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"abstract": "BACKGROUND\nReconstruction intramedullary nail spanning the whole length of the femur has been the gold standard treatment for complete atypical diaphyseal fractures of the femur (ADF). However, in cases of incomplete ADF combined with severe bowing, this approach might have complications and lead to iatrogenic complete fracture. We report two cases of incomplete ADF with severe bowing using a precontoured plate (PCP) after rapid prototyping (RP) of the deformed femurs with three-dimensional printing (3DP) technology.\n\n\nMETHODS\nTwo patients presented with gradually worsening thigh pain, especially during walking. The patients had been using bisphosphonates for 4 and 10 years, respectively. Radiography showed an incomplete fracture in the lateral cortex of the right femur shaft. The lateral bowing angles measured in the affected femurs were 15° and 14°, and the anterior bowing angles were 20° and 16°, respectively. In bone scans, both patients showed hot uptake in the right mid-shaft of the femur. Preoperatively, the affected femur of the patient was reconstructed by 3DP RP using CT, and the plate was bent to the shape of the bone model. The ADF was fixed with a PCP using the minimally invasive plate osteosynthesis technique. Both patients were encouraged to start full weight-bearing and return to their preinjury activity level in daily life immediately after surgery. At 2 years postoperatively, radiography showed healing of the fracture site without recurrence of thigh pain and implant-related problems.\n\n\nCONCLUSIONS\nAlthough intramedullary nailing is the standard surgical treatment for complete ADF, PCP using 3DP RP could be an effective treatment option for incomplete ADF with severely curved femur.",
"affiliations": "Department of Orthopaedic Surgery, Kyungpook National University Hospital, Daegu, South Korea.;Department of Orthopaedic Surgery, Kyungpook National University Hospital, Daegu, South Korea.;Department of 3D Convergence Technology, Institute of Advance Convergence Technology, Daegu, South Korea.;Department of 3D Convergence Technology, Institute of Advance Convergence Technology, Daegu, South Korea.;Department of Orthopaedic Surgery, Kyungpook National University Hospital, Daegu, South Korea.;Department of Orthopaedic Surgery, Kyungpook National University Hospital, Daegu, South Korea.",
"authors": "Won|Heejae|H|https://orcid.org/0000-0003-0803-6086;Baek|Seung-Hoon|SH|https://orcid.org/0000-0002-8909-3287;Kim|Cheol-Hwan|CH|https://orcid.org/0000-0002-5591-4147;Kim|Dong-Hyeon|DH|https://orcid.org/0000-0002-1591-1208;Yoon|Jee-Wook|JW|https://orcid.org/0000-0002-5295-854X;Kim|Shin-Yoon|SY|https://orcid.org/0000-0002-5445-648X",
"chemical_list": null,
"country": "Australia",
"delete": false,
"doi": "10.1111/os.12867",
"fulltext": "\n==== Front\nOrthop Surg\nOrthop Surg\n10.1111/(ISSN)1757-7861\nOS\nOrthopaedic Surgery\n1757-7853 1757-7861 John Wiley & Sons Australia, Ltd Melbourne \n\n33283486\n10.1111/os.12867\nOS12867\nCase Report\nCase Reports\nPrecontoured Plate Fixation for Incomplete Atypical Diaphyseal Fracture of Femur using Three‐Dimensional Printing Rapid Prototyping: Two Cases Reports\nPrecontoured Plate Fixation for Incomplete Atypical Diaphyseal Fracture of Femur using Three‐dimensional Printing Rapid PrototypingWon Heejae MDhttps://orcid.org/0000-0003-0803-6086\n1\n Baek Seung‐Hoon MD, PhDhttps://orcid.org/0000-0002-8909-3287\n1\n\n2\ninsideme@paran.com Kim Cheol‐Hwan MDhttps://orcid.org/0000-0002-5591-4147\n3\n Kim Dong‐Hyeon PhDhttps://orcid.org/0000-0002-1591-1208\n3\n Yoon Jee‐Wook MDhttps://orcid.org/0000-0002-5295-854X\n1\n Kim Shin‐Yoon MD, PhDhttps://orcid.org/0000-0002-5445-648X\n1\n\n2\n \n1 \nDepartment of Orthopaedic Surgery\nKyungpook National University Hospital\nDaegu\nSouth Korea\n\n\n2 \nDepartment of Orthopaedic Surgery, School of Medicine\nKyungpook National University\nDaegu\nSouth Korea\n\n\n3 \nDepartment of 3D Convergence Technology\nInstitute of Advance Convergence Technology\nDaegu\nSouth Korea\n\n* Address for correspondence Seung‐Hoon Baek, MD, PhD, Department of Orthopaedic Surgery, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, 130, Dongdeok‐ro, Jung‐Gu, Daegu, South Korea 41944 Tel: +82‐53‐420‐5633; Fax: +82‐53‐422‐6605; Email: insideme@paran.com\n06 12 2020 \n2 2021 \n13 1 10.1111/os.v13.1353 359\n09 8 2020 10 9 2020 18 10 2020 © 2020 The Authors. Orthopaedic Surgery published by Chinese Orthopaedic Association and John Wiley & Sons Australia, Ltd.