA-ILD patients who started ABA treatment were consecutively enrolled. Chest high-resolution computed tomography (HRCT), clinical, laboratory and respiratory function variables were collected at baseline and after 18 months of ABA treatment. HRCT abnormalities were evaluated using a computer-aided method (CaM). ABA response was established based on the change in the percentage of fibrosis evaluated at HRCT-CaM, dividing patients into “worsened” (progression ≥ 15%), “improved” (reduction ≥ 15%), and “stable” (changes within the 15% range). The multivariate regression model was used to assess the associations between RA characteristics and ABA response.\n\nResults\n\nForty-four patients (81% women, mean age 59.1 ± 8.0, mean disease duration of 7.5 ± 3.1 years) were studied. Five patients (11.4%) showed RA-ILD progression, 32 patients (72.6%) were considered stable, and 7 patients (16.0%) showed an RA-ILD improvement. The proportion of current smokers was significantly different between “worsened” patients, respect to those defined as \"improved/stable” (p = 0.01). Current smoking habit (p = 0.005) and concomitant methotrexate treatment (p = 0.0078) were the two variables related to RA-ILD progression in multivariate regression analysis.\n\nConclusion\n\nTreatment with ABA is associated with a RA-ILD stability or improvement in the 88.6% of patients. Current smoking habit and concomitant treatment with methotrexate are the modifiable factors associated with RA-ILD worsening.Key Points\n\n• Abatacept plays a favourable role in the control of RA-ILD, with a significant worsening in only 11.4% of patients during a 18-month follow-up period.\n\n• The predictive variables related to RA-ILD progression during abatacept therapy are the concomitant treatment with methotrexate and current smoking habit.\n\n\t\n\nKeywords\n\nAbatacept\nHigh-resolution computed tomography\nInterstitial lung disease\nRheumatoid arthritis\nUniversità Politecnica delle MarcheOpen access funding provided by Università Politecnica delle Marche within the CRUI-CARE Agreement.\n\nissue-copyright-statement© International League of Associations for Rheumatology (ILAR) 2021\n==== Body\npmcIntroduction\n\nRheumatoid arthritis (RA) is a progressive systemic autoimmune disorder characterized by articular and extra-articular manifestations affecting about 0.5% of the adult population in Western countries [1]. Interstitial lung disease (ILD) is one of the most important extra-articular manifestations in RA [2]. The prevalence of RA-ILD varies from 1 to 67% depending on the method used to assess lung involvement and the study design [3–6]. The most commonly associated risk factors for predicting RA-ILD are advanced age, old age at onset of RA, male gender, smoking status and presence of anti-citrullinated peptide antibodies (ACPA) [7, 8]. In addition, some effective drugs used to treat RA can cause lung toxicity [9].\n\nHigh-resolution computed tomography (HRCT) of chest provides valuable information about ILD, including the pattern and extent of the disease [10]. HRCT abnormalities are found in 48–68% of asymptomatic patients and 90% of symptomatic patients with RA [11, 12]. During an average follow-up of 1.5 years, up to 57% of patients with asymptomatic RA-ILD have experienced a HRCT progression [13]. The usual interstitial pneumonia (UIP) pattern is more frequent in men and is associated with a worse prognosis, while the non-specific interstitial pneumonia (NSIP) pattern is more related to the female gender and has a better prognosis [14, 15]. The 5-year survival rate is 36% in patients with RA-ILD-UIP and 94% in patients with RA-ILD-NSIP, confirming the favourable outcome of patients with this last pattern [14].\n\nThis scenario highlights the need for effective treatment for RA-ILD, but its management is still debated and somewhat controversial [16]. In addition, the pulmonary toxicity of some disease-modifying anti-rheumatic drugs (DMARDs), particularly methotrexate (MTX), is still debated [17]. Immunosuppressive treatments also increase the risk of infection and, in particular, of severe lung infection with a high rate of hospitalization. On the other hand, certain biologic DMARDs (bDMARDs) demonstrated a promising effectiveness in slowing or stopping the progression of RA-ILD. Among these, abatacept (ABA), a T lymphocyte co-stimulation antagonist used in the treatment of RA, has shown some efficacy in the treatment of RA-ILD. ABA is also promising in light of the reduced infectious risk if compared to other bDMARDs [18]. However, the number of studies published on this issue is still small and mostly retrospective [19–21].\n\nTherefore, the main aim of this study was to evaluate the efficacy and safety of ABA treatment in RA-ILD patients and, as a second aim, to identify predictors of an unfavourable treatment outcome.\n\nMethods\n\nStudy population and assessment\n\nThis study included patients with a diagnosis of RA according to the American College of Rheumatology/European League Against Rheumatism classification criteria [22] and with a coexisting diagnosis of ILD, according to the criteria of the American Thoracic Society/ATS/ERS 2015 [23].\n\nFrom January 2016 to December 2019, RA-ILD patients attending the outpatient and inpatient clinics of the Rheumatology Clinic of the Polytechnic University of Marche (Italy) were consecutively enrolled. Inclusion criteria were the presence of RA-ILD and the need to start biotechnological drug for active RA, refractory to current therapy, if present. Patients who were concomitantly receiving MTX or other conventional synthetic DMARDs (csDMARDs) and/or glucocorticoids with a dosage of less than 10 mg/day prednisone or equivalent were included. We also included RA patients previously treated with bDMARS, discontinued due to intolerance or ineffectiveness. Patients with a history of pulmonary disease except for ILD, active malignancy, chronic heart failure and previous treatment with ABA were excluded.\n\nABA treatment was started at a dose of 125 mg/week subcutaneously for all patients, and this time was considered as time zero of the study. Patients were then followed according to normal daily practice with semiannual outpatient visits. A trained nurse monitored the administration of the drug and the occurrence of adverse events weekly by phone or e-mail.\n\nBaseline data were collected by a rheumatologist at time zero and included demographic variables, smoking habits, disease duration (defined as time since RA diagnosis), concomitant therapies and assessment of disease activity (Clinical Disease Activity Index (CDAI) [24] and Health Assessment Questionnaire-Disability Index (HAQ-DI) [25]). The presence of rheumatoid factor (RF) and ACPA was recorded. On the same day, pulmonary symptoms were assessed using the modified Borg Dyspnoea Index (BDI) [26].\n\nPulmonary function test (PFT), single-breath diffusion lung capacity of carbon monoxide (DLCO, % predicted, corrected for haemoglobin) and HRCT were performed within 2 weeks of the starting of ABA and after 18 months. Patients who discontinued ABA due to intolerance or ineffectiveness (CDAI persistently higher than 14) or who did not undergo HRCT after 18 months were excluded from the study. The diagnosis of ILD was performed using chest HRCT, and a quantitative evaluation of pulmonary fibrosis was performed using a computerized method of quantification (CaM), based on what has been described in detail in previous works [27–29]. HRCT images were reconstructed and analysed by OsiriX MD 7, a DICOM visualization software (OsiriX MD version 7, 64-bit format) on a Mac Mini (2.8 GHz Intel Core 2 Duo Desktop Computer, 16 GB random access memory; Apple Computer, Cupertino, CA, USA) with Mac OSX 10.12.2 operating system. Lung parenchymal abnormalities on HRCT were coded and evaluated by two independent radiologists, expert in lung diseases and blinded to the clinical data, using the CaM quantification process. No patient underwent lung biopsy.\n\nHRCT examination was repeated at 18 months after time zero, i.e. initiation of ABA treatment. This examination was also assessed semiquantitatively with CaM.\n\nThe local Ethics Committee (Comitato Unico Regionale—ASUR Marche, No 2015 0458 AS) approved the protocol. The study was conducted in accordance with the Helsinki Declaration in its fifth edition (2000). All patients signed the informed consent.\n\nStatistical analysis\n\nData were recorded in a Microsoft Excel database and processed with MedCalc 19.0.6 (statistical software packages for Windows XP). The Kolmogorov–Smirnov test was used to verify the normal distribution. Where appropriate, the medians and interquartile ranges (IQR), as well as the means and standard deviations (SD), are presented.\n\nA parametric two-sample t test and one-way analysis of variance (ANOVA) test were used to compare continuous variables and the χ2 test to compare categorical variables between patients. A two-sided coupled t test and the non-parametric Wilcoxon signed rank test were used to compare values at baseline and after 18-months of follow-up.\n\nThe analyses of the chest HRCT investigations performed at baseline and after 18 months were conducted dividing patients into three groups on the basis of the CaM-HRCT progression: patients with a lung fibrosis progression ≥ 15% were defined as “worsened”, those with a reduction of ≥ 15% were defined as “improved”, all other patients were defined as “stable”. The 15% CaM variation threshold resulted from the determination of the standard deviation of the mean value variation after 18 months of follow-up.\n\nFinally, we performed multivariate corrected regression analysis in order to assess the strength of the association between RA characteristics at baseline and HRCT response to ABA. The quantification of CaM was considered as dependent variable. The covariates included age, sex, disease duration, age at disease onset, smoking habit, RF presence, ACPA presence, CDAI and HAQ-DI. The results were expressed as multivariate regression coefficient (R) and corrected square regression coefficient (R2) for the number of variables included in the analysis. This allows to calculate the predictivity of each multivariate model based on the number of variables inserted in the model. The significance has been set to p < 0.05.\n\nResults\n\nFifty-four patients were included at time zero: 10 (18.5%) patients were eliminated during the course of the study, of whom 4 patients experienced a minor adverse event (3 for skin rush and one patient for diarrhoea) and 6 patients for ineffectiveness of ABA after 6 months of treatment (CDAI persistently higher than 22). No severe adverse events or deaths were reported in the followed cohort.\n\nWe therefore analysed the data of 44 patients (81% women) who completed the study. The mean age was 59.1 ± 8.0 years, and the mean disease duration was 7.5 ± 3.1 years. Twenty-three (52.3%) patients were ACPA positive and 28 (63.6%) RF positive. At baseline the percentage of current smokers was 38.6%. Mean clinical and instrumental data at time zero are summarised in Table 1. All patients were concomitantly treated with csDMARD, in particular MTX (20 patients, 45.5%), hydroxychloroquine (10 patients, 22.7%), leflunomide (8 patients, 18.2%), sulfasalazine (6 patients, 13.6%) at time zero. Sixteen (36.4%) patients were previously treated with a bDMARD, including etanercept (6 patients, 13.6%), adalimumab (6 patients, 13.6%), and tocilizumab (4 patients, 9.2%). A total of 31 (70.4%) patients were treated with corticosteroids at a mean dose of 3.7 (range 1.25–8.5) mg prednisolone/day equivalent. No patients developed tuberculosis during ABA therapy. Four patients underwent prophylactic antituberculous therapy in the month prior to inclusion in the study due to QuantiFERON test positivity.Table 1 Demographic characteristics, disease activity, functional disability, lung function, and high-resolution computed tomography data at the baseline (T0) and after 18 months of treatment (T18), expressed in means and standard deviations\n\n\tT0\t\t T18\t\t\t\n\tMean\tSD\tMean\tSD\tp*\t\nAge (years)\t59.05\t8.03\t–\t-\t\t\nDisease duration (years)\t7.55\t3.09\t–\t-\t\t\nCDAI\t34.66\t10.05\t10.11\t7.58\t < 0.001\t\nHAQ-DI\t1.45\t0.32\t0.75\t0.29\t < 0.001\t\nBorg Dyspnea Index\t2.54\t1.23\t1.90\t1.01\t0.01\t\nDLco (% predicted)\t58.69\t8.24\t61.26\t11.23\t0.22\t\nFVC (% predicted)\t82.29\t4.86\t81.24\t11.97\t0.59\t\nHRCT-CaM fibrosis (percentage)\t19.41\t5.89\t18.94\t6.06\t0.71\t\nLegend and abbreviations: * = two-sided paired Student t test; SD = standard deviation; CDAI = Clinical Disease Activity Index; HAQ-DI = Health Assessment Questionnaire Disability Index; DLco = diffusion lung capacity of carbon monoxide; FVC = forced vital capacity; HRCT = high-resolution computed tomography; CaM = computer-aided method.\n\nThe patients experienced a significant improvement in RA disease activity and joint function. The mean CDAI score decreased from 34.66 to 10.11 (p < 0.001), and the mean HAQ-DI score decreased from 1.45 to 0.75 (p < 0.001) at 18 months (Table 1).\n\nWith regard to chest HRCT findings, significant changes in the CaM score were not detectable in the whole cohort (p = 0.71). At the end of the 18 months follow-up, 5 (11.4%) patients showed a HRCT deterioration of RA-ILD, 32 (72.6%) were considered stable, and 7 (16.0%) patients showed an HRCT improvement. Figure 1 shows an example of an improved patient. Analysing the differences between groups, the proportions of current smokers and of patients treated with MTX were significantly higher in the “worsened” compared to those defined as “improved/stable” (80% vs 33.35%, p = 0.01 and 60% vs 38.6%, p = 0.01, respectively).Fig. 1 High-resolution computed tomography scans of a patient with rheumatoid arthritis-associated interstitial lung disease at baseline, starting abatacept treatment (A), and after 18 months of therapy (B). In A are detectable “ground-glass” opacities (asterisks) and pulmonary consolidations (arrowheads), while in B “ground-glass” opacities are significantly reduced and pulmonary consolidations disappeared\n\nAt the multivariate regression analysis, the predictive variables related to RA-ILD progression during ABA therapy were concomitant treatment with MTX (p = 0.0078) and current smoking habit (p = 0.0054). Gender, disease duration, ACPA presence, RF presence, DLco, FVC, CDAI and HAQ-DI were not significantly associated with RA-ILD worsening (Table 2).Table 2 Multivariate regression analysis of the variables predictive of pulmonary fibrosis evaluated at high-resolution computed tomography by the computer-aided method (dependent variable)\n\nIndependent variables\tCoefficient\tStandard error\tt\tp\tr partial\t\n(Constant)\t1.6370\t\t\t\t\t\nAge (years)\t-0.0012\t0.0050\t-0.238\t0.8131\t-0.0427\t\nGender\t0.0254\t0.1084\t0.235\t0.8161\t0.0420\t\nDisease duration (years)\t0.0157\t0.0176\t0.891\t0.3799\t0.1580\t\nACPA positivity\t-0.0129\t0.0712\t-0.182\t0.8566\t-0.0327\t\nRF positivity\t0.0030\t0.0790\t0.038\t0.9694\t0.0069\t\nCurrent smokers\t-0.3485\t0.1165\t-2.992\t0.0054\t-0.4733\t\nMethotrexate use\t-0.3956\t0.1390\t-2.847\t0.0078\t-0.4552\t\nDLco (% predicted)\t0.0052\t0.0061\t0.848\t0.4030\t0.1505\t\nFVC (% predicted)\t-0.0088\t0.0088\t-1.006\t0.3224\t-0.1777\t\nCDAI\t-0.0074\t0.0038\t-1.962\t0.0588\t-0.3324\t\nHAQ-DI\t-0.0173\t0.1459\t-0.119\t0.9059\t-0.0214\t\nAbbreviations: ACPA = anti-cytrullinated protein antibodies; RF = rheumatoid factor; DLco = diffusion lung capacity of carbon monoxide; FVC = forced vital capacity; CDAI = Clinical Disease Activity Index; HAQ-DI = Health Assessment Questionnaire Disability Index\n\nDiscussion\n\nIn this study it has been demonstrated that ABA plays a favourable role in the control of RA-ILD, with a significant worsening in only 11.4% of patients during the 18-month follow-up period.\n\nThis study consolidates some research already conducted regarding the value of ABA in RA-ILD. The first study on the safety of ABA in RA-ILD described four patients with RA-ILD exacerbated or manifested for the first time during treatment with csDMARDs. The patients were treated with ABA for a mean period of 35 months, without showing a worsening of lung function [20]. Nakashita and colleagues investigated the effect of ABA and other bDMARDs in two retrospective studies of RA-ILD patients [30, 31]. In the first study, they evaluated a group of patients starting therapy with bDMARDs and divided them into two groups according to the presence or absence of ILD at HRCT screening of the chest. After 12 months, patients who developed exacerbations or new ILD were all on TNFi therapy, whereas patients treated with ABA or tocilizumab had no exacerbations or onset of ILD in either group [30]. In the second study, patients with RA-ILD were evaluated, 16 of whom were starting ABA treatment and 46 of whom were starting TNFi treatment. After 12 months, ABA-treated patients showed no worsening of RA-ILD at chest HRCT, whereas 30% of TNFi-treated patients revealed a worsening of RA-ILD [31].\n\nA Spanish multicentre retrospective study examined 63 RA-ILD patients, 15 of whom developed ILD immediately after the introduction of csDMARDs or bDMARDs. The authors investigated HRCT findings at baseline and after 12 months only in patients with persistent dyspnoea (22 patients, 34%). Of these, 50% showed stabilisation, 36.4% improvement and 13.6% worsening of ILD [19]. The same Spanish group recently expanded the multicentre study including 263 RA-ILD patients treated with ABA [21]. After 12 months of treatment, only 3 of 67 asymptomatic patients at baseline had mild dyspnoea, while 20% showed improvement in dyspnoea. FVC remained stable or improved in 87.7% of patients and DLCO in 90.6% of patients. HRCT improved in 24 cases (18.8%), while it worsened in 30 (23.4%) and the rest of patients remained stable. They also found a corticosteroid-sparing effect of ABA therapy.\n\nThis study is currently the one with the largest number of RA-ILD patients enrolled and treated with ABA. The obtained results show a clear majority of patients who “remain stable” or “improve” compared to those who “worsen”, thus affirming that ABA is a safe treatment in RA-ILD patients. Kurata and colleagues showed also that, in a RA population, after the initiation of bDMARD therapy, pre-existing airway disease is an independent risk factor for the onset or exacerbation of ILD, whereas ABA therapy is a protective factor [32]. ABA has a low-risk of worsening pre-existing ILD and could therefore play an important role in the clinical management of RA-ILD patients. We could speculate that ABA has a “protective effect” on the onset/exacerbation of ILD because, on one hand, the efficacy of blocking T-cell co-stimulation in the non-infectious lung inflammatory process has been demonstrated in the animal model of interstitial pneumonia; on the other hand, it is the drug with the lowest infectious risk compared to the other bDMARDs, thus causing a lower incidence of respiratory tract infections [18, 33, 34]. Regarding the latter, it is important to point out that other biotechnology drugs, recommended for RA patients with pre-existing ILD, have a high infectious risk and high rate of neutropenia or reduction of serum immunoglobulins [35, 36]. In fact, although there are no comparison studies, rituximab and tocilizumab treatments are associated with higher infectious risk than ABA in meta-analyses, and there are reports of exacerbations of persistent ILD or onset of ILD in RA patients on rituximab or tocilizumab therapy [37, 38]. In addition, further observations should be pointed out if we consider antifibrotic drugs in RA-ILD therapy. There are still some ongoing studies on this topic, but currently available data, extrapolated from some case reports, describe the successful use of nintedanib or pirfenidone in RA-ILD. Therefore, we believe that careful choice of therapy for RA-ILD patients is useful, particularly if a restrictive pulmonary syndrome is already present.\n\nIn the case of persistent active synovitis during ABA therapy, we suggest combining one or more DMARDs, preferably hydroxychloroquine or sulfasalazine for their low toxic effects on the lung if there are more than three inflamed joints, while it would be useful to undergo the patient to locoregional infiltrative therapy if there are two or fewer inflamed joints. In case of persistent active disease, it’s useful replacing the biotechnological drug as international guidelines suggest. For this reason, patients with high disease activity were excluded from our study.\n\nIn our cohort the percentage of “worsened” patients is higher than the evidence in the international literature, and this may be related to the different HRCT assessment method. To our knowledge, this is the first study using HRCT-CaM to estimate response to therapy in patients with RA-ILD. Recently we demonstrated that a quantitative analysis of ILD using a CaM is more responsive than applying a semi-quantitative visual method in assessing ILD progression in systemic sclerosis [27]. Therefore, the possibility of using standardised CaMs shared by the scientific community for HRCT quantification of ILD could be evaluated, both in research and clinical settings, due to the greater sensitivity in detecting differences [5] and more reliable results.\n\nAs a second goal, namely the identification of progression predictors for treatment response, current smokers and MTX-treated patients seemed to respond poorly to ABA. The relationship between cigarette smoking and respiratory disease is well documented. In addition, a strong causal relationship between cigarette smoking, the presence of ACPA and the development of RA-ILD has been widely demonstrated [39]. Therefore, all smoking patients should be helped to stop smoking because of its documented pulmonary toxicity.\n\nIn contrast, the relationship between MTX therapy and pulmonary response to ABA is challenging to explain [40]. MTX-induced pulmonary toxicity, presented as acute/subacute or rarely as chronic pneumonia, has been a subject of debate for many years [41, 42]. In recent years, however, this has been questioned with more emphasis on the increased risk of pulmonary infections in patients during MTX therapy rather than direct lung damage. In a meta-analysis of 21 studies from 1990 to 2011, including 8,276 RA patients, it was found that MTX was not associated with an increased risk of total adverse respiratory events and that there were no differences in the risk of pulmonary involvement between patients taking MTX and those not taking it. There was an increased risk of lower respiratory tract infection [43]. In clinical practice, distinguishing MTX-induced pulmonary toxicity from RA-ILD is a challenge and detecting the presence of an infection can be difficult. The worsening of ILD detected in the combined ABA and MTX patients in our study is therefore a fact of non-unique interpretation. Mochizuki and coworkers performed a retrospective study of 131 RA-patients treated with ABA and MTX, and they too found MTX to be a negative prognostic factor for lung response to ABA, as the RA-ILD patients who worsened were all on MTX-ABA combination therapy [44]. The most reasonable interpretation in light of recent data is that patients requiring ABA and MTX combination therapy have a more aggressive disease and may have more frequent extra-articular involvement. Although MTX is still the drug of choice for RA therapy, it may be advisable to reduce or discontinue it when clinical remission is achieved in RA-ILD patients, also in the light of international guidelines [45].\n\nThis scenario is also complicated by the presence of subclinical ILD in about 30% of RA patients, evaluated with chest HRCT [46, 47]. The lack of a valid screening tool to detect the presence of ILD in connective tissue diseases is another point of interest, due to the high exposure to ionising radiation of chest HRCT. A good correlation between HRCT and chest ultrasound in ILD detection has been demonstrated [48, 49], offering a valid and feasible tool for the detection of pulmonary involvement in RA patients [50], but not yet validated in international studies.\n\nThis study has some limitations: firstly, a low number of enrolled patients; secondly, a control group was not recruited; finally, we do not have data on the onset of ILD.\n\nIn conclusion, the use of ABA in the treatment of RA-ILD patients can be considered a first choice, especially for its proven safety and therefore for its likely efficacy on lung damage. It can also be stated that MTX therapy should be used with caution in patients with ILD due to the increased risk of infection.\n\nAuthor contribution\n\nFS conceived and designed the study and the protocol. MC and AG performed the HRCT examinations and their relative interpretation and were involved in revising the paper for important intellectual content. FS, MT, and MDC carried out data interpretation and analysis. FS, MT, MDC, and MC wrote the paper. MT, FS and MDC were involved in drafting the article or revising it critically for important intellectual content. All authors approved the final version to be submitted for publication.\n\nFunding\n\nOpen access funding provided by Università Politecnica delle Marche within the CRUI-CARE Agreement.\n\nCompliance with ethical standards\n\nDisclosure\n\nNone.\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. 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Salaffi F Carotti M Di Carlo M Tardella M Giovagnoni A High resolution computed tomography of the lung in patients with rheumatoid arthritis Medicine 2019 98 38 e17088 31567944\n6. Zou YQ Li YS Ding XN The clinical significance of HRCT in evaluation of patients with rheumatoid arthritis-associated interstitial lung disease: a report from China Rheumatol Intern 2012 32 669 673\n7. Mori S Koga Y Sugimoto M Different risk factors between interstitial lung disease and airway disease in rheumatoid arthritis Respir Med 2012 106 1591 1599 22867979\n8. Bergström U Jacobsson LT Nilsson JÅ Pulmonary dysfunction, smoking, socio-economic status and the risk of developing rheumatoid arthritis Rheumatology (Oxford) 2011 50 2005 2013 21859698\n9. Hyldgaard C Hilberg O Pedersen AB A population-based cohort study of rheumatoid arthritis-associated interstitial lung disease: comorbidity and mortality Ann Rheum Dis 2017 76 1700 1706 28611082\n10. Bellia M Cannizzaro F Scichilone N HRCT and scleroderma: semi-quantitative evaluation of lung damage and functional abnormalities Radiol Med 2009 114 190 203 19266260\n11. Kanat F Levendoglu F Teke T Radiological and functional assessment of pulmonary involvement in the rheumatoid arthritis patients Rheumatol Int 2007 27 459 466 17028857\n12. Zrour SH Touzi M Bejia I Correlations between high-resolution computer tomography of the chest and clinical function in patient with rheumatoid arthritis. Prospective study in 75 patients Joint Bone Spine 2005 72 41 47 15681247\n13. Dawson J Fewins H Desmond J Lynch M Graham D Predictors of progression of HRCT diagnosed fibrosing alveolitis in patients with rheumatoid arthritis Ann Rheum Dis 2002 61 517 521 12006324\n14. Lee HK Kim DS Yoo B Histopathologic pattern and clinical features of rheumatoid arthritis-associated interstitial lung disease Chest 2005 127 2019 2027 15947315\n15. Kim EJ Elicker BM Maldonado F Usual interstitial pneumonia in rheumatoid arthritis-associated interstitial lung disease Eur Respir J 2010 35 1322 1328 19996193\n16. Mori S Management of rheumatoid arthritis patients with interstitial lung disease: safety of Biological antirheumatic drugs and assessment of pulmonary Fibrosis Clin Med Insights Circ Resp Pulm Med 2015 9 Suppl 1 41 49\n17. Roubille C Haraoui B Interstitial lung diseases induced or exacerbated by DMARDS and biologic agents in rheumatoid arthritis: a systematic literature review Semin Arthritis Rheum 2014 43 613 626 24231065\n18. Yun H Xie F Delzell E Comparative risk of hospitalized infection associated with biologic agents in rheumatoid arthritis patients enrolled in medicare Arthtiris Rheumatol 2016 68 56 66\n19. Fernández-Díaz C Loricera j, Castañeda S, Abatacept in patients with rheumatoid arthritis and interstitial lung disease: a national multicenter study of 63 patients Semin Arthritis Rheum 2018 48 22 27 29422324\n20. Mera-Varela A Pérez-Pampín E Abatacept therapy in rheumatoid arthritis with interstitial lung disease J Clin Rheumatol 2014 20 445 446 25417684\n21. Fernández-Díaz C Castañeda S Melero-González RB Abatacept in interstitial lung disease associated with rheumatoid arthritis: national multicenter study of 263 patients Rheumatology (Oxford) 2020 59 12 3906 3916 33068439\n22. Aletaha D Neogi T Silman AJ 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative Arthritis Rheum 2010 62 2569 2581 20872595\n23. Raghu G Rochwerg B Zhang Y An official ATS/ERS/JRS/ALAT clinical practice guideline: treatment of idiopathic pulmonary fibrosis. an update of the 2011 clinical practice guideline American journal of respiratory and critical care medicine 2015 192 e3 19 26177183\n24. Aletaha D Nell VP Stamm T Acute phase reactants add little to composite disease activity indices for rheumatoid arthritis: validation of a clinical activity score Arthritis Res Ther 2005 7 R796 806 15987481\n25. Fries JF Spitz P Kraines RG Measurement of patient outcome in arthritis Arthritis Rheum 1980 23 137 145 7362664\n26. Borg GA Psychophysical bases of perceived exertion Med Sci Sports Exerc 1982 14 377 381 7154893\n27. Salaffi F Carotti M Tardella M Computed tomography assessment of evolution of interstitial lung disease in systemic sclerosis: comparison of two scoring systems Eur J Intern Med 2020 76 71 75 32089425\n28. Ariani A Carotti M Gutierrez M Utility of an open-source DICOM viewer software (OsiriX) to assess pulmonary fibrosis in systemic sclerosis: preliminary results Rheumatol Int 2014 34 511 516 23949623\n29. Salaffi F, Carotti M, Bosello S et al (2015) Computer-aided quantification of interstitial lung disease from high resolution computed tomography images in systemic sclerosis: correlation with visual reader-based score and physiologic tests. Biomed Res Int 2015: 834262.\n30. Nakashita T, Ando K, Kaneko N, Takahashi K, Motojima S (2014) Potential risk of TNF inhibitors on the progression of interstitial lung disease in patients with rheumatoid arthritis. BMJ Open 4:e00561.\n31. Nakashita T Ando K Takahashi K Motojima S Possible effect of abatacept on the progression of interstitial lung disease in rheumatoid arthritis patients Respir Investig 2016 54 376 379 27566388\n32. Kurata I Tsuboi H Terasaki M Effect of biological disease-modifying anti-rheumatic drugs on airway and interstitial lung disease in patients with rheumatoid arthritis Intern Med 2019 58 1703 1712 30799358\n33. Harigai M Ishiguro N Inokuma S Postmarketing surveillance of the safety and effectiveness of abatacept in Japanese patients with rheumatoid arthritis Mod Rheumatol 2016 26 491 498 26635183\n34. Michot JM Bigenwald C Champiat S Immune-related adverse events with immune checkpoint blockade: a comprehensive review Eur J Cancer 2016 54 139 148 26765102\n35. Holroyd CR Seth R Bukhari M The British Society for Rheumatology biologic DMARD safety guidelines in inflammatory arthritis Rheumatology (Oxford) 2019 58 2 e3 e42 30137552\n36. Manfredi A Cassone G Furini F Tocilizumab therapy in rheumatoid arthritis with interstitial lung disease: a multicenter retrospective study Intern Med J 2019 50 9 1085 1090\n37. Zhou T Shen Q Peng H Incidence of interstitial pneumonitis in non-Hodgkin's lymphoma patients receiving immunochemotherapy with pegylated liposomal doxorubicin and rituximab Ann Hematol 2018 97 1 141 147 29086009\n38. Akiyama M Kaneko Y Yamaoka K Association of disease activity with acute exacerbation of interstitial lung disease during tocilizumab treatment in patients with rheumatoid arthritis: a retrospective, case-control study Rheumatol Int 2016 36 6 881 889 27072347\n39. Israël-Assayag E Fournier M Cormier Y Blockade of T cell costimulation by CTLA4-Ig inhibits lung inflammation in murine hypersensitivity pneumonitis J Immunol 1999 163 6794 6799 10586079\n40. Sandhu A Dhir V Ahmad S Clinico-genetic model to predict methotrexate intolerance in rheumatoid arthritis Clin Rheumatol 2020 39 201 206 31522319\n41. Salaffi F Manganelli P Carotti M Subiaco S Lamanna G Cervini C Methotrexate-induced pneumonitis in patients with rheumatoid arthritis and psoriatic arthritis: report of five cases and review of the literature Clin Rheumatol 1997 16 296 304 9184269\n42. Khadadah ME Jayakrishnan B Al-Gorair S Effect of methotrexate on pulmonary function in patients with rheumatoid arthritis—a prospective study Rheumatol Int 2002 22 204 207 12215867\n43. Conway R Low C Coughlan RJ O'Donnell MJ Carey JJ Methotrexate and lung disease in rheumatoid arthritis: a meta-analysis of randomized controlled trials Arthritis Rheumatol 2014 66 803 812 24757133\n44. Mochizuki T Ikari K Yano K Long-term deterioration of interstitial lung disease in patients with rheumatoid arthritis treated with abatacept Modern Rheumatology 2018 29 3 413 417 29798700\n45. Singh JA Saag KG Bridges SL Jr Akl EA Bannuru RR Sullivan MC American College of Rheumatology guideline for the treatment of rheumatoid arthritis Arthritis Care Res (Hoboken) 2016 68 1 25 26545825\n46. Olson AL Swigris JJ Sprunger DB Rheumatoid arthritis-interstitial lung disease-associated mortality Am J Respir Crit Care Med 2011 183 372 378 20851924\n47. Delle Sedie A Doveri M Frassi F Ultrasound lung comets in systemic sclerosis: a useful tool to detect lung interstitial fibrosis Clin Exp Rheumatol 2010 28 5 Suppl 62 S54 21050546\n48. Tardella M Gutierrez M Salaffi F Ultrasound in the assessment of pulmonary fibrosis in connective tissue disorders: correlation with high- resolution computed tomography J Rheumatol 2012 39 1641 1647 22753655\n49. Tardella M Di Carlo M Carotti M Filippucci E Grassi W Salaffi F Ultrasound B-lines in the evaluation of interstitial lung disease in patients with systemic sclerosis Medicine 2018 97 e0566 29718851\n50. Di Carlo M, Tardella M, Filippucci E, Carotti M, Salaffi F (2021) Lung ultrasound in patients with rheumatoid arthritis: definition of significant interstitial lung disease. Clin Exp Rheumatol PMID: 33938789\n\n",
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"abstract": "In a prospective study of 43,117 people, prescriptions issued by general practitioners over two years were linked with records of hospital admissions and deaths. For 57 people injured or killed while driving cars, motorcycles, or bicycles the medicines that had been dispensed in the three months before were compared with those dispensed for 1,425 matched controls. There was a highly significant association between use of minor tranquillisers and the risk of a serious road accident (relative risk estimate 4.9). the increased risk of accidents to drivers given tranquillisers could be due to the known psychomotor effects of these drugs or to effects of the conditions being treated. Whatever the reason, patients taking drugs such as diazepam should be warned that they are at special risk.",
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"abstract": "Subcutaneous allergen immunotherapy (SCIT) is highly effective but safety risks exist.\n\n\n\nThe aims of this study were to: (1) identify clinical practices that could influence fatal and nonfatal systemic allergic reactions (SRs) to SCIT, and (2) identify SCIT-associated infections.\n\n\n\nFrom 2008 to 2016, 27% to 51% of American Academy of Allergy, Asthma, and Immunology/American College of Allergy, Asthma, and Immunology members completed an annual survey of SCIT-related SRs of varying severity. Injection-related local cutaneous and systemic infections were queried for 2014-2016. For 2014-2016, respondents were queried about timing of onset of SRs, postinjection waiting times, and prescription/use of epinephrine autoinjectors.\n\n\n\nData were gathered on 54.4 million injection visits (2008-2016). Two confirmed fatalities from SCIT occurred between 2008 and 2014. An additional 5 confirmed fatalities occurred between 2015 and 2017. No infections occurred in 17.3 million injection visits (2014-2016). Among practices monitoring patients for at least 30 minutes, 15% of SRs occurred after 30 minutes. Practices prescribing an epinephrine autoinjector >90% of the time (29% of practices) did not experience lower rates of delayed grade 3/4 SRs. Of patients experiencing grade 3/4 delayed SRs, 26% and 8% used prescribed self-injectable epinephrine devices during 2014-2015 and 2015-2016, respectively.\n\n\n\nThere is an unexplained slight increase in SCIT-related fatalities for 2015-2017, although mean annual reported events over 9 years (0.8 fatal reactions per year) have declined. SCIT-related infections were not identified during 2 years of surveillance. The 15% incidence of delayed-onset SRs (>30 minutes) is similar to a prior annual survey. Prescribing epinephrine autoinjectors for SCIT does not appear to improve outcomes, possibly due to low rates of self-administration.",
"affiliations": "Division of Immunology, Allergy, and Rheumatology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Allergy Partners of Central Indiana, Indianapolis, Ind. Electronic address: epsteite@uc.edu.;Dalla Lana School of Public Health, Occupational and Environmental Health Division, University of Toronto, Toronto, Ontario, Canada.;Bernstein Clinical Research Center, Cincinnati, Ohio.;Division of Immunology, Allergy, and Rheumatology, Department of Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio; Bernstein Clinical Research Center, Cincinnati, Ohio.",
"authors": "Epstein|Tolly G|TG|;Liss|Gary M|GM|;Berendts|Karen Murphy|KM|;Bernstein|David I|DI|",
"chemical_list": "D001993:Bronchodilator Agents; D004837:Epinephrine",
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"keywords": "Asthma; Cluster immunotherapy; Epinephrine prescription; Fatalities; Infection risk; SCIT; Safety; Subcutaneous allergen immunotherapy",
"medline_ta": "J Allergy Clin Immunol Pract",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000707:Anaphylaxis; D001993:Bronchodilator Agents; D003888:Desensitization, Immunologic; D004837:Epinephrine; D017809:Fatal Outcome; D006801:Humans; D006969:Hypersensitivity, Immediate; D007239:Infections; D007273:Injections, Intramuscular; D007279:Injections, Subcutaneous; D008297:Male; D012646:Self Administration",
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"references": null,
"title": "AAAAI/ACAAI Subcutaneous Immunotherapy Surveillance Study (2013-2017): Fatalities, Infections, Delayed Reactions, and Use of Epinephrine Autoinjectors.",