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.Background\nReconstruction intramedullary nail spanning the whole length of the femur has been the gold standard treatment for complete atypical diaphyseal fractures of the femur (ADF). However, in cases of incomplete ADF combined with severe bowing, this approach might have complications and lead to iatrogenic complete fracture. We report two cases of incomplete ADF with severe bowing using a precontoured plate (PCP) after rapid prototyping (RP) of the deformed femurs with three‐dimensional printing (3DP) technology.\n\nCase presentation\nTwo patients presented with gradually worsening thigh pain, especially during walking. The patients had been using bisphosphonates for 4 and 10 years, respectively. Radiography showed an incomplete fracture in the lateral cortex of the right femur shaft. The lateral bowing angles measured in the affected femurs were 15° and 14°, and the anterior bowing angles were 20° and 16°, respectively. In bone scans, both patients showed hot uptake in the right mid‐shaft of the femur. Preoperatively, the affected femur of the patient was reconstructed by 3DP RP using CT, and the plate was bent to the shape of the bone model. The ADF was fixed with a PCP using the minimally invasive plate osteosynthesis technique. Both patients were encouraged to start full weight‐bearing and return to their preinjury activity level in daily life immediately after surgery. At 2 years postoperatively, radiography showed healing of the fracture site without recurrence of thigh pain and implant‐related problems.\n\nConclusion\nAlthough intramedullary nailing is the standard surgical treatment for complete ADF, PCP using 3DP RP could be an effective treatment option for incomplete ADF with severely curved femur.\n\n\n\n\n\nAlthough intramedullary nailing is the standard surgical treatment for complete atypical femoral fractures, using a precontoured plate after rapid prototyping of the deformed femur with three‐dimensional printing could be an effective treatment option for incomplete atypical femoral fractures with severely curved femur.\n\nDiaphyseal femoral fractureIncomplete fracturePrecontoured plateMinimally invasive surgeryThree‐dimensional printingInstitute for Information and Communications Technology Promotion 10.13039/501100010418 source-schema-version-number2.0cover-dateFebruary 2021details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_JATSPMC version:5.9.7 mode:remove_FC converted:04.02.2021\nDisclosure: All authors declare that they have no conflict of interest.\n\n\nGrant Sources: This work was supported by the Information & Communication Technology (ICT) Research & Development program of the Institute for Information and Communications Technology Promotion (IITP) and the Ministry of Science and ICT (MSIT) (2019–0‐01682, Development of custom artificial ankle joint fusion SW technology based on ceramic 3D printing).\n==== Body\nIntroduction\nFor complete atypical diaphyseal fractures of the femur (ADF), reconstruction intramedullary nailing (IMN) panning the whole length of the femur has been considered the standard surgical treatment\n1\n, \n2\n. However, in cases of incomplete ADF combined with severe bowing, this procedure might result in complications and lead to iatrogenic complete fracture, resulting in delayed union or non‐union\n3\n, \n4\n. Plating has been proposed as an alternative\n5\n, \n6\n but may have disadvantages, such as the potential risk of developing neck fractures, the considerable time necessary to modify the plate into a form that fits perfectly to the bowed femur during the operation, and the insufficient length to cover the whole femur due to the complexity of the three‐dimensional (3D) deformity\n7\n. We report two cases of incomplete ADF with markedly curved femurs using a pre‐contoured plate (PCP) after rapid‐prototyping (RP) the deformed femurs with three‐dimensional printing (3DP) technology.\n\nCase Reports\n\nPatient 1\n\nA 75‐year‐old woman presented to our clinic with a 3‐month history of right thigh pain. She was able to walk independently outdoors before symptom onset. The patient had no history of recent trauma, and thigh pain was aggravated during walking, especially in the stance phase. However, she had no pain in other sites. The patient had used ibandronate 4 years previously due to osteoporosis. The patient had undergone internal fixation with proximal femur nail for intertrochanteric fracture of the left femur 11 years previously in another institution and internal fixation for left distal radius fracture 6 years previously in our institution. The patient complained of limb‐length discrepancy due to a shorter left leg after the previous surgery on the left femur. Besides osteoporosis, the patient had never been diagnosed with any disease affecting the bone metabolism, such as osteogenesis imperfecta.