"title_normalized": "aaaai acaai subcutaneous immunotherapy surveillance study 2013 2017 fatalities infections delayed reactions and use of epinephrine autoinjectors"
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{
"abstract": "Immune checkpoint inhibitors (ICIs) have been shown to improve overall and progression-free survival in various cancers but have been associated with various immune-related adverse events (IRAEs), including interstitial lung disease, especially organizing pneumonia. We report 2 cases of isolated severe airway disease attributable to ICIs, a rarely reported pattern of lung toxicity. The first patient received nivolumab with or without ipilimumab in a randomized double-blind trial for locoregional metastatic melanoma. The second patient was treated with nivolumab for lung adenocarcinoma. An IRAE was suspected in both cases due to a temporal relationship between ICI initiation and symptom onset. ICIs were stopped, and high-dose prednisone, inhaled corticosteroids, and bronchodilators were administered, allowing a rapid clinical and functional improvement in Patient 1. In Patient 2, despite prolonged high-dose prednisone, only a stabilization of forced expiratory volume in 1 s could be achieved, and the disease course was complicated by respiratory infections resulting in further loss of lung function. The patient died 1 year later due to progression of metastatic disease. These 2 cases suggest that pulmonary IRAEs secondary to ICIs may present as isolated bronchitis or bronchiolitis, with variable outcomes following ICI withdrawal and systemic corticosteroids.",
"affiliations": "Respiratory Medicine Department, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;Respiratory Medicine Department, Lausanne University Hospital (CHUV), Lausanne, Switzerland, cecile.daccord@chuv.ch.;Division ofRespiratory Medicine, Cantonal Hospital, Neuchâtel, Switzerland.;Division of Respiratory Medicine, Morges Hospital - EHC, Morges, Switzerland.;Center of Respiratory Medicine and Pulmonary Rehabilitation, Rolle Hospital - GHOL, Rolle, Switzerland.;Department of Medical Oncology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;Institute of Pathology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;Radiodiagnostic and Interventional Radiology, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;Respiratory Medicine Department, Lausanne University Hospital (CHUV), Lausanne, Switzerland.;Respiratory Medicine Department, Lausanne University Hospital (CHUV), Lausanne, Switzerland.",
"authors": "Mitropoulou|Georgia|G|;Daccord|Cécile|C|;Sauty|Alain|A|;Pasche|Antoine|A|;Egger|Bernard|B|;Aedo Lopez|Veronica|V|;Letovanec|Igor|I|;Beigelman-Aubry|Catherine|C|;Nicod|Laurent P|LP|;Lazor|Romain|R|",
"chemical_list": "D058666:Adrenergic beta-2 Receptor Agonists; D005938:Glucocorticoids; D000082082:Immune Checkpoint Inhibitors; D000077594:Nivolumab",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000504968",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7931",
"issue": "99(2)",
"journal": "Respiration; international review of thoracic diseases",
"keywords": "Bronchiolitis; Bronchitis; Drug-related side effects and adverse reactions; Immunotherapy; Ipilimumab; Lung; Nivolumab",
"medline_ta": "Respiration",
"mesh_terms": "D000077192:Adenocarcinoma of Lung; D000310:Adrenal Gland Neoplasms; D058666:Adrenergic beta-2 Receptor Agonists; D000368:Aged; D001982:Bronchial Diseases; D001992:Bronchoalveolar Lavage Fluid; D001999:Bronchoscopy; D004417:Dyspnea; D005260:Female; D005541:Forced Expiratory Volume; D005938:Glucocorticoids; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D008175:Lung Neoplasms; D008207:Lymphatic Metastasis; D008297:Male; D008482:Mediastinum; D008545:Melanoma; D008875:Middle Aged; D000077594:Nivolumab; D011653:Pulmonary Diffusing Capacity; D012131:Respiratory Insufficiency; D012878:Skin Neoplasms; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "0137356",
"other_id": null,
"pages": "181-186",
"pmc": null,
"pmid": "31914436",
"pubdate": "2020",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Immunotherapy-Induced Airway Disease: A New Pattern of Lung Toxicity of Immune Checkpoint Inhibitors.",
"title_normalized": "immunotherapy induced airway disease a new pattern of lung toxicity of immune checkpoint inhibitors"
} | [
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{
"abstract": "BACKGROUND\nAntipsychotic agents are well known for their arrhythmigenic effect on ventricular arrhythmia. Though a few case reports observed the occurrence of atrial fibrillation (AF) after antipsychotic exposure, information about their implication in AF is limited.\n\n\nMETHODS\nBased on the National Health Insurance Database in Taiwan, we conducted a nested case-control study to investigate the relationship between antipsychotics and AF. From 2001 to 2010, a total of 34,053 cases of AF and 34,919 matched controls were enrolled. Antipsychotic exposure was measured and binding affinity to neurotransmitter receptors was calculated. Both medical and psychiatric comorbidities were identified and adjusted in multivariate logistic regression analysis.\n\n\nRESULTS\nCurrent antipsychotic use was associated with a 17% increased risk of AF relative to nonusers (adjusted OR: 1.17, 95% CI: 1.10-1.26). A dose-dependent relationship of antipsychotic exposure and AF risk was observed (P for trend <0.001). Antipsychotics with higher binding affinity to muscarinic M2 receptors were associated with a higher incidence of AF. In subgroup analysis, subjects with preexisting hypertension, diabetes, or coronary artery diseases were at greater risk of developing AF following antipsychotic exposure.\n\n\nCONCLUSIONS\nAntipsychotic exposure was associated with increased risk of AF, especially for agents with higher cardiac muscarinic receptor binding affinity. Physicians should monitor the occurrence of new-onset AF, and strictly control underlying medical risk factors while prescribing antipsychotic agents to high-risk populations.",
"affiliations": "Division of Cardiology, Department of Medicine, Taipei, Taiwan; Cardiovascular Research Center, Taipei, Taiwan; Institute of Clinical Medicine, Taipei, Taiwan.;Division of Cardiology, Department of Medicine, Taipei, Taiwan; Institute of Clinical Medicine, Taipei, Taiwan.;Department of Psychiatry, Taipei, Taiwan; Division of Psychiatry, School of Medicine, Taipei, Taiwan.;Department of Nursing, Taipei, Taiwan.;Department of Nursing, Taipei, Taiwan.;Department of Nursing, Taipei, Taiwan.;Department of Medical Research and Education, Taipei, Taiwan; Cardiovascular Research Center, Taipei, Taiwan.;Division of Cardiology, Department of Medicine, Taipei, Taiwan; Cardiovascular Research Center, Taipei, Taiwan; Institute of Clinical Medicine, Taipei, Taiwan.;Division of Cardiology, Department of Medicine, Taipei, Taiwan; Department of Medical Research and Education, Taipei, Taiwan; Cardiovascular Research Center, Taipei, Taiwan; Institute of Clinical Medicine, Taipei, Taiwan.;Division of Cardiology, Department of Medicine, Taipei, Taiwan; Department of Medical Research and Education, Taipei, Taiwan; Cardiovascular Research Center, Taipei, Taiwan; Institute of Pharmacology National Yang-Ming University, Taipei, Taiwan.;Division of Cardiology, Department of Medicine, Taipei, Taiwan; Healthcare and Management Center, Taipei Veterans General Hospital, Taipei, Taiwan.;Division of Cardiology, Department of Medicine, Taipei, Taiwan; Healthcare and Management Center, Taipei Veterans General Hospital, Taipei, Taiwan; Cardiovascular Research Center, Taipei, Taiwan; Institute of Clinical Medicine, Taipei, Taiwan. Electronic address: hbleu@vghtpe.gov.tw.",
"authors": "Chou|Ruey-Hsing|RH|;Lo|Li-Wei|LW|;Liou|Ying-Jay|YJ|;Shu|Jiah-Hwang|JH|;Hsu|Hsiu-Chuan|HC|;Liang|Ying|Y|;Huang|Chin-Chou|CC|;Huang|Po-Hsun|PH|;Lin|Shing-Jong|SJ|;Chen|Jaw-Wen|JW|;Chan|Wan-Leong|WL|;Leu|Hsin-Bang|HB|",
"chemical_list": "D014150:Antipsychotic Agents",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijcard.2016.11.185",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0167-5273",
"issue": "227()",
"journal": "International journal of cardiology",
"keywords": "Antipsychotic agents; Atrial fibrillation; Autonomic dysfunction; Psychiatric diseases",
"medline_ta": "Int J Cardiol",
"mesh_terms": "D017677:Age Distribution; D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D014150:Antipsychotic Agents; D001281:Atrial Fibrillation; D016022:Case-Control Studies; D016001:Confidence Intervals; D016208:Databases, Factual; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D012016:Reference Values; D012189:Retrospective Studies; D018570:Risk Assessment; D012720:Severity of Illness Index; D017678:Sex Distribution; D016019:Survival Analysis; D013624:Taiwan",
"nlm_unique_id": "8200291",
"other_id": null,
"pages": "134-140",
"pmc": null,
"pmid": "27855291",
"pubdate": "2017-01-15",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Antipsychotic treatment is associated with risk of atrial fibrillation: A nationwide nested case-control study.",
"title_normalized": "antipsychotic treatment is associated with risk of atrial fibrillation a nationwide nested case control study"
} | [
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{
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}
],
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},
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"literaturereference": "CHOU RH, LO LW, LIOU YJ, SHU JH, HSU HC, LIANG Y, ET AL. ANTIPSYCHOTIC TREATMENT IS ASSOCIATED WITH RISK OF ATRIAL FIBRILLATION: A NATIONWIDE NESTED CASE-CONTROL STUDY. INTERNATIONAL JOURNAL OF CARDIOLOGY 15-JAN-2017;227:134-140.",
"literaturereference_normalized": "antipsychotic treatment is associated with risk of atrial fibrillation a nationwide nested case control study",
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},
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},
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},
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}
] |
{
"abstract": "BACKGROUND Intrahepatic cholangiocarcinoma is a rare condition which typically occurs in males between 50 and 70 years of age, and presents with symptoms related to biliary obstruction including jaundice, pruritus, and dark urine. Other common symptoms at presentation include abdominal pain, weight loss, and fever. CASE REPORT We present a case of a 67-year-old female initially presenting with chest pain at rest, found to have a lung nodule on diagnostic imaging at the time of admission. On further imaging, a 9 cm liver lesion was incidentally discovered, initially suspicious for hepatocellular carcinoma on imaging, with initial biopsy staining CK7 positive, and CK20 negative. The patient also had an elevated alpha-fetoprotein level. Biopsy results were later confirmed as moderately differentiated adenocarcinoma consistent with intrahepatic cholangiocarcinoma. CONCLUSIONS This report illustrates an unusual presentation of intrahepatic cholangiocarcinoma. Although rare, cholangiocarcinoma is diagnosed most frequently as an incidental finding on imaging studies. With quick work-up and successful biopsy results, patients can undergo surgical or chemo-radiation therapy earlier, potentially leading to a longer survival time.",
"affiliations": "Graduate Medical Education, Camden Clark Medical Center, Parkersburg, WV, USA.;Department of Internal Medicine, Camden Clark Medical Center, Parkersburg, WV, USA.",
"authors": "Tasch|Joseph J|JJ|;Dube|Nirva|N|",
"chemical_list": "D014408:Biomarkers, Tumor; D000509:alpha-Fetoproteins",
"country": "United States",
"delete": false,
"doi": "10.12659/ajcr.906165",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 2931759110.12659/AJCR.906165906165ArticlesAn Unusual Presentation of Advanced Intrahepatic Cholangiocarcinoma: When Biopsy Results Fail Tasch Joseph J. ABDEF1Dube Nirva D2\n1 Graduate Medical Education, Camden Clark Medical Center, Parkersburg, WV, U.S.A.\n2 Department of Internal Medicine, Camden Clark Medical Center, Parkersburg, WV, U.S.A.Authors’ Contribution:\n\nA Study Design\n\nB Data Collection\n\nC Statistical Analysis\n\nD Data Interpretation\n\nE Manuscript Preparation\n\nF Literature Search\n\nG Funds Collection\n\nConflict of interest: None declared\n\nCorresponding Author: Joseph Tasch, e-mail contacts: jjtasch@camdenclark.org, skoglexa@gmail.com2018 10 1 2018 19 35 40 12 7 2017 17 9 2017 © Am J Case Rep, 20182018This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Female, 67\n\nFinal Diagnosis: Intrahepatic cholangiocarcinoma\n\nSymptoms: Atypical chest pain\n\nMedication: —\n\nClinical Procedure: Liver biopsy\n\nSpecialty: Internal Medicine/Oncology\n\nObjective:\nRare disease\n\nBackground:\nIntrahepatic cholangiocarcinoma is a rare condition which typically occurs in males between 50 and 70 years of age, and presents with symptoms related to biliary obstruction including jaundice, pruritus, and dark urine. Other common symptoms at presentation include abdominal pain, weight loss, and fever.\n\nCase Report:\nWe present a case of a 67-year-old female initially presenting with chest pain at rest, found to have a lung nodule on diagnostic imaging at the time of admission. On further imaging, a 9 cm liver lesion was incidentally discovered, initially suspicious for hepatocellular carcinoma on imaging, with initial biopsy staining CK7 positive, and CK20 negative. The patient also had an elevated alpha-fetoprotein level. Biopsy results were later confirmed as moderately differentiated adenocarcinoma consistent with intrahepatic cholangiocarcinoma.\n\nConclusions:\nThis report illustrates an unusual presentation of intrahepatic cholangiocarcinoma. Although rare, cholangio-carcinoma is diagnosed most frequently as an incidental finding on imaging studies. With quick work-up and successful biopsy results, patients can undergo surgical or chemo-radiation therapy earlier, potentially leading to a longer survival time.\n\nMeSH Keywords:\nCarcinoma, HepatocellularChest PainCholangiocarcinomaSolitary Pulmonary Nodule\n==== Body\nBackground\nIntrahepatic tumors have traditionally been classified as primary liver cancers. The term cholangiocarcinoma has recently been used to describe bile duct cancers within the intrahepatic, perihilar, and distal (extrahepatic) biliary tree. The tumors typically originate either within the small intrahepatic ductules or larger intrahepatic ducts proximal to the bifurcation of the left/right hepatic ducts [1].\n\nClassically, patients with advanced disease will present with symptoms including jaundice, pruritus, clay-colored stools, and dark urine [1]. Multiple risk factors have been associated with the development of cholangiocarcinoma, including primary sclerosing cholangitis, congenital hepatic fibrosis, choledochal cysts, liver fluke infections, cholelithiasis, hepatolithiasis, Thorotrast contrast dye exposure, viral hepatitis, other chronic liver diseases, obesity, and HIV infection [2].\n\nWhile the molecular pathogenesis remains unclear, it is suspected that conversion from normal to malignant bile epithelium generally requires a stepwise accumulation of genetic abnormalities. Molecular defects involving several oncogenes and tumor suppressor genes have been studied and seem to be related to more aggressive tumor phenotypes [3].\n\nCase Report\nA 67-year-old Caucasian female presented with complaints of atypical chest pain, described as a sensation of nausea, with bilateral superior chest/low anterior cervical pressure and paresthesia. She developed a posterior throbbing headache while she was sitting on her couch to rest. These symptoms relapsed every five to 10 minutes over several hours; then occurred on several isolated occasions over the next three to four days until the time of admission. She also mentioned several episodes of bilious emesis during her first occurrence. At the time of presentation, she denied overt chest pain, hemoptysis, fever, chills, shortness of breath, diarrhea or constipation, or urinary symptoms.\n\nPast medical/surgical history included COPD of unspecified severity with no home oxygen requirement, hypothyroidism, hypertension, GERD, depression, diabetes mellitus type 2, diastolic congestive heart failure, remote fall history with right intertrochanteric fracture, and history of a cholecystectomy performed three years prior, hysterectomy, thyroidectomy, and right total knee replacement. Social history included former tobacco abuse, quit date three years prior, with 72 pack year history. She denied current or former recreational drug or alcohol use. Family history included mother with fatal course of bronchitis, a father with history of metastatic melanoma at age 70 years, and a brother with history of a myocardial infarction.\n\nOn admission, the patient’s initial vitals included blood pressure 130/78 mm Hg, pulse 80, respirations 20, temperature 97.9°F (36.6°C), and an oxygen saturation of 97% on room air. Physical examination revealed a well-developed, obese, alert and oriented female in no acute distress, sitting up in bed. Dermatologic examination revealed multiple healed surgical scars present over abdomen and right knee. Head, ears, eyes, nose, throat (HEENT)/ neck/ cardiovascular/ respiratory/ gastrointestinal/ musculoskeletal/ neurological/ and immunological examinations were all grossly unremarkable. Initial ECG was unremarkable for acute ischemic changes.\n\nLaboratory assessments on admission were as follows: white blood cell count (WBC) 12.3; hemoglobin/hematocrit (Hgb/Hct) 14.0/44.0; platelets 219; sodium 142; potassium 4.8; chloride 104; carbon dioxide 23; blood urea nitrogen (BUN) 25; creatinine 1.00; calcium 10.2; troponin <0.012; CKMB 0.47; CPK 75; INR 0.85; prothrombin time 9.9; partial thromboplastin time 30.4; and hemoglobin A1c 5.8%.\n\nThe patient was admitted to a telemetry floor as an acute coronary syndrome rule out. Serial ECG’s and cardiac enzymes were unremarkable for an acute ischemic cardiac process. A single anterior-posterior view chest x-ray showed presence of emphysema and a possible small left upper lobe lung nodule.\n\nFurther imaging of the patient’s chest with CT imaging utilizing IV contrast revealed mild emphysema and a 9 mm lobulated nodule in the left upper lobe (Figure 1), which was considered likely to represent a granuloma. Evidence of prior granulomatous disease with probable focal scarring in both lower lobes was observed, and several small punctate nodular densities were noted laterally in the right mid lung field. Lastly, a large, nearly 10 cm heterogeneous low density mass posteriorly in the right hepatic lobe, noted to be new since a November 2013 study, and considered concerning for neoplasm was noted, with no notable chest lymphadenopathy, pneumothorax, or pleural effusion.\n\nA CT scan of the abdomen/pelvis with and without IV contrast was then obtained the following day, showing the presence of a large, heterogeneous, centrally necrotic irregular mass in the posterior segment of the right lobe of the liver superiorly measuring approximately 7.5×9.8×8.5 cm (Figure 2A), which demonstrated irregular discontinuous peripheral enhancement, thought to be highly suggestive of primary hepatocellular carcinoma. A 3 cm heterogeneous irregular mass was also noted in the medial aspect of the right kidney demonstrating mild continuous enhancement, concerning for primary renal cell carcinoma (Figure 2B). No evidence of bowel obstruction, acute inflammatory process, or adenopathy was seen within the abdomen or pelvis. Lastly, a tiny left renal cyst was observed.\n\nIt is important to mention the patient’s prior cholecystectomy was performed at an outside institution and information surrounding the surgery was unavailable. However, a CT abdomen/pelvis without contrast was obtained several months after the surgery, though still three years prior to this admission, due to an episode of right flank pain. This imaging modality showed presence of mild hepatic steatosis with an absent gallbladder. Additionally, the 3 cm mass over the right kidney was present on this study and appeared to have been unchanged from prior study. This lesion hence forward was considered benign.\n\nAt this time, an alpha-fetoprotein (AFP) level was obtained and determined to be 15.7. A CT-guided core biopsy was also obtained of the right hepatic lesion, specifically four 18-gauge samples were obtained, two from the central portion of the mass and two from the anterior periphery. It revealed the presence of poorly differentiated adenocarcinoma, with immunohistochemical staining showing malignant glands positive for CK7, while negative for CK20 and CDX2. The patient at this time was discharged from the hospital with close follow-up scheduled with the oncology office for further work-up.\n\nOutcome and follow-up\nThe patient had a PET scan with CT fusion approximately one week after discharge showing nonspecific activity over the small left upper lobe nodule with a standardized activity unit (SUV) of 1.7, with hypermetabolic activity (SUV 11.5) seen over the right hepatic mass. The kidneys and adrenal glands were reportedly unremarkable. The differential at this point was considered broad by the oncology service, and included neoplasms of bile duct, breast, and lung origins.\n\nThe patient required an additional CT-guided liver biopsy procedure, where six more 18-gauge core samples were obtained (Figure 3). These were obtained two weeks after discharge, and were sent for tissue of origin testing at an outside facility, utilizing micro RNA testing. The results suggested the presence of moderately differentiated adenocarcinoma consistent with cholangiocarcinoma.\n\nLater, a CT-guided biopsy of the patient’s left lung lesion was consistent with metastatic cholangiocarcinoma. The patient was then started on chemotherapy with gemcitabine and oxaliplatin. The patient tolerated only a few cycles of chemotherapy before readmission several months later for hepatic encephalopathy and septic shock, which the patient would die from during the hospital stay.\n\nDiscussion\nThe patient, after the repeat hepatic biopsy results, was formally diagnosed with primary intrahepatic cholangiocarcinoma. Roughly 5% to 10% of cholangiocarcinomas are of the intrahepatic subtype, and they typically originate from small intrahepatic ductules or large intrahepatic ducts proximal to the bifurcation of the right and left hepatic ducts [4]. Tumors occurring at the confluence of the left and right hepatic ducts represent Klatskin tumors [5]. Less than 10% of cases documented are found to represent intrahepatic disease [6]. Over the last several decades, the incidence of intrahepatic cholangiocarcinoma has increased internationally. However, the increased incidence is not correlated to an increase in earlier staged lesions [7,8].\n\nCholangiocarcinoma can be divided into three subtypes: sclerosing, nodular, and papillary [9]. Sclerosing tumors are noted to be by far the most common, causing a rather significant desmoplastic reaction, with extensive fibrosis. The pathology report of our patient’s tumor commented specifically on the large amount of necrotic and fibrotic changes, making this the most likely subtype.\n\nCommon signs and symptoms include jaundice, pruritus, clay-colored stools, and dark urine when the tumor invasion leads to biliary system obstruction. The intrahepatic subtype can also result in complaints of abdominal pain, weight loss, fever, malaise, fatigue, and night sweats. However, some patients remain asymptomatic, with lesions seen incidentally on screening imaging for abnormal liver function tests, or in known hepatitis B or C patients [10]. The patient in our case possessed none of the described symptoms; however, she did mention a non-specific chest pressure and paresthesia sensation. The initial presentation was misleading due to the absence of common symptoms associated with intrahepatic malignancy, especially since the patient’s chest pain symptoms improved during her hospital stay. This made the need for a confirmatory tissue diagnosis paramount to facilitate appropriate care.\n\nThere are several risk factors for cholangiocarcinoma, including primary sclerosing cholangitis (PSC) and fibropolycystic liver disease [11]. Chronic liver diseases, including liver cirrhosis and hepatitis, have also been correlated with cholangiocarcinoma, specifically of the intrahepatic subtype. We felt that this patient did not possess these conditions, given the absence of alcohol and drug use history, the original CT abdomen/pelvis study showing no presence of cirrhotic changes, and follow-up laboratory studies showing normal liver function tests. Additionally a check for hepatitis B surface antigen after discharge was negative.\n\nThe patient was noted to have a slightly elevated AFP level, which led to the consideration of primary hepatocellular carcinoma, especially given the initial radiology impression strongly in favor of a primary hepatocellular carcinoma lesion. This was also taken into consideration with the patient’s initial biopsy results staining positive for CK7 but negative for CK20, which is nonspecific for primary hepatocellular carcinoma or cholangiocarcinoma. Given these characteristics of the liver lesion, there was suspicion for hepatocellular carcinoma. However, after obtaining the initial pathology report showing the presence of poorly differentiated adenocarcinoma, the accuracy of the results was in question.\n\nIt was also unclear where the site of origin laid, whether in the bile ducts, breasts, or the lungs being the primary sites of concern. After discussion with the pathologists, the recommendation to obtain slides for micro RNA testing was made, although this implied additional tissue was needed, so the patient was scheduled for another hepatic biopsy. Despite the presence of some necrosis on the initial samples, this was considered minimal by the pathologists report and did not significantly alter the results. Additionally, the sample sizes ranged from 1.0 cm to 1.8 cm, which were considered large enough for accurate interpretation.\n\nThere was also some discussion over the possibility of an underlying combined hepatocellular-cholangiocarcinoma. Combined hepatocellular-cholangiocarcinoma is known as a recently acknowledged distinct subtype of cholangiocarcinoma, seen in patients with elements of both cholangiocarcinoma and hepatocellular carcinoma [2]. For our patient, further laboratory work was obtained after discharge, including a normal hepatitis B surface antigen, with normal liver function tests and total bilirubin. In conjunction with the aforementioned biopsy results, this diagnosis was excluded. Primary colon cancer was ruled out initially from the first CT diagnostic imaging performed, in addition to the PET scan results.\n\nIt was important to differentiate between hepatocellular carcinoma and cholangiocarcinoma. Although both malignancies can be treated curatively with hepatic resection, liver transplant, or chemoembolization, advanced disease therapies differ more significantly. Advanced hepatocellular carcinoma has been treated with doxorubicin as single drug therapy, but has shown inefficacy with a response rate of about 15% to 20% [12]. Multiple other agents, such as cisplatin, 5-fluorouracil, etoposide, and combinations thereof, have demonstrated either similar or lower efficacy. The tyrosine kinase inhibitor sorafenib has been developed recently, though it has shown only an improved survival of three months [13]. These modalities were considered as the final diagnosis was being made.\n\nOnce the final diagnosis was determined, multiple combinations of agents were considered for this patient’s chemotherapy. The first choice therapy considered was the combination of gemcitabine and cisplatin, which has been shown to provide a median survival of approximately 9.30 months [14], and 11.7 months [15], with palliative care having a survival timeframe averaging six months, with a five-year survival rate around 1.2% [16]. However, the patient was noted at the time of her office visit to have a slightly elevated serum creatinine of 1.40, and was not considered a candidate for this drug regimen. Instead, the patient was started on a non-cisplatin regimen, including oxaliplatin with gemcitabine which has also been shown to have a median survival of 11 months in unresectable biliary tract cancers [17].\n\nRegretfully, there was little discussion regarding the role of chemotherapy versus palliative care during this patient’s initial hospital visit. In retrospect, this patient survived about nine months from time of diagnosis with 10 cycles of oxaliplatin with gemcitabine administered over a five-month period. Though this patient initially tolerated the chemotherapy regimen, she became increasing weak, eventually developing an altered mental state leading to a hospital admission, where she would die as a result of her disease. It is difficult to state whether being exposed to the effects of chemotherapy was a more desirable outcome for this patient. Palliative care could have been offered to determine if the goals of care the patient desired were different than what the chemotherapy regimen offered. Also, palliation could have optimized the quality of life the patient had until death. Every treatment option, including palliative therapy alone, should be offered and explained to patients who are diagnosed with an advanced stage malignancy.\n\nConclusions\nThe presented case demonstrates several important aspects of intrahepatic cholangiocarcinoma. First, several patients can present without symptoms or abnormal liver functions tests, relying heavily on incidental imaging findings to initiate work-up. Second, radiology findings and tumor markers must be correlated with pathology findings for a final diagnosis, especially in cases where a general consensus for a specific diagnosis does not exist. Our patient showed a unique presentation since in the setting of an elevated AFP, the radiologist’s findings correlating with hepatocellular carcinoma, and the initial biopsy samples staining positive for CK7 but negative for CK20; our patient was ultimately diagnosed with cholangiocarcinoma.\n\nThe final diagnosis required a second CT-guided hepatic biopsy for confirmation, which occurred after discharge and required two additional weeks. Only after the second biopsy sample confirmed the diagnosis of moderately-differentiated cholangiocarcinoma, did the attending oncologist recommend that the patient be evaluated by a surgeon for potential hepatic resection. It was decided that the patient would not be a candidate for such a procedure, and the patient was sent for a biopsy of the left upper lobe lesion in order to determine the stage of the malignancy.\n\nAdditionally, the patient required a biopsy of the left lung lesion to be scheduled at an outside facility, which required more time to contribute to the final diagnosis and complete tumor staging. This procedure could only be done at an outside tertiary care facility, since interventional radiology was not an available subspecialty offered at the institution where primary work-up had occurred. This delay prevented the patient from undergoing chemotherapy at an earlier time, which could have potentially led to an increased survival time.\n\nMost cases of cholangiocarcinoma are extrahepatic in nature, and present most commonly with abnormal laboratory findings. The aforementioned case describes an intrahepatic subtype, with complicating components suggesting a possible hepatocellular carcinoma. This patient required multiple hepatic biopsies to confirm a final diagnosis, resulting in an increased hospital stay, a higher financial burden, and a delay in treatment. Clinicians should be made more aware of the misleading nature of intrahepatic cholangiocarcinoma to improve the efficiency of obtaining an accurate, final diagnosis. Retrospectively, further evaluation for hepatitis B and C, in addition to utilizing more samples from the first CT-guided liver biopsy during the initial hospital stay should have been conducted to determine the underlying diagnosis at a faster pace.\n\nWe would like to thank Dr. Robert Herceg, MD for his support in obtaining the liver pathology slides. We also thank Dr. Peter Strobl MD and Dr. Philip Strobl MD for their time and assistance in obtaining the radiology images. Lastly, we thank Dr. Nik Shah MD for his overall direction and guidance, and for assistance obtaining records from the oncology office.\n\nConflict of Interests\n\nNone.\n\nFigure 1. Axial CT image of the pulmonary nodule, felt to represent a granuloma in the left upper lobe.\n\nFigure 2. (A, B) These images show the 9.4×9.8 cm right hepatic lobe mass on axial and coronal views; (B) 3 cm heterogeneous kidney mass (yellow arrow).\n\nFigure 3. Hematoxylin and eosin stained slide of the repeated liver biopsy at approximately 400× magnification. Malignant cells are seen surrounding the biliary ductules (red arrows).\n==== Refs\nReferences:\n1. Patel T Cholangiocarcinomas-controversies and challenges Nat Rev Gastroenterol Hepatol 2011 8 189 200 21460876 \n2. Chapman RW Risk factors for biliary tract carcinogenesis Ann Oncol 1999 10 Suppl. 4 308 11 10436847 \n3. Khan SA Davidson BR Goldin RD Guidelines for the diagnosis and treatment of cholangiocarcinoma: An update Gut 2012 61 12 1657 69 22895392 \n4. Nagorney DM Pawlik TM Chun YS Perihilar bile ducts. American Joint Committee on Cancer, Cancer Staging Manual, 8th Amin MB American Joint Committee on Cancer Chicago 2017 312 \n5. Klatskin G Adenocarcinoma of the hepatic duct at its bifurcation within the porta hepatis. An unusual tumor with distinctive clinical and pathological features Am J Med 1965 38 2 241 56 14256720 \n6. DeOliveira ML Cunningham SC Cameron JL Cholangiocarcinoma: Thirty-one-year experience with 564 patients at a single institution Ann Surg 2007 245 755 62 17457168 \n7. Patel T Increasing incidence and mortality of primary intrahepatic cholangiocarcinoma in the United States Hepatology 2001 33 1353 57 11391522 \n8. Jarnagin WR Cholangiocarcinoma of the extrahepatic bile ducts Semin Surg Oncol 2000 19 156 76 11126380 \n9. Nakeeb A Pitt HA Sohn TA Cholangiocarcinoma. A spectrum of intrahepatic, perihilar, and distal tumors Ann Surg 1996 224 463 73 discussion 473–75 8857851 \n10. Saha SK Zhu AX Fuchs CS Brooks GA Forty-year trends in cholangiocarcinoma incidence in the U.S.: Intrahepatic disease on the rise Oncologist 2016 21 5 594 99 27000463 \n11. Akiba J Nakashima O Hattori S Clinicopathologic analysis of combined hepatocellular-cholangiocarcinoma according to the latest WHO classification Am J Surg Pathol 2013 37 496 505 23388123 \n12. Yeo W Mok TS Zee B A randomized phase III study of doxorubicin versus cisplatin/interferon alpha-2b/doxorubicin/fluorouracil (PIAF) combination chemotherapy for unresectable hepatocellular carcinoma J Natl Cancer Inst 2005 97 1532 38 16234567 \n13. Cao H Phan H Yang L Improved chemotherapy for hepatocellular carcinoma Anticancer Res 2012 32 1379 86 22493374 \n14. Lee G Kang J Kim H Combination chemotherapy with gemcitabine and cisplatin as first-line treatment for immunohistochemically proven cholangiocarcinoma Am J Clin Oncol 2006 29 127 31 16601429 \n15. Valle J Wasan H Palmer D Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer N Engl J Med 2010 362 1273 81 20375404 \n16. Carriaga MT Henson DE Liver, gallbladder, extrahepatic bile ducts, and pancreas Cancer 1995 75 Suppl. 1 171 90 8000995 \n17. Harder J Riecken B Kummer O Outpatient chemotherapy with gemcitabine and oxaliplatin in patients with biliary tract cancer Br J Cancer 2006 95 848 52 16969352\n\n",
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"mesh_terms": "D000368:Aged; D001650:Bile Duct Neoplasms; D001653:Bile Ducts, Intrahepatic; D014408:Biomarkers, Tumor; D001706:Biopsy; D018281:Cholangiocarcinoma; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D033162:Incidental Findings; D009367:Neoplasm Staging; D000509:alpha-Fetoproteins",
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"title": "An Unusual Presentation of Advanced Intrahepatic Cholangiocarcinoma: When Biopsy Results Fail.",
"title_normalized": "an unusual presentation of advanced intrahepatic cholangiocarcinoma when biopsy results fail"
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{
"abstract": "To raise awareness among pediatric intensive care specialists of catecholaminergic polymorphic ventricular tachycardia; an uncommon cause of polymorphic ventricular tachycardia and ventricular fibrillation arrest in children and young adults where epinephrine (adrenaline), even when given according to international protocols, can be counter-productive and life-threatening. We review three cases of cardiac arrest in children, later proven to be catecholaminergic polymorphic ventricular tachycardia related, where delay in recognition of this condition resulted in significantly longer resuscitation efforts, more interventions, and a longer time to return of spontaneous circulation.\n\n\n\nRetrospective case series.\n\n\n\nTertiary children's hospital.\n\n\n\nThree previously well children 4, 5, and 10 years old presented with cardiac arrest triggered by light activity, partial water immersion, and running, respectively. Initial resuscitation was bystander cardiopulmonary resuscitation and community defibrillation in all three cases. Electrocardiograms revealed multifocal ventricular ectopy, and in two (4 and 10 yr old), this correlated with repeated administration of epinephrine during repeated ventricular tachycardia and ventricular fibrillation cardiac arrest resuscitation cycles. This ultimately resolved immediately (at 78 and 140 min, respectively) with IV opiates once catecholaminergic polymorphic ventricular tachycardia was suspected. During recovery, on extracorporeal membrane oxygenation, epinephrine challenge in two children induced polymorphic ventricular tachycardia, bidirectional ventricular tachycardia, and ventricular fibrillation, which was cardioverted with flecainide in the 4-year-old. The third case was recognized early as catecholaminergic polymorphic ventricular tachycardia and was managed by avoiding epinephrine and using opiates and general anesthesia after the initial (single) cardioversion, and had a much better clinical course, without recourse to extracorporeal membrane oxygenation. All three carried de novo RyR2 (cardiac ryanodine) mutations.\n\n\n\nThose involved in resuscitation of young people should be aware of catecholaminergic polymorphic ventricular tachycardia and be suspicious of persistent ventricular ectopy, polymorphic, or bidirectional ventricular tachycardia during resuscitation. Appropriate management is avoidance of epinephrine, administration of general anesthesia, IV opiates, and consideration of flecainide.",