\n\nOn physical examination, there was mild tenderness in the right mid‐thigh. There was no clinical sign of infection, such as erythema, and local heat was not observed. The results of routine laboratory tests, including serum C‐reactive protein level and erythrocyte sedimentation rate, were within normal limits. Plain radiography showed transverse radiolucent fracture line on the apex of the lateral cortex of the right mid‐shaft of the femur (Fig. 1), but the contralateral side of the femur was intact. According to Sasaki et al.\n8\n, the lateral bowing angle was 14° and the anterior bowing angle was 16°. Bone single photon emission computed tomography (SPECT) showed hot uptake in the right femoral shaft (Fig. 2). The bone mineral density (BMD) of the lumbar spine (L1–4, 0.639 g/cm2; T‐score: −3.9) and the proximal femur (0.607 g/cm2; T‐score, −2.7) was evaluated by dual‐energy X‐ray absorptiometry (DEXA).\n\nFig. 1 Radiographs of patient 1. Plain radiographs showed transverse radiolucent line on the apex of the lateral cortex of the right mid‐shaft of the femur.\n\nFig. 2 Bone single photon emission CT of patient 1. (A) Preoperative nuclear medical images showed hot uptake in the right femoral shaft (arrowhead). (B) Two years after surgery, no or minimal uptake of the right femoral mid‐shaft was observed (arrowhead).\n\nThe patient was advised to discontinue ibandronate use and start teriparatide injection\n2\n, \n9\n. According to the scoring system for identifying impending complete fractures in incomplete atypical femoral fractures (AFF)\n10\n, the patient scored a total of 9 points, an indication for prophylactic surgery: 2 for diaphyseal lesion, 3 for functional pain, 3 for intact on the contralateral side, and 1 point for a focal radiolucent line. Due to severe bowing of the affected femur, we planned to perform prophylactic PCP spanning the whole length of the bowed femur. CT was performed on the patient's right femur, and a bone model was reconstructed using KM3D version 1.0 (Kyungpook National University, Institute of Advanced Convergence Technology, Daegu, Korea). A locking compression plate (DePuySynthes, Oberdorf, Switzerland) was precontoured preoperatively according to the shape of the bone model (Fig. 3). The bone model was sterilized for intraoperative use and placed on the same position to that of the femur under C‐arm guidance to enhance the accurate position of the PCP (Fig. 4A). Taking into consideration the 3D bending of the plate, an anterolateral skin incision, instead of a lateral incision, for plate entry was made, and submuscular insertion of PCP was performed using the routine minimally invasive plate osteosynthesis (MIPO) technique (Fig. 4B). To reduce the potential risk of femoral neck fracture due to stress concentration, one 80‐mm locking screw was inserted through the screw hole in the plate and two additional cannulated screws were inserted using the same incision at the entry site (Fig. 4C). The patient was encouraged to start full weight bearing and return to the pre‐injured activity level of daily life immediately after surgery.\n\nFig. 3 Precontoured plate for patient 1. The locking compression plate was precontoured according to the shape of the bone model. Because of the three‐dimensional complex deformity of the severely bowed femur, the proximal part of the precontoured plate was placed on the anterolateral aspect of the proximal femur. (A) Anteroposterior view. (B) Lateral view.\n\nFig. 4 Surgical process of patient 1. (A) Before making the incision, the sterilized bone model was placed on the same position to that of the femur under C‐arm guidance to enhance the accurate position of the PCP and reduce the operative time. (B) After submuscular insertion of PCP, we confirmed the correct position of the plate matching the bowed femur using both fluoroscopic guidance and preoperative images (shown in Fig. 3 using a smartphone). (C) Immediate postoperative radiography demonstrated the accurate position of the PCP, similar to the preoperative planning shown in Fig. 3, with additional screws toward the right femoral neck.\n\nThigh pain subsided 6 weeks postoperatively, and the patient returned to complete daily life. Radiography performed 2 years postoperatively showed bone union and no progression of femoral bowing or implant‐related problems (Fig. 5).\n\nFig. 5 Radiographs of patient 1 at last follow up. Radiographs taken at 2 years postoperatively showed bone union and no progression of femoral bowing or implant‐related problems.\n\n\nPatient 2\n\nA 78‐year‐old woman visited our orthopaedic department due to right thigh pain for 6 months. Thigh pain developed insidiously and gradually worsened. She had been unable to walk independently for 1 week. The patient had no history of recent trauma. No pain was noted in other sites. The patient had been using alendronate for treatment of osteoporosis for 10 years. The patient underwent total knee arthroplasty