"affiliations": "Green Lane Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland, New Zealand.;Paediatric Intensive Care Unit, Starship Children's Hospital, Auckland, New Zealand.;Children's Emergency Department, Starship Children's Hospital, Auckland, New Zealand.;Green Lane Paediatric and Congenital Cardiac Services, Starship Children's Hospital, Auckland, New Zealand.",
"authors": "Bellamy|David|D|;Nuthall|Gabrielle|G|;Dalziel|Stuart|S|;Skinner|Jonathan R|JR|",
"chemical_list": "D019837:Ryanodine Receptor Calcium Release Channel; D004837:Epinephrine",
"country": "United States",
"delete": false,
"doi": "10.1097/PCC.0000000000001847",
"fulltext": "\n==== Front\nPediatr Crit Care MedPediatr Crit Care MedPCCPediatric Critical Care Medicine1529-7535Lippincott Williams & Wilkins 0000710.1097/PCC.0000000000001847Review ArticleCatecholaminergic Polymorphic Ventricular Tachycardia: The Cardiac Arrest Where Epinephrine Is Contraindicated* Bellamy David MBChB1Nuthall Gabrielle MBChB, FRACP, CICM23Dalziel Stuart MBChB, FRACP, PhD45Skinner Jonathan R. MD, MRCP (UK), FRACP, FHRS1561 Green Lane Paediatric and Congenital Cardiac Services, Starship Children’s Hospital, Auckland, New Zealand.2 Paediatric Intensive Care Unit, Starship Children’s Hospital, Auckland, New Zealand.3 Department of Paediatrics Child and Youth Health, the University of Auckland, Auckland, New Zealand.4 Children’s Emergency Department, Starship Children’s Hospital, Auckland, New Zealand.5 Departments of Surgery and Paediatrics: Child and Youth Health, the University of Auckland, Auckland, New Zealand.6 Cardiac Inherited Disease Group, Auckland City Hospital, Auckland, New Zealand.For information regarding this article, E-mail: jskinner@adhb.govt.nz3 2019 01 3 2019 20 3 262 268 Copyright © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and the World Federation of Pediatric Intensive and Critical Care Societies.2019This is an open-access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC-ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.Objectives:\nTo raise awareness among pediatric intensive care specialists of catecholaminergic polymorphic ventricular tachycardia; an uncommon cause of polymorphic ventricular tachycardia and ventricular fibrillation arrest in children and young adults where epinephrine (adrenaline), even when given according to international protocols, can be counter-productive and life-threatening. We review three cases of cardiac arrest in children, later proven to be catecholaminergic polymorphic ventricular tachycardia related, where delay in recognition of this condition resulted in significantly longer resuscitation efforts, more interventions, and a longer time to return of spontaneous circulation.\n\nDesign:\nRetrospective case series.\n\nSetting:\nTertiary children’s hospital.\n\nPatients and Results:\nThree previously well children 4, 5, and 10 years old presented with cardiac arrest triggered by light activity, partial water immersion, and running, respectively. Initial resuscitation was bystander cardiopulmonary resuscitation and community defibrillation in all three cases. Electrocardiograms revealed multifocal ventricular ectopy, and in two (4 and 10 yr old), this correlated with repeated administration of epinephrine during repeated ventricular tachycardia and ventricular fibrillation cardiac arrest resuscitation cycles. This ultimately resolved immediately (at 78 and 140 min, respectively) with IV opiates once catecholaminergic polymorphic ventricular tachycardia was suspected. During recovery, on extracorporeal membrane oxygenation, epinephrine challenge in two children induced polymorphic ventricular tachycardia, bidirectional ventricular tachycardia, and ventricular fibrillation, which was cardioverted with flecainide in the 4-year-old. The third case was recognized early as catecholaminergic polymorphic ventricular tachycardia and was managed by avoiding epinephrine and using opiates and general anesthesia after the initial (single) cardioversion, and had a much better clinical course, without recourse to extracorporeal membrane oxygenation. All three carried de novo RyR2 (cardiac ryanodine) mutations.\n\nConclusions:\nThose involved in resuscitation of young people should be aware of catecholaminergic polymorphic ventricular tachycardia and be suspicious of persistent ventricular ectopy, polymorphic, or bidirectional ventricular tachycardia during resuscitation. Appropriate management is avoidance of epinephrine, administration of general anesthesia, IV opiates, and consideration of flecainide.\n\narrhythmiacardiopulmonary resuscitationcatecholaminergic polymorphic ventricular tachycardiapediatric resuscitationOPEN-ACCESSTRUE\n==== Body\nCatecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic condition with an estimated prevalence of 1 in 10,000 (1, 2), characterized by epinephrine (adrenaline)-induced polymorphic ventricular tachycardia (VT) leading to syncope and sudden death in children and adolescents. Genetic tests in those who died from sudden unexplained death (autopsy negative) under 35 years old reveal this condition almost as commonly as long QT syndrome (3, 4). Common triggers include exercise or emotion (1, 5–8). Outpatient diagnosis depends on exercise-induced ventricular ectopy, bidirectional, or polymorphic VT (2, 9). Epinephrine challenges have been used to demonstrate provocation of polymorphic or bidirectional VT (9–11). Genetic testing reveals mutations in the cardiac ryanodine receptor gene (RyR2) in 50–60% of those with CPVT (1, 2, 6–9, 12). Long-term treatments for CPVT are β-blockers, flecainide, and left cardiac sympathetic denervation (2, 7, 13–17) with implantable cardiac defibrillator (ICD) indicated in some patients (1, 2, 9, 15, 18).\n\nEpinephrine is recommended as part of current advanced cardiopulmonary resuscitation (CPR) guidelines (19–22). Here we describe three children who presented following cardiac arrest, ultimately proven to be due to CPVT, where the clinical course was either made worse through the administration of epinephrine and/or improved by the use of opiate analgesia and/or general anesthesia with avoidance of epinephrine. In two of these cases, we also describe how epinephrine testing while on extracorporeal membrane oxygenation (ECMO) was used to diagnose CPVT, and in one where flecainide stopped the VT.\n\nEach subject is enrolled in the consent-based and ethically approved Cardiac Inherited Disease Registry New Zealand, which permits deidentified publication of clinical and genetic information. Because some potentially identifying features are presented, signed informed consent was obtained from each of the parents after they reviewed the article.\n\nCASES\nCase A\nA 4-year-old boy (approximately 20 kg) collapsed while playing outside with another young child, unwitnessed by any adults. An estimated 2–4 minutes passed before CPR was started by an adult family member. Ambulance staff arrived 5 minutes after initiation of CPR and found the child in asystole. Return of spontaneous circulation occurred 10 minutes after initiation of chest compressions and bag-mask ventilation only. On route to hospital at 23 minutes after CPR was started, he had another cardiac arrest, described as pulseless electrical activity (PEA). At this time, the first bolus of IV epinephrine (0.2 mg~0.01 mg/kg) was given, after which he went into ventricular fibrillation (VF) and was shocked with 100 J into sinus bradycardia at 50–60 beats/min.\n\nIn the emergency department, at 34 minutes, he was breathing spontaneously with a sinus bradycardia of 40 beats/min and poor peripheral perfusion, he received two further boluses of 0.2 mg IV epinephrine, 3 and 7 minutes later. There were frequent multimorphic ventricular extrasystoles (VEs). At 46 minutes, he had another VF arrest, at which point CPR was recommenced then two 100 J shocks, IV saline (10 mL/kg), and calcium (1 mL/kg 10% calcium gluconate) were given. After this, he was intubated and ventilated. He was still in VF after the intubation, and with CPR continuing, an additional 0.2 mg epinephrine bolus was given at 56 minutes with another direct current (DC) shock and amiodarone (10 µg/kg), after which he reverted to sinus rhythm at 110 beats/min for around 6 minutes, but with intermittent ventricular ectopy.\n\nAt 64 minutes, he had another low output arrest with sinus rhythm but very weak/absent central pulses and interspersed runs of VT. A fifth epinephrine bolus was given followed by an epinephrine infusion was started at 0.05 µg/kg/min. In addition, he received IV magnesium, lignocaine, and saline boluses and had a further 0.2 mg epinephrine bolus 10 minutes later, after which the epinephrine infusion was increased to 0.5 µg/kg/min. The rhythm alternated between sinus bradycardia and rapid polymorphic VT.\n\nAt 78 minutes on the advice of a pediatric electrophysiologist, the epinephrine infusion was stopped and 200 µg (10 µg/kg) of fentanyl was given IV. This dramatically altered the course of events. Within minutes, CPR was ceased as he had a return of spontaneous circulation with a sinus bradycardia of 50 beats/min and mean blood pressure of 75–85 mm Hg. Following the resuscitation, he was put on ECMO because of severe metabolic acidosis (pH, 6.9; lactate, 6.1 mmol/L), hypoxemia, and poor myocardial function (ejection fraction, 18%).\n\nIn total, he received six epinephrine boluses, an epinephrine infusion, and 4 DC shocks for VF.\n\nThe 12 lead electrocardiogram was normal and the left ventricular function returned rapidly to normal while on ECMO. There were no features to suggest myocarditis, and there was no family history of sudden death or syncope.\n\nAfter 24 hours on ECMO, with stable hemodynamic and metabolic parameters, and good ejection on echocardiography, an epinephrine challenge was done to confirm the diagnosis of CPVT. An infusion was started at 0.2 µg/kg/min which induced polymorphic VT. A flecainide bolus of 40 mg over a few minutes led to gradual resolution of the tachycardia, confirming the diagnosis (Figs. 1–3).\n\nFigure 1. Series of 12 lead electrocardiograms. All recorded at 25 mm/s. Initiation of ventricular tachycardia with epinephrine challenge.\n\nFigure 2. Series of 12 lead electrocardiograms. All recorded at 25 mm/s. More organized, bidirectional ventricular tachycardia after the commencement of the flecainide infusion.\n\nFigure 3. Series of 12 lead electrocardiograms. All recorded at 25 mm/s. Termination of ventricular tachycardia during flecainide administration, resolving here to frequent ventricular ectopy and after this into sinus rhythm.\n\nAn ICD was inserted, and regular atenolol and flecainide were started. Genetic testing confirmed a de novo RyR2 mutation (p.Ser2246Leu), absent in both parents. His ICD has not fired in 12 months of follow-up.\n\nCase B\nCase B, a 10-year-old girl (weight 30 kg), had a background of presumed epileptic seizures associated with exercise. While running, she was witnessed to collapse, followed by a brief seizure. She was found to be pulseless and not breathing. CPR was initiated by bystanders for 8 minutes before ambulance staff arrived. DC shock (150 J) was delivered for VF, and 0.8 mg (~0.03 mg/kg) IV epinephrine was given. Return of spontaneous circulation was recorded after 20 minutes, and she was transported to the local hospital. A second VF arrest occurred at 38 minutes, on arrival at the hospital, with delivery of a 70 J DC shock and return of spontaneous circulation. IV magnesium and amiodarone were given, and a propofol infusion was started. She had another VF arrest and received seven recorded DC shocks, but no epinephrine. She returned to sinus rhythm at 81 beats/min, with occasional ventricular ectopy and remained stable for over an hour on a propofol infusion.\n\nAt 2 and 3 hours, she had further VF arrests receiving five and four DC shocks, respectively. She was given IV magnesium, amiodarone, and after her cardiac rhythm stabilized, she was started on an amiodarone infusion. She received no epinephrine during these resuscitations.\n\nShe was transferred to the PICU at a tertiary children’s hospital following the third VF arrest and proceed to have three further arrests in the next 8 hours with frequent multimorphic ventricular ectopy between arrests. Another arrest occurred at 9 hours, and she received 5 DC shocks and an IV epinephrine bolus, IV magnesium, and atropine. She was started on an epinephrine infusion at 0.05 µg/kg/min, up titrated to 0.2 µg/kg/min. After the infusion was started, she received two further epinephrine boluses and four further DC shocks over 10 minutes. Specialist pediatric electrophysiology advice was sought, CPVT was suspected, and at 20 minutes into the arrest, IV fentanyl (10 µg/kg) was given, continuous IV epinephrine was stopped, and the VT/VF storm settled over 2 minutes. A final VF arrest occurred 40 minutes later, which resolved with a DC shock, IV lignocaine, magnesium, and further fentanyl (10 µg/kg).\n\nShe was started on ECMO as she had very poor ventricular function, poor cardiac output, and bradycardia. Family history was negative, the resting electrocardiogram was normal, the heart was structurally normal on echocardiography, and there was nothing to suggest myocarditis.\n\nTo confirm the suspicion of CPVT, while stable on ECMO, she received a 0.2 mg epinephrine bolus, then a 0.2 µg/kg/min infusion of epinephrine which caused a short run of ventricular bigeminy and finally a 0.5 µg/kg/min infusion that caused self-reverting VT/VF (Figs. 4 and 5).\n\nFigure 4. Series of 12 lead electrocardiograms. All recorded at 25 mm/s. Ventricular bigeminy following epinephrine infusion at 0.2 μg/min.\n\nFigure 5. Ventricular fibrillation following epinephrine infusion at 0.5 μg/min.\n\nShe underwent a left cardiac sympathectomy, had an ICD implanted, and was started on nadolol and flecainide; genetic testing confirmed a de novo RyR2 mutation (p.Ser2246Leu), absent in both parents. She had no further episodes of cardiac arrest, and her ICD has not fired in 74 months of follow-up.\n\nCase C\nCase C, a 5-year-old girl, weighing 17 kg, was climbing down into the water from the back of a boat to the point where her legs were submerged in water when she became suddenly unresponsive, and fell backward into the water. She was pulled back onto the boat, and CPR was started by a family member. A nurse who was nearby continued CPR “more aggressively.” An estimated 10 minutes passed before a nearby automatic external defibrillator was located and applied. A shockable rhythm was identified, and a shock delivered. CPR was continued until emergency services arrived by helicopter approximately 15 minutes following the arrest, she was breathing spontaneously, and CPR was stopped. She was taken to the local hospital with a Glasgow Coma Score of 7, where an electrocardiogram showed polymorphic broad complexes at 200 beats/min. The electrocardiogram was faxed to specialists at the tertiary children’s hospital and reviewed by the electrophysiology specialist. CPVT was suspected, and the local team was advised to avoid epinephrine and anesthetise her and deliver opiates. This suspicion was based on key features in the history—particularly that the child was previously well and that loss of consciousness occurred in water, along with the presence of multimorphic ventricular ectopy on the electrocardiogram (Figs. 1–5). She was treated with fentanyl (10 µg/kg) followed by rocuronium, intubation, and ventilation at which point her rhythm stabilized and her tachycardia resolved. A fentanyl infusion (3 µg/kg/hr) was started. She was transferred to the ICU at the tertiary children’s hospital. She had no further arrests, nor any ventricular ectopy. She underwent cerebral cooling but did not require ECMO. Family history was negative, the resting electrocardiogram was normal, and the heart was structurally normal on echocardiography.\n\nCase C had a hybrid ICD inserted and was started on nadolol and flecainide; genetic testing revealed a denovo RyR2 mutation (p.Gly4140Glu). She had no further episodes of arrest, and her ICD has not fired in 43 months of follow-up.\n\nDISCUSSION\nThe first two cases presented here show that the repeated use of epinephrine was ineffective and likely contributed to VT/VF storms over many hours. A comparison with the third case, where epinephrine was avoided, and fentanyl delivered early, led to a dramatically better clinical course.\n\nCPVT thus presents a unique challenge to resuscitators who work with children and adolescents because it must be managed differently from other types of arrhythmias. Most cases are children between 4 and 14 years old (although presentation at age >40 yr and in infants is recognized), and occur with some level of activity, especially swimming, or with fright or excitement (23). There is usually frequent ventricular ectopy between arrests. There is a male predominance. Aside from frequent ectopy, these characteristics are also common among children who suffer cardiac arrest secondary to long QT syndrome type 1 (6, 11, 24), a condition in which epinephrine is not contraindicated during resuscitation attempts, even though exercise, swimming, and excitement are known triggers for long QT type 1 in particular. The finding of bidirectional VT, as demonstrated in Figure 2, is practically pathognomonic for CPVT (1, 5, 9, 24, 25), although it has been associated with Andersen-Tawil syndrome (25) and digoxin overdose (26).\n\nOnce recognized, the optimum therapies available are IV opiates and general anesthetics (which are useful treatments in any VT/VF storm anyway). In CPVT, these work to reduce the catecholaminergic stimulation to break the cycle that triggers the VT. The dose of IV fentanyl used in our cases, 10 μg/kg, is a high dose which may not be familiar to emergency physicians who commonly use a tenth of the dose for analgesia. However, this high dose is required to reduce the catecholaminergic stimulation. Hypotension and low cardiac output can be difficult to manage because catecholamines should be avoided, and ECMO may have to be considered to support cardiac output and blood pressure. Adjunct medications for rhythm control include flecainide and β-blockers (27). Long-term management includes long-term β-blockade, flecainide, left cervical sympathetic denervation, and ICDs (1, 14, 16–18, 24). Flecainide has been shown to have a specific effect in CPVT in a mouse model in reducing sarcoplasmic calcium release (16). In CPVT, the intracellular calcium levels typically cascade out of control with an adrenergic stimulus making cardiomyocytes highly excitable and vulnerable to dysrhythmia. The therapeutic effect of flecainide in the mouse has been replicated in humans (with or without the typical RyR2 gene mutations), so much so that in combination with β-blockers an ICD may sometimes be withheld even after a cardiac arrest (14–17).\n\nAn awareness that epinephrine may sometimes be proarrhythmic in other acute cardiac deterioration is important; examples may include myocarditis or acute myocardial ischemia (such as due to anomalous coronary arterial supply). Epinephrine may also induce paradoxical hypotension during the acute management of cardiac arrest due to obstructive hypertrophic cardiomyopathy (28). In such cases, β1-adrenergic effects increase contractility and thus the outflow obstruction, whereas β2-adrenergic effects reduce systemic vascular resistance. Similarly, in quetiapine poisoning, the drug’s α-adrenergic blockade allows epinephrine’s potent β2-adrenergic effects on the peripheral vasculature to dominate, worsening vasodilation (29). It is worthy of note that an initial rhythm of asystole, sometime after a cardiac arrest, does not exclude a primary VF or polymorphic VT event. We have previously reported a case of CPVT where syncope correlated with polymorphic VT, recorded by an implanted digital loop recorder; the device only activated when prolonged asystole was detected after this (30). The finding of PEA in the first case in this series is unusual and presumably reflected an acutely hypoxic myocardium. Thus neither asystole nor PEA at presentation in a young person with a sudden unexpected cardiac arrest excludes CPVT.\n\nCPVT is an important differential diagnosis of any young person (typically 3 to 40 yr old) who has suffered an unexplained sudden cardiac arrest. Features which should raise suspicion include the following: 1) victim was previously well; 2) cardiac arrest occurred during a physical activity (especially in water) or with excitement; 3) electrocardiogram shows frequent VEs (usually but not always multimorphic); 4) VEs become more frequent (or join to form VT) with epinephrine, and become less frequent with opiates and anesthesia; and 5) bidirectional VT (where ventricular complex QRS axis alternate by 180°) is virtually pathognomonic when seen but is not needed for the diagnosis (Fig. 3).\n\nAn algorithm has been proposed for the investigation of such patients in the ICU (11). Confirmation of the diagnosis, even if the patient has suffered brain death and treatment may be withdrawn, will guide further investigations and prognosis for surviving family (10, 11). During epinephrine or isoprenaline infusions, flecainide should be immediately available. In the event of good neurologic recovery, an exercise test is diagnostic (2, 9, 11).\n\nCONCLUSIONS\nA high suspicion for CPVT is important for all clinicians responsible for the emergency resuscitation of children and young adults (24). In the context of unremitting ventricular arrhythmia, not responding appropriately to standard resuscitation measures, IV opiates and general anesthesia, potentially flecainide, and the avoidance of epinephrine, can be life-saving.\n\nACKNOWLEDGMENTS\nWe gratefully acknowledge Charlene Nell, Department of Cardiology, Green Lane Cardiovascular Services, Auckland City Hospital, New Zealand, for assistance with article preparation.\n\n*See also p. 297.\n\nDr. Skinner receives salary support from Cure Kids.\n\nThe authors have disclosed that they do not have any potential conflicts of interest.\n\nEach child is enrolled in the Cardiac Inherited Disease Registry, part of which gives consent for publication of deidentified data. In addition, although there are no identifying features (name, year of birth, etc.) and no photos, each family has reviewed this article and consent has been obtained for publication from the guardians of each of the three children.\n==== Refs\nREFERENCES\n1. 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"mesh_terms": "D002648:Child; D002675:Child, Preschool; D004837:Epinephrine; D005260:Female; D006801:Humans; D015278:Intensive Care Units, Pediatric; D008297:Male; D058687:Out-of-Hospital Cardiac Arrest; D012189:Retrospective Studies; D019837:Ryanodine Receptor Calcium Release Channel; D017180:Tachycardia, Ventricular",
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"title": "Catecholaminergic Polymorphic Ventricular Tachycardia: The Cardiac Arrest Where Epinephrine Is Contraindicated.",
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"reactionmeddraversionpt": "21.1",
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},
{
"reactionmeddrapt": "Drug ineffective for unapproved indication",
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},
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},
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] |
{
"abstract": "The high genetic barrier to resistance of dolutegravir might allow for its use as maintenance monotherapy in patients with HIV. We investigated whether dolutegravir monotherapy was non-inferior to combination antiretroviral therapy (ART) for maintaining virological suppression in patients with HIV-1 infection successfully treated with combination ART.\n\n\n\nWe did this open-label, phase 2, randomised non-inferiority trial at two medical centres in the Netherlands. Eligible patients (aged ≥18 years) were on combination ART, had been virologically suppressed (HIV RNA <50 copies per mL) for at least 6 months, and had CD4 nadirs of 200 cells per μL or higher, HIV RNA zeniths of 100 000 copies per mL or less, and no history of virological failure. Patients were randomly assigned (1:1), via a web-based block randomisation method (variable block sizes of 4 and 6), to switch to dolutegravir monotherapy (50 mg once a day) either immediately or after a delay of 24 weeks of continued combination ART. Randomisation was stratified by HIV RNA zenith (<50 000 copies per mL vs 50 000-99 999 copies per mL). Investigators and patients were not masked to group allocation. The primary endpoint was the proportion of patients with plasma HIV RNA viral loads of less than 200 copies per mL at week 24, with a non-inferiority margin of 12%. We did analyses in the on-treatment and intention-to-treat populations. This trial is registered with ClinicalTrials.gov, NCT02401828.\n\n\n\nBetween March 10, 2015, and Feb 4, 2016, we randomly assigned 51 patients to the immediate switch group and 53 patients to the delayed switch group. One patient who received immediate monotherapy discontinued treatment at week 12 because of disturbed sleep. At week 24, dolutegravir monotherapy was non-inferior to combination ART, with plasma HIV RNA loads of 200 copies per mL or higher observed in 2% (1/50) of patients in the immediate switch group and in no patients in the delayed switch group (difference 2%, 95% CI -5 to 12). Of patients assigned to the delayed switch group, 47 (89%) switched to dolutegravir monotherapy at week 24, two (4%) of whom subsequently discontinued monotherapy because of headache (n=1) and disturbed sleep (n=1). Eight (8%) of the 95 patients who remained on dolutegravir monotherapy had virological failure; all had therapeutic plasma concentrations of dolutegravir. In three (38%) of the eight patients, mutations associated with resistance were detected in the integrase gene. According to a predefined stopping rule, detection of these mutations led to premature study discontinuation.\n\n\n\nDolutegravir monotherapy was non-inferior to combination ART at 24 weeks. However, virological failure continued to occur thereafter and led to dolutegravir resistance. Dolutegravir should not be used as maintenance monotherapy.\n\n\n\nErasmus Trustfonds.",
"affiliations": "Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Viroscience, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Viroscience, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Viroscience, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Biostatistics, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands; Department of Viroscience, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands.;Department of Internal Medicine/Infectious Diseases, University Medical Center Groningen, University of Groningen, Groningen, Netherlands.;Department of Internal Medicine and Infectious Diseases, Erasmus MC University Medical Center, Rotterdam, Netherlands. Electronic address: b.rijnders@erasmusmc.nl.",
"authors": "Wijting|Ingeborg|I|;Rokx|Casper|C|;Boucher|Charles|C|;van Kampen|Jeroen|J|;Pas|Suzan|S|;de Vries-Sluijs|Theodora|T|;Schurink|Carolina|C|;Bax|Hannelore|H|;Derksen|Maarten|M|;Andrinopoulou|Eleni-Rosalina|ER|;van der Ende|Marchina|M|;van Gorp|Eric|E|;Nouwen|Jan|J|;Verbon|Annelies|A|;Bierman|Wouter|W|;Rijnders|Bart|B|",
"chemical_list": "D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; C562325:dolutegravir",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/S2352-3018(17)30152-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2352-3018",
"issue": "4(12)",
"journal": "The lancet. HIV",
"keywords": null,
"medline_ta": "Lancet HIV",
"mesh_terms": "D000328:Adult; D023241:Antiretroviral Therapy, Highly Active; D024882:Drug Resistance, Viral; D005260:Female; D006678:HIV; D015658:HIV Infections; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009426:Netherlands; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D016896:Treatment Outcome; D019562:Viral Load",
"nlm_unique_id": "101645355",
"other_id": null,
"pages": "e547-e554",
"pmc": null,
"pmid": "29107562",
"pubdate": "2017-12",
"publication_types": "D017427:Clinical Trial, Phase II; D003160:Comparative Study; D000073843:Equivalence Trial; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Dolutegravir as maintenance monotherapy for HIV (DOMONO): a phase 2, randomised non-inferiority trial.",
"title_normalized": "dolutegravir as maintenance monotherapy for hiv domono a phase 2 randomised non inferiority trial"
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}
],
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{
"reactionmeddrapt": "Acquired gene mutation",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Virologic failure",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Drug resistance",
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}
],
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},
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"literaturereference": "WIJTING I, ROKX C, BOUCHER C, VAN KAMPEN J, PAS S, DE VRIES-SLUIJS T ET AL. DOLUTEGRAVIR AS MAINTENANCE MONOTHERAPY FOR HIV (DOMONO): A PHASE 2, RANDOMISED NON-INFERIORITY TRIAL. THE LANCET HIV. 2017.",
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"qualification": "1",
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},
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}
] |
{
"abstract": "A female patient receiving pantoprazole during a corticosteroid therapy for encephalomyelitis disseminata developed severe acute hepatitis one month after initiation of pantoprazole treatment. Other causes of hepatic dysfunction including viral hepatitis, autoimmune hepatitis, primary sclerosing cholangitis, primary biliary cirrhosis, haemochromatosis or Wilson's disease were excluded. Liver biopsy showed severe hepatic lesions with extensive necroses of the parenchyma. One week after discontinuation of pantoprazole the liver function began to improve and gradually the patient fully recovered. One year earlier the patient had been treated with pantoprazole before and had developed a milder form of hepatitis then. This case argues for an idiosyncratic hepatocellular damage caused by pantoprazole.",
"affiliations": "Department of Gastroenterology and Hepatology, University Hospital of Heidelberg, Heidelberg, Germany. Catharina.Sandig@med.uniheidelberg.de",
"authors": "Sandig|C|C|;Flechtenmacher|C|C|;Stremmel|W|W|;Eisenbach|C|C|",
"chemical_list": "D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D054328:Proton Pump Inhibitors; D000077402:Pantoprazole",
"country": "Germany",
"delete": false,
"doi": "10.1055/s-0029-1245613",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0044-2771",
"issue": "49(2)",
"journal": "Zeitschrift fur Gastroenterologie",
"keywords": null,
"medline_ta": "Z Gastroenterol",
"mesh_terms": "D053799:2-Pyridinylmethylsulfinylbenzimidazoles; D056486:Chemical and Drug Induced Liver Injury; D005260:Female; D006801:Humans; D017114:Liver Failure, Acute; D008875:Middle Aged; D000077402:Pantoprazole; D054328:Proton Pump Inhibitors",
"nlm_unique_id": "0033370",
"other_id": null,
"pages": "207-10",
"pmc": null,
"pmid": "21298607",
"pubdate": "2011-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Pantoprazole induces severe acute hepatitis.",
"title_normalized": "pantoprazole induces severe acute hepatitis"
} | [
{
"companynumb": "DE-MYLANLABS-2018M1020438",
"fulfillexpeditecriteria": "1",
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"medicinalproduct": "GLATIRAMER ACETATE."
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"reactionmeddraversionpt": "21.0",
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},
{
"reactionmeddrapt": "Hepatic function abnormal",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Prothrombin level decreased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatomegaly",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatic necrosis",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatic lesion",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood alkaline phosphatase increased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatitis acute",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Alanine aminotransferase increased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Aspartate aminotransferase increased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood bilirubin increased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Jaundice",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SANDIG C, FLECHTENMACHER C, STREMMEL W, EISENBACH C.. PANTOPRAZOLE INDUCES SEVERE ACUTE HEPATITIS. Z GASTROENTEROL. 2011?49(2):207-10. DOI HTTP://DX.DOLORG/10.1055/ S-0029-1245613. Z GASTROENTEROL. 2011?49(2):207-10",
"literaturereference_normalized": "pantoprazole induces severe acute hepatitis",
"qualification": "1",
"reportercountry": "DE"
},
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"receiptdate": "20180404",
"receivedate": "20180404",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14716069,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180711"
}
] |
{
"abstract": "We presented a case of 54-year old man, with dyslipidemia who, during his work, was exposed to prolonged electromagnetic radiation. Because of his concerns about the development of atherosclerosis, higher doses of simvastatin than recommended by the doctor, were used by him. After five weeks of such therapy the central nervous system symptoms such as: memory loss, cognitive disorders, sleeplessness, nervousness were presented. It is probable that the mentioned above symptoms were caused by high doses of drug took by the patient, and increased in blood-brain barrier permeability caused by electromagnetic radiation which lasted for about eight years.",
"affiliations": null,
"authors": "Schetz|Daria|D|;Sein Anand|Jacek|J|",
"chemical_list": "D019821:Simvastatin",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-2240",
"issue": "71(9)",
"journal": "Przeglad lekarski",
"keywords": null,
"medline_ta": "Przegl Lek",
"mesh_terms": "D050197:Atherosclerosis; D003072:Cognition Disorders; D062787:Drug Overdose; D050171:Dyslipidemias; D004574:Electromagnetic Fields; D006801:Humans; D008297:Male; D008569:Memory Disorders; D008875:Middle Aged; D009784:Occupational Diseases; D019821:Simvastatin; D012893:Sleep Wake Disorders",
"nlm_unique_id": "19840720R",
"other_id": null,
"pages": "499-501",
"pmc": null,
"pmid": "25632791",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Neurological disturbances in patient who ingested high doses of simvastatin.",
"title_normalized": "neurological disturbances in patient who ingested high doses of simvastatin"
} | [
{
"companynumb": "PL-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-94900",
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"occurcountry": "PL",
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{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": "1",
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"drugauthorizationnumb": "76285",
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"drugcharacterization": "1",
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"drugdosagetext": "80 MG, QOD",
"drugenddate": null,
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"drugindication": "DYSLIPIDAEMIA",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "2",
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"medicinalproduct": "SIMVASTATIN."
},
{
"actiondrug": "2",
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"activesubstancename": "SIMVASTATIN"
},
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"drugindication": "DYSLIPIDAEMIA",
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"medicinalproduct": "SIMVASTATIN."
}
],
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"reaction": [
{
"reactionmeddrapt": "Insomnia",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Anxiety",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Aggression",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Treatment noncompliance",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Disturbance in attention",
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"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Memory impairment",
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"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Overdose",
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},
{
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"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Depression",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "2"
}
],
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},
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},
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},
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},
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"transmissiondate": "20171127"
},
{
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"medicinalproduct": "SIMVASTATIN."
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"reaction": [
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"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Amnesia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nervousness",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Insomnia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
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"literaturereference_normalized": "neurological disturbances in patient who ingested high doses of simvastatin",
"qualification": "3",
"reportercountry": "PL"
},
"primarysourcecountry": "PL",
"receiptdate": "20150402",
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"receiver": {
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},
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"safetyreportid": 10978545,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
},
{
"companynumb": "PL-MYLANLABS-2015M1010737",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": "2",
"activesubstance": {
"activesubstancename": "SIMVASTATIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "090868",
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": "60MG",
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"drugenddateformat": null,
"drugindication": "DYSLIPIDAEMIA",
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"medicinalproduct": "SIMVASTATIN."
},
{
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"activesubstancename": "SIMVASTATIN"
},
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"medicinalproduct": "SIMVASTATIN."
}
],
"patientagegroup": null,
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"reaction": [
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Aggression",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Cognitive disorder",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Depression",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Anxiety",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
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"literaturereference_normalized": "neurological disturbances in patient who ingested high doses of simvastatin",
"qualification": "1",
"reportercountry": "PL"
},
"primarysourcecountry": "PL",
"receiptdate": "20150402",
"receivedate": "20150402",
"receiver": {
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},
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"safetyreportversion": 1,
"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150821"
}
] |
{
"abstract": "BACKGROUND\nDeep vein thrombosis is an important cause of morbidity and mortality. However, its association with adenomatous polyposis coli is extremely rare. Here we present an interesting case of deep vein thrombosis associated with adenomatous polyposis coli.\n\n\nMETHODS\nA 15 year old female who was having fever and diarrhea for 5 months developed bilateral asymmetric painful swelling of lower limbs for 1 month. Doppler ultrasound of lower limbs revealed presence of thrombosis from inferior vena cava up to popliteal vein. Colonoscopy and biopsy were suggestive of adenomatous polyposis coli. However, she could not tolerate anticoagulant therapy and was put on aspirin therapy for 6 months to which she responded well with the resolution of thrombus.\n\n\nCONCLUSIONS\nRole of aspirin therapy may be considered whenever a patient of venous thrombosis cannot tolerate anticoagulant therapy.",
"affiliations": "Department of Medicine, Calcutta National Medical College and Hospital, Kolkata, India.;Department of Medicine, Calcutta National Medical College and Hospital, Kolkata, India.;Department of Medicine, Gangarampur Subdivisional Hospital, India.;Department of Medicine, Calcutta National Medical College and Hospital, Kolkata, India.;Department of Medicine, Calcutta National Medical College and Hospital, Kolkata, India.;Department of Medicine, North Bengal Medical College & Hospital, India.;Department of Family Medicine, Calcutta Medical Research Institute, Kolkata, India.",
"authors": "Agrawal|Neha|N|;Santra|Tuhin|T|;Kar|Arnab|A|;Guha|Pradipta|P|;Bar|Mita|M|;Adhikary|Apu|A|;Datta|Sumana|S|",
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"fulltext": "\n==== Front\nCaspian J Intern MedCaspian J Intern MedCJIMCaspian Journal of Internal Medicine2008-61642008-6172Babol University of Medical Sciences Babol, Iran cjim-7-142Case ReportDeep vein thrombosis in a patient of adenomatous polyposis coli treated successfully with aspirin: A case report Agrawal Neha MD1Santra Tuhin MD1*Kar Arnab MD2Guha Pradipta MD1Bar Mita MD1Adhikary Apu MD3Datta Sumana MD41 Department of Medicine, Calcutta National Medical College and Hospital, Kolkata, India.2 Department of Medicine, Gangarampur Subdivisional Hospital, India.3 Department of Medicine, North Bengal Medical College & Hospital, India.4 Department of Family Medicine, Calcutta Medical Research Institute, Kolkata, India.* Correspondence: Tuhin Santra, Department of Medicine, Calcutta National Medical College & Hospital, 24/32, Gorachand Road, Entally, Kolkata- 700014. E-mail: dralka.y@gmail.com, Tel: 0091 9432106081, Fax: 0091 Spring 2016 7 2 142 145 30 5 2015 24 8 2015 30 8 2015 This is an Open Access article distributed under the terms of the Creative Commons Attribution License, (http://creativecommons.org/licenses/by/3.0/) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nDeep vein thrombosis is an important cause of morbidity and mortality. However, its association with adenomatous polyposis coli is extremely rare. Here we present an interesting case of deep vein thrombosis associated with adenomatous polyposis coli.\n\nCase Presentation:\n A 15 year old female who was having fever and diarrhea for 5 months developed bilateral asymmetric painful swelling of lower limbs for 1 month. Doppler ultrasound of lower limbs revealed presence of thrombosis from inferior vena cava up to popliteal vein. Colonoscopy and biopsy were suggestive of adenomatous polyposis coli. However, she could not tolerate anticoagulant therapy and was put on aspirin therapy for 6 months to which she responded well with the resolution of thrombus.\n\nConclusion:\nRole of aspirin therapy may be considered whenever a patient of venous thrombosis cannot tolerate anticoagulant therapy.\n\nKey Words\nDeep vein thrombosisAdenomatous polyposis coliDiarrheaAspirin\n==== Body\nVenous thromboembolism is an important cause of hospital acquired morbidity and mortality (1). Its association with adenomatous polyposis coli is a rare event (2, 3). Malignancy or major operative procedure associated with colonic polyp may predispose to thromboembolic event (2). There has been previously published few reports of diarrhea associated with deep vein thrombosis (4-6). Etiology of diarrhea in those cases was unrelated to colonic polyp. However, association of deep vein thrombosis with non-malignant colonic polyp presenting with diarrhea is an extremely rare event with a report of only one case in previous English literature (3). Mainstay of therapy of deep vein thrombosis is anticoagulation. However, fatal bleeding episode following anticoagulation in our patient lead to withdrawal of anticoagulation therapy. The patient was treated successfully with low dose aspirin therapy (75mg/day) with complete resolution of thrombus. \n\nCase Presentation\nA 15-year-old unmarried female presented to us with complain of asymmetric onset lower limb swelling for last 1 month. The swelling initially involved the left lower limb and for last 1 week she had also developed right lower limb swelling. The swelling which was initially painless later became painful. \n\nShe was also having low grade irregular fever for last 5 months along with small amount of non-foul smelling mucus containing recurrent episodes of diarrhea for the same duration along with a history of significant weight loss. She had an episode of hematochezia 1 day after admission. There was no history of abdominal pain, vomiting, abdominal distension, facial puffiness, oliguria, bleeding from any other sites, joint pain, skin rash, recent contact with tuberculosis, recent surgery or prolonged immobilization. She had mild pallor and her body mass index (BMI) was 17.5 kg/mt2. She had bilateral pitting pedal edema along with raised local temperature and a positive Homans’ sign and Moses’ sign.\n\nHer routine investigations revealed a hemoglobin level of 8.9 g/dl, total leucocyte count (TLC) of 10,500/mm3, erythrocyte sedimentation rate (ESR) of 6 mm. in 1st hour, low albumin level (2.5g/dl) and serum creatinine of 0.9 mg/dl. Stool examination revealed presence of mucous, blood and pus cells. Chest x-ray, ultrasonography of whole abdomen was unremarkable. She was found to be HIV negative. Duplex color doppler of both lower limbs revealed presence of intraluminal thrombus involving the inferior vena cava (IVC) from the level just beyond the origin of left renal vein up to the popliteal vein. Contrast enhanced CT (computed tomography) of abdomen was done which confirmed the presence of IVC (inferior vena cava) thrombosis (figure 1). \n\nFigure 1 CT abdomen showing thrombus in IVC\n\nColonoscopy revealed presence of multiple polyps, may be up to 100 in number with size being 0.5-1 cm. of diameter up to the level of cecum (Figure 2). Biopsy from the sigmoid polyp revealed adenomatous polyp without any evidence of malignancy (figure3). Her prothrombin time (P time), activated partial thromboplastin time (aPTT) and fibrinogen level was within normal limit and she had a raised fibrin degradation product (FDP) level (2671.2 ng/ml). Her antinuclear antibody (ANA), anti-double stranded DNA (anti ds-DNA), lupus anticoagulant and anticardiolipin antibody was negative and she had a normal homocysteine and protein C and protein S level.\n\nFigure 2 Multiple polyps in colon\n\nFigure 3 Biopsy from sigmoid polyp revealing adenomatous polyp without any evidence of malignancy\n\nSo, she was diagnosed to have adenomatous polyp with deep vein thrombosis and she was put on injection enoxaparin and tablet warfarin. But 2 days after she developed life threatening hematochezia and patient went to shock and the therapy was stopped. Repeat P time was normal. The patient was successfully resuscitated and after hematochezia was stopped, she was put on tablet warfarin but again she developed hematochezia. Thus, both the enoxaparin and warfarin therapy were discontinued. After control of hematochezia she was then put on a trial of aspirin therapy (75 mg/day). No bleeding manifestations occurred and repeat doppler ultrasound study after 2 months revealed partial recanalization within the thrombus with resolution of her symptoms. Doppler ultrasound after 4 months revealed complete recanalization and aspirin therapy was continued for a total duration of 6 months.\n\nDiscussion\nVenous thromboembolism is associated with several risk factors. Prolonged immobility, major surgery, malignancy, trauma, presence of antiphospholipid antibody, use of oral contraceptives are important leading causes of thromboembolic event (7, 8). \n\nIt may occur in association with other chronic inflammatory conditions like inflammatory bowel disease, tuberculosis or with malabsorption syndromes which present with abdominal symptoms like diarrhea, pain abdomen, ascites (5, 6, 9). However, to the best of our knowledge, deep vein thrombosis associated with non-malignant colonic polyp has been described only once in previous English literature (3). \n\nIn that case, deep vein thrombosis was postulated secondary to immobility associated with poor health which is not applicable to our case. Dehydration associated with diarrhea might be an explainable risk factor for development of deep vein thrombosis in our patient (10).\n\nAgain, major bleeding episode associated with anticoagulant therapy prevented its further use in our patient. Aspirin has been tried as thromboprophylaxis for venous thromboembolism in high risk patients (11, 12). However, its use for venous thrombosis is still not recommended although it is recommended for arterial thromboembolic event. Aspirin which suppresses cell proliferation by inhibiting prostaglandin synthesis has been assessed as possible inhibitors of colon cancer (13). We treated our patient successfully with aspirin 75 mg/day for 6 months with complete resolution of symptoms and thrombus.\n\nConclusion\nThis is a well-documented clinical, radiological and histological case report of recognized association of deep vein thrombosis with adenomatous polyposis coli. Role of aspirin therapy may be considered whenever a patient of venous thrombosis cannot tolerate anticoagulant therapy.\n\nAcknowledgments\nThe authors thank the patient who agreed and allowed us to present her in this paper.\n\n\n\nConflict of Interests: The authors have no conflict of interests or financial disclosures.\n==== Refs\nReferences\n1 Butcher JH Pasi KJ Fatal postoperative pulmonary embolism in mild haemophilia Haemophilia 2006 12 179 82 16476094 \n2 Meshikhes AW Al-Ghazal T Portal vein thrombosis after restorative proctocolectomy for familial adenomatous polyposis and sigmoid cancer Case Rep Gastroenterol 2012 6 124 30 22532810 \n3 Longcroft-Wheaton G O'Brien J Woolf K Hypoalbuminaemia and colonic polyps: a case of protein-losing enteropathy with cap polyposis? Br J Hosp Med (Lond) 2007 68 444 5 17847696 \n4 Javid Bhat K Bhat S Dutt K Gupta S Jeelani Samoon H Chronic diarrhea, eosinophilic ascites, acute pancreatitis and deep venous thrombosis: a case report Caspian J Intern Med 2014 5 182 5 25202449 \n5 Kim W Kang B Kim BW Crohn's disease initially accompanied by deep vein thrombosis and ulnar neuropathy without metronidazole exposure Gut Liver 2013 7 252 4 23560164 \n6 Beyan E Pamukcuoglu M Beyan C Deep vein thrombosis associated with celiac disease Bratisl Lek Listy 2009 110 263 4 19507658 \n7 Freedman JE Loscalzo J Longo DL Fauci AS Kasper DL Hauser SL Jameson JL Loscalzo J Arterial and venous thrombosis Harrison’s principles of internal medicine 2012 18th ed New York McGraw Hill Inc 983 8 \n8 Heit JA Silverstein MD Mohr DN et al Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study Arch Intern Med 2000 160 809 15 10737280 \n9 Gupta R Brueton M Fell J Lyall H An Afghan child with deep vein thrombosis J R Soc Med 2003 96 289 91 12782695 \n10 Zitomersky NL Verhave M Trenor CC 3rd Thrombosis and inflammatory bowel disease: a call for improved awareness and prevention Inflamm Bowel Dis 2011 17 458 70 20848518 \n11 Pulmonary Embolism Prevention (PEP) Trial Collaborative Group Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial Lancet 2000 355 1295 302 10776741 \n12 Collaborative overview of randomised trials of antiplatelet therapy--III: Reduction in venous thrombosis pulmonary embolism by antiplatelet prophylaxis among surgical medical patients Antiplatelet Trialists' Collaboration BMJ 1994 308 235 43 8054013 \n13 Mayer RJ Longo DL Fauci AS Kasper DL Hauser SL Jameson JL Loscalzo J Gastrointestinal tract cancer Harrison’s principles of internal medicine 2012 18th ed New York McGraw Hill Inc 764 76\n\n",
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"abstract": "OBJECTIVE\nTo report about a case of acute renal failure due to absence of communication between physician and patient.\n\n\nMETHODS\nA 78 year old man with human immunodeficiency virus (HIV) accessed our hospital and was brought to our attention in August 2011 for severe renal failure. Clinical history revealed that he had been taking highly active antiretroviral therapy with lamivudine/abacavir and fosamprenavir since 2006. In April 2011 due to an augmentation in creatinine plasma levels, a reduction in lamivudine dosage to 100 mg/day and the prescription of abacavir 300 mg/day became necessary. Unfortunately, the patient took both lamivudine and abacavir therefore the association of the two medications (lamivudine/abacavir) lead to asthenia and acute renal failure within a few days.\n\n\nCONCLUSIONS\nThis case emphasizes the importance about how physicians must pay very careful attention during drug prescription, most particularly, as far as elderly patients are concerned. In fact, communication improvement between physicians and patients can prevent increase of adverse drug reactions related to drug dispensing, with consequential reduction of costs in the healthcare system.",
"affiliations": "Department of Health Science, School of Medicine, University of Catanzaro and Operative Unit of Pharmacology, Mater Domini University Hospital, Viale Europa, Germaneto, 88100 Catanzaro, Italy. gallelli@unicz.it",
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"title": "A case of adverse drug reaction induced by dispensing error.",
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{
"abstract": "Depression and mood disorders occur commonly following emergent cardiac surgery. Selective serotonin reuptake inhibitors are commonly used antidepressants. We report the development of severe hyponatremia leading to adverse clinical effects due to escitalopram and thiazide diuretic use concomitantly in a patient with depression after emergency coronary artery bypass grafting.",
"affiliations": "Department of Cardiovascular Surgery, Hitit University Corum Education and Training Hospital, Corum, Turkey.;Department of Cardiovascular Surgery, Hitit University Corum Education and Training Hospital, Corum, Turkey.;Department of Chest Disease, Hitit University Corum Education and Training Hospital, Corum, Turkey.;Department of Cardiovascular Surgery, Hitit University Corum Education and Training Hospital, Corum, Turkey.;Department of Nephrology, Hitit University Corum Education and Training Hospital, Corum, Turkey.;Department of Nephrology, Hitit University Corum Education and Training Hospital, Corum, Turkey.;Department of Cardiovascular Surgery, Hitit University Corum Education and Training Hospital, Corum, Turkey.",
"authors": "Diken|Adem İlkay|Aİ|;Yalçınkaya|Adnan|A|;Erçen Diken|Özlem|Ö|;Aksoy|Eray|E|;Doğan|İbrahim|İ|;Yılmaz|Seyhan|S|;Çağlı|Kerim|K|",
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"issue": "31(2)",
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"mesh_terms": "D000928:Antidepressive Agents; D015283:Citalopram; D001026:Coronary Artery Bypass; D003863:Depression; D004359:Drug Therapy, Combination; D004630:Emergencies; D006801:Humans; D007010:Hyponatremia; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders; D011183:Postoperative Complications; D017367:Serotonin Uptake Inhibitors; D012720:Severity of Illness Index; D049993:Sodium Chloride Symporter Inhibitors",
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"pages": "96-7",
"pmc": null,
"pmid": "26687322",
"pubdate": "2016-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hyponatremia Due to Escitalopram and Thiazide Use After Cardiac Surgery.",
"title_normalized": "hyponatremia due to escitalopram and thiazide use after cardiac surgery"
} | [
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},
{
"reactionmeddrapt": "Confusional state",
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},
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"reactionmeddrapt": "Hypercapnia",
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},
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"reactionmeddrapt": "Somnolence",
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},
{
"reactionmeddrapt": "Hallucination",
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},
{
"reactionmeddrapt": "Drug interaction",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Dyspnoea",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypoxia",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "1"
}
],
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},
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"literaturereference": "ILKAY DIKEN A,YALSC?NKAYA A,ERSCEN DIKEN O,AKSOY E,DOGAN I,Y?LMAZ S,CAGL? K. HYPONATREMIA DUE TO ESCITALOPRAM AND THIAZIDE USE AFTER CARDIAC SURGERY. CARDIAC SURGERY AND HYPONATREMIA. 2015?1-2.",
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"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "DK",
"receiptdate": "20160316",
"receivedate": "20160106",
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"receivertype": "6"
},
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},
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] |
{
"abstract": "BACKGROUND\nA variety of sources indicate that oxytocin has beneficial effects on several components of sexuality. This is a case report on a male who had significant, broad-spectrum improvements in sexual function during a course of intranasal oxytocin treatment for social anxiety.\n\n\nOBJECTIVE\nTo document a case of diverse, salutary effects of oxytocin on sexual function.\n\n\nMETHODS\nThe patient was in individual treatment for a variety of difficulties, including social avoidance and relational problems. A biopsychosocial evaluation ruled out medical conditions and substance-related issues as a cause of sexual difficulties. After obtaining informed consent, an off-label trial of intranasal oxytocin was administered targeting his social anxiety and relational avoidance.\n\n\nRESULTS\nOxytocin positively impacted a number of components of sexual function, including libido, erection, and orgasm, and was well tolerated.\n\n\nCONCLUSIONS\nThis is the first case we are aware of documenting broad-spectrum benefits of chronic intranasal oxytocin on male sexual function. Future trials of oxytocin for psychiatric indications should specifically monitor its effects on sexuality, and trials directly investigating oxytocin's impact on aspects of sexual function are warranted.",
"affiliations": "University of California, San Diego Medical Center Department of Psychiatry, San Diego, CA 92103-8218, USA. kai@kaimacdonald.com",
"authors": "MacDonald|Kai|K|;Feifel|David|D|",
"chemical_list": "D010121:Oxytocin",
"country": "Netherlands",
"delete": false,
"doi": "10.1111/j.1743-6109.2012.02703.x",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1743-6095",
"issue": "9(5)",
"journal": "The journal of sexual medicine",
"keywords": null,
"medline_ta": "J Sex Med",
"mesh_terms": "D000281:Administration, Intranasal; D000328:Adult; D006801:Humans; D007989:Libido; D008297:Male; D009948:Orgasm; D010121:Oxytocin; D010410:Penile Erection; D020018:Sexual Dysfunctions, Psychological",
"nlm_unique_id": "101230693",
"other_id": null,
"pages": "1407-10",
"pmc": null,
"pmid": "22458365",
"pubdate": "2012-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Dramatic improvement in sexual function induced by intranasal oxytocin.",
"title_normalized": "dramatic improvement in sexual function induced by intranasal oxytocin"
} | [
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"reaction": [
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{
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},
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] |
{
"abstract": "Detecting Pneumocystis jirovecii by bronchoalveolar lavage or lung biopsy is the gold standard for diagnosis of P. jirovecii pneumonia (PJP); however, these techniques are not always applicable in children because of their high invasiveness. We report two pediatric cases of PJP diagnosed by polymerase chain reaction (PCR) of gastric lavage that were successfully treated. To date, there are no reported cases of using PCR of gastric lavage to diagnose PJP. On the day of PJP onset, both the infants required respiratory support and infiltrative shadows were observed in both lung fields on chest radiography. Furthermore, their (1 → 3)-β-D glucan levels were elevated. P. jirovecii was detected by PCR of gastric lavage and trimethoprim-sulfamethoxazole was administered for 3 weeks, following which their condition improved. They were long-term steroid users, but without any prophylaxis. PCR of gastric lavage in cases of suspected PJP may help in confirming the diagnosis in children who have mild to moderate airway symptoms, or have difficulty with invasive examination like bronchoscopy.",
"affiliations": "Department of Pediatrics, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo ku, Chiba City, Chiba, 260-8677, Japan. Electronic address: harukakagawa52@gmail.com.;Department of Infectious Diseases, Medical Mycology Research Center, Chiba University, 1-8-1 Inohana Chuo ku, Chiba City, Chiba, 260-8677, Japan.;Department of Pediatrics, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo ku, Chiba City, Chiba, 260-8677, Japan.;Department of Pediatrics, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo ku, Chiba City, Chiba, 260-8677, Japan.;Department of Pediatrics, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo ku, Chiba City, Chiba, 260-8677, Japan.;Department of Pediatrics, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo ku, Chiba City, Chiba, 260-8677, Japan.;Department of Pediatrics, Chiba University Graduate School of Medicine, 1-8-1 Inohana Chuo ku, Chiba City, Chiba, 260-8677, Japan.",
"authors": "Takei|Haruka|H|;Ishiwada|Naruhiko|N|;Hishiki|Haruka|H|;Takeshita|Kenichi|K|;Naito|Sachiko|S|;Endo|Mamiko|M|;Shimojo|Naoki|N|",
"chemical_list": "D004269:DNA, Bacterial; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.jiac.2019.01.016",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1341-321X",
"issue": "25(6)",
"journal": "Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy",
"keywords": "Gastric lavage; Pediatrics; Pneumocystis jirovecii; Pneumocystis jirovecii pneumonia; Polymerase chain reaction",
"medline_ta": "J Infect Chemother",
"mesh_terms": "D004269:DNA, Bacterial; D005751:Gastric Lavage; D006801:Humans; D016867:Immunocompromised Host; D007223:Infant; D052577:Infant, Extremely Low Birth Weight; D007231:Infant, Newborn; D007234:Infant, Premature; D008297:Male; D045363:Pneumocystis carinii; D011020:Pneumonia, Pneumocystis; D016133:Polymerase Chain Reaction; D016896:Treatment Outcome; D015662:Trimethoprim, Sulfamethoxazole Drug Combination",
"nlm_unique_id": "9608375",
"other_id": null,
"pages": "477-479",
"pmc": null,
"pmid": "30797688",
"pubdate": "2019-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Two pediatric cases of Pneumocystis jirovecii pneumonia diagnosed by polymerase chain reaction of gastric lavage.",
"title_normalized": "two pediatric cases of pneumocystis jirovecii pneumonia diagnosed by polymerase chain reaction of gastric lavage"
} | [
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}
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{
"abstract": "Congenital rubella syndrome (CRS) is caused by rubella virus infection of the pregnant mother leading to teratogenic effects on the fetus. Although rare in the developed world, manifestations reach far into adulthood and underscore the importance of careful evaluation before surgery. We present a case of an adult with CRS in whom unexpected prolonged postoperative respiratory depression occurred. Perioperative workup of CRS and investigations pertaining to the patient's respiratory insufficiency are discussed.",
"affiliations": "From the Department of Anesthesiology, University of Miami, Miller School of Medicine, Miami, Florida.",
"authors": "Souki|Fouad|F|;Shettar|Shashank S|SS|",
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"pmc": null,
"pmid": "25611847",
"pubdate": "2013-11-01",
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"title": "Prolonged respiratory depression after general anesthesia in an adult with congenital rubella syndrome.",
"title_normalized": "prolonged respiratory depression after general anesthesia in an adult with congenital rubella syndrome"
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{
"abstract": "Isoniazid (INH) is a prodrug activated by the mycobacterial enzyme KatG, a multifunctional catalase peroxidase. KatG converts INH to reactive antimycobacterial species. For decades, an association between INH and drug-induced lupus erythematosus has been recognized. We present the case of a patient with primary progressive multiple sclerosis whose disease commenced weeks after initiating INH therapy for prevention of tuberculosis. Possible mechanisms by which INH may trigger autoimmunity in humans are discussed.",
"affiliations": "Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center at Dallas, Dallas, TX, USA.;Neurology Section, VA North Texas Health Care System, Medical Service, 4500 South Lancaster Rd, Dallas, TX 75216, USA.",
"authors": "Nourbakhsh|Bardia|B|;Stüve|Olaf|O|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1177/1756285614540361",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1756-2856",
"issue": "7(5)",
"journal": "Therapeutic advances in neurological disorders",
"keywords": "Autoimmunity; Isoniazid; Multiple Sclerosis",
"medline_ta": "Ther Adv Neurol Disord",
"mesh_terms": null,
"nlm_unique_id": "101480242",
"other_id": null,
"pages": "253-6",
"pmc": null,
"pmid": "25342979",
"pubdate": "2014-09",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": "16510748;7578866;17153847;8780061;2141035;24035809;9668163;21513360;22907116;7201590;6685237;10219776;17074073;6847134;6537847",
"title": "Isoniazid in autoimmunity: a trigger for multiple sclerosis?",
"title_normalized": "isoniazid in autoimmunity a trigger for multiple sclerosis"
} | [
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},
{
"reactionmeddrapt": "Movement disorder",
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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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}
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{
"abstract": "The aim of this phase II trial was to assess the efficacy and tolerability of docetaxel/vinorelbine as second-line therapy. Thirty-two patients with a performance status (PS) of <or= 2 (5 with locally advanced and 27 with metastatic non-small-cell lung cancer [NSCLC]) who were previously treated with platinum-based chemotherapy, were recruited. Docetaxel 75 mg/m2 on day 1 and vinorelbine 20 mg/m2 on days 1 and 5 were administered every 3 weeks with dexamethasone premedication but without prophylactic granulocyte colony-stimulating factor and antibiotics. The overall response rate (intent-to-treat analysis) was 9.5%, including 3 patients with a partial response, 15 (47%) with stable disease, and 9 (28%) with progressive disease. Myelosupression was the limiting toxicity, with 8 episodes of febrile neutropenia and 3 deaths due to sepsis. Median overall survival and progression-free survival were 25 weeks and 13 weeks, respectively. Patients with a PS of 2 (P < 0.02) and elevated lactate dehydrogenase (P < 0.01) had a worse prognosis. Histology of adenocarcinoma appeared to positively influence survival (P = 0.09). Our study confirms that the docetaxel/vinorelbine schedule has activity in NSCLC patients pretreated with platinum-based therapies.",
"affiliations": "Department of Medical Oncology, Hospital de Cruces, Osakidetza, Basque Country, Spain.",
"authors": "Muñoz|Alberto|A|;Rubio|Itziar|I|;Mañé|Juan Manuel|JM|;Ferreiro|Josefa|J|;Fernández|Ricardo|R|;Abón|Guadalupe|G|;de Argumedo|Gonzalo López|GL|;Fuente|Natalia|N|;Barceló|José Ramón|JR|;López-Vivanco|Guillermo|G|",
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"issue": "4(3)",
"journal": "Clinical lung cancer",
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"pages": "168-73",
"pmc": null,
"pmid": "14706166",
"pubdate": "2002-11",
"publication_types": "D016428:Journal Article",
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"title": "Phase II study of docetaxel/vinorelbine in patients with non-small-cell-lung cancer previously treated with platinum-based chemotherapy.",
"title_normalized": "phase ii study of docetaxel vinorelbine in patients with non small cell lung cancer previously treated with platinum based chemotherapy"
} | [
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] |
{
"abstract": "Two cases of pregnant patients with acute lymphoblastic leukaemia (ALL) are presented. ALL is rare in pregnancy. The basic principle of ALL treatment is combination chemotherapy with sequential administration of induction, consolidation and maintenance therapy, and this also holds for ALL in pregnancy. The prognosis of ALL in pregnancy is poor and termination of the pregnancy needs to be considered.",
"affiliations": "Department of Obstetrics and Gynaecology, Maastricht University Hospital, Maastricht, the Netherlands. jfmm@xs4all.nl",
"authors": "Molkenboer|J F M|JF|;Vos|A H|AH|;Schouten|H C|HC|;Vos|M C|MC|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-2977",
"issue": "63(9)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000028:Abortion, Induced; D000022:Abortion, Spontaneous; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011379:Prognosis",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "361-3",
"pmc": null,
"pmid": "16244384",
"pubdate": "2005-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute lymphoblastic leukaemia in pregnancy.",
"title_normalized": "acute lymphoblastic leukaemia in pregnancy"
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"abstract": "Hepatocellular carcinoma (HCC) is an aggressive liver tumor that occurs with chronic liver disease. Surgical resection is the mainstay of therapy for localized disease whereas therapeutic options for advanced disease are limited. The innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against programmed death receptor 1 (PD-1), have shown promise in the treatment of solid malignancies. The PD-1 inhibiting antibodies, nivolumab and pembrolizumab prolonged overall survival in randomized trials in metastatic melanoma and advanced non-small cell lung cancer. This is a report of a 75-year-old male patient with metastatic HCC who was initially treated with the standard of therapy sorafenib. After failure of sorafenib therapy, pembrolizumab was started. There was a dramatic response to pembrolizumab with decrease in tumor size and drop in alfa fetoprotein. To the best of our knowledge, this is the first case report of metastatic HCC responsive to pembrolizumab after failure of sorafenib.",
"affiliations": "Cancer Center of Kansas, Wesley Medical Center.;Internal Medicine, University of Kansas School of Medicine-Wichita.;Internal Medicine, University of Kansas School of Medicine-Wichita.",
"authors": "Truong|Phu|P|;Rahal|Ahmad|A|;Kallail|K James|KJ|",
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"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.631GastroenterologyOncologyMetastatic Hepatocellular Carcinoma Responsive to Pembrolizumab Muacevic Alexander Adler John R Truong Phu 1Rahal Ahmad 2Kallail K. James 21 \nCancer Center of Kansas, Wesley Medical Center 2 \nInternal Medicine, University of Kansas School of Medicine-Wichita \nAhmad Rahal arahal@kumc.edu4 6 2016 6 2016 8 6 e63127 3 2016 4 6 2016 Copyright © 2016, Truong et al.2016Truong et al.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 author and source are credited.This article is available from http://www.cureus.com/articles/4359-metastatic-hepatocellular-carcinoma-responsive-to-pembrolizumabHepatocellular carcinoma (HCC) is an aggressive liver tumor that occurs with chronic liver disease. Surgical resection is the mainstay of therapy for localized disease whereas therapeutic options for advanced disease are limited. The innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against programmed death receptor 1 (PD-1), have shown promise in the treatment of solid malignancies. The PD-1 inhibiting antibodies, nivolumab and pembrolizumab prolonged overall survival in randomized trials in metastatic melanoma and advanced non-small cell lung cancer. This is a report of a 75-year-old male patient with metastatic HCC who was initially treated with the standard of therapy sorafenib. After failure of sorafenib therapy, pembrolizumab was started. There was a dramatic response to pembrolizumab with decrease in tumor size and drop in alfa fetoprotein. To the best of our knowledge, this is the first case report of metastatic HCC responsive to pembrolizumab after failure of sorafenib.\n\npembrolizumabmetastatic hepatocellular carcinomaimmune checkpoint inhibitorsThe content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.\n==== Body\nIntroduction\nHepatocellular carcinoma (HCC) is an aggressive tumor of the liver that usually occurs with chronic liver disease. HCC is frequently diagnosed late in its course with a median survival following diagnosis of approximately 6–20 months [1-2]. Extrahepatic spread is present at the time of diagnosis in approximately 5–15% of cases [3]. The most common sites of metastasis are lung, intra-abdominal lymph nodes, bone, and adrenal glands. The mainstay of therapy for localized disease is surgical resection. In metastatic disease, therapeutic options are limited. Molecular targeted therapy with sorafenib monotherapy is the standard systemic treatment for advanced HCC [4].\n\nSubstantial progress has been made in the development of immunotherapy for the treatment of a variety of solid malignancies. The immune checkpoint proteins, programmed death receptor 1 (PD-1) and programmed death receptor ligand (PD-L1), play a major role in the immune resistance of tumor cells [5]. PD-1 is a checkpoint protein expressed on T cells, B cells, and NK cells. It is an inhibitory molecule that binds to PD-L1. PD-L1 is expressed on the surface of multiple tissue types, including both normal and cancer cells. The PD-1-PD-L1 interaction helps keep the T cells from attacking tumor cells in the body. We report a case of metastatic HCC that responded dramatically to the immunotherapeutic agent pembrolizumab, a PD-1 inhibitor, after failure of standard therapy with sorafenib. Informed consent was obtained from the patient for this study.\n\nCase presentation\nA 75-year-old male patient presented with abdominal pain and with a past medical history significant for hypertension, gastroesophageal reflux disease, and anemia. An abdominal exam was positive for right upper quadrant tenderness. Laboratory findings revealed normal complete blood count, normal renal panel, but mildly elevated liver enzymes (aspartate aminotransferase (AST) = 66, alanine aminotransferase (ALT) = 38). A computerized tomography (CT) scan of the abdomen and pelvis showed a hyper-vascular mass in the left lobe of the liver. CT-guided biopsy of the mass showed HCC. The patient underwent exploratory laparotomy, total left hepatic lobectomy, and cholecystectomy. Active post-surgical surveillance with alpha fetoprotein (AFP) and CT scan of the abdomen was done for three years with no evidence of disease recurrence. Three years after initial presentation, the patient noticed a mass below the xiphoid process. AFP was elevated at 2751 mcg/L (normal 10–20 mcg/L). A CT scan of the abdomen showed a large anterior subxiphoid abdominal wall soft tissue mass measuring 8 x 6 cm with multiple small satellite lesions consistent with metastatic disease (Figure 1).\n\n\nFigure 1 CT Abdomen Before Treatment With Pembrolizumab\nAxial contrast enhanced CT of the abdomen showing an 8 x 6 cm mass with central necrosis consistent with recurrent HCC.\n\n\n\n\nBased on the elevated AFP and CT findings, the patient was considered to have relapsed metastatic HCC. He was started on standard therapy with sorafenib 200 mg orally twice a day for a week, then 400 mg orally twice a day. His course of treatment was complicated with hand-foot syndrome and the sorafenib dose was reduced from 400 mg to 200 mg twice daily. After five months of therapy with sorafenib, AFP increased from 2751 mcg/L to 8877 mcg/L and a repeat CT scan of the abdomen showed that the mass in the subxiphoid area was larger. With disease progression and failure of sorafenib, the patient was given the option of palliative care versus pembrolizumab on a compassionate use basis. After informed consent to individual therapy, off-label treatment with the anti-PD-1 antibody pembrolizumab (2 mg/kg every three weeks) was initiated. After six cycles of therapy, a CT scan of the abdomen showed a major decrease in subxiphoid mass size from 8 x 6 cm to 4 x 1.6 cm (Figure 2) and AFP dropped from 8877 mcg/L to 1.7 mcg/L. The patient tolerated therapy with pembrolizumab without adverse effects.\n\n\nFigure 2 CT Abdomen After Treatment With Pembrolizumab\nAxial contrast-enhanced CT of the abdomen showing marked interval decrease in the size of the recurrent HCC measuring 2.2 x 1.6 cm.\n\n\n\n\nDiscussion\nThe innovative blockade of immune checkpoints with targeted immunotherapies, such as monoclonal antibodies against PD-1 and PD-L1, have shown great promise in Phase I clinical trials with activity seen in melanoma, non-small cell lung cancer, and renal cell cancer [6-7]. The PD-1 receptor is an inhibitory receptor and a negative regulator of T-cell effector mechanisms that limits immune responses against cancer [6]. Pembrolizumab is a highly selective, humanized monoclonal immunoglobulin against PD-1 that is designed to block the negative immune-regulatory signaling of the PD-1 receptor expressed by T cells, B cells, and macrophages [6]. Many tumors express high levels of PD-L1 to suppress antitumor immunity. PD-1 is expressed on antigen-stimulated T cells. When bound to the PDL-1, PD-1 results in T-cell suppression in peripheral tissues [8]. Anti-PD-1 works by inhibiting the interaction of PD-1 and PDL-1, thus reversing immune suppression induced by cancer cells [9].\n\nHCC is typically an aggressive tumor that arises in the setting of underlying chronic liver disease in most cases. For patients with localized disease, surgery is the treatment of choice. When patients present with metastatic disease, therapeutic options are limited. Chemotherapy has not been used routinely for patients with advanced HCC, since HCC is considered to be a relatively chemotherapy-refractory tumor. Molecular targeted therapy with sorafenib is the standard systemic treatment for advanced HCC. Our patient was started on sorafenib, however, the tumor progressed and he failed standard therapy. Then, he was started on pembrolizumab with a significant improvement in AFP and subxiphoid mass. He tolerated pembrolizumab well with absence of colitis, hepatitis, pneumonitis, or pituitary dysfunction. After eight months of treatment, pembrolizumab not only caused shrinkage of tumor, but also improved survival in our patient with an Eastern Cooperative Oncology Group (ECOG) score of zero.\n\nOur case revealed the potential efficacy of an anti-PD-1 antibody for treatment of metastatic HCC. An open-label, single-institution, non-randomized, single-arm study titled \"Phase II study of Pembrolizumab (Keytruda) in Advanced Hepatocellular Carcinoma (HCC)\" is currently evaluating the efficacy of pembrolizumab therapy in patients with advanced HCC. Results from this trial will contribute to determination of the benefit of PD-1 blockade in HCC.\n\nConclusions\nA promising avenue of clinical research in HCC is the use of immune checkpoint inhibitors. As far as we know, this is the first case report of advanced HCC responsive to pembrolizumab after failure of sorafenib therapy. Pembrolizumab and other immune checkpoint inhibitors could be a new developing therapy for patients with advanced HCC resistant to sorafenib.\n\nThe authors have declared that no competing interests exist.\n\nHuman Ethics\nConsent was obtained by all participants in this study\n==== Refs\nReferences\n1 Diagnosis of primary cancer of the liver Br Med J Kew MC Dos Santos HA Sherlock S 408 411 4 1971 http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1799483/ 5124443 \n2 A new prognostic system for hepatocellular carcinoma: a retrospective study of 435 patients Hepatology The Cancer of the Liver Italian Program (CLIP) investigators 751 755 28 1998 http://www.ncbi.nlm.nih.gov/pubmed/?term=9731568 9731568 \n3 Clinical features and prognosis of patients with extrahepatic metastases from hepatocellular carcinoma World J Gastroenterol Uka K Aikata H Takaki S 414 420 13 2007 17230611 \n4 Sorafenib in advanced hepatocellular carcinoma N Engl J Med Llovet JM Ricci S Mazzaferro V 378 390 359 2008 18650514 \n5 The blockade of immune checkpoints in cancer immunotherapy Nat Rev Cancer Pardoll DM 252 264 12 2012 22437870 \n6 Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma N Engl J Med Hamid O Robert C Daud A 134 144 369 2013 23724846 \n7 PD-1 and its ligands in tolerance and immunity Annu Rev Immunol Keir ME Butte MJ Freeman GJ 677 704 26 2008 18173375 \n8 The PD-1 pathway in tolerance and autoimmunity Immunol Rev Francisco LM Sage PT Sharpe AH 219 242 236 2010 20636820 \n9 PD-1 and PD-1 ligands: from discovery to clinical application Int Immunol Okazaki T Honjo T 813 824 19 2007 17606980\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "8(6)",
"journal": "Cureus",
"keywords": "immune checkpoint inhibitors; metastatic hepatocellular carcinoma; pembrolizumab",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e631",
"pmc": null,
"pmid": "27433410",
"pubdate": "2016-06-04",
"publication_types": "D002363:Case Reports",
"references": "20636820;18650514;17230611;22437870;23724846;18173375;17606980;5124443;9731568",
"title": "Metastatic Hepatocellular Carcinoma Responsive to Pembrolizumab.",
"title_normalized": "metastatic hepatocellular carcinoma responsive to pembrolizumab"
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"medicinalproduct": "PEMBROLIZUMAB."
},
{
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"activesubstancename": "SORAFENIB"
},
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}
],
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"reaction": [
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "19.1",
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},
{
"reactionmeddrapt": "Palmar-plantar erythrodysaesthesia syndrome",
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}
],
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},
"primarysource": {
"literaturereference": "TRUONG P; RAHAL A; KALLAIL KJ. METASTATIC HEPATOCELLULAR CARCINOMA RESPONSIVE TO PEMBROLIZUMAB.. CUREUS. 2016;8 (6):E631-E631",
"literaturereference_normalized": "metastatic hepatocellular carcinoma responsive to pembrolizumab",
"qualification": "3",
"reportercountry": "US"
},
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"receiptdate": "20160802",
"receivedate": "20160802",
"receiver": {
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},
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},
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}
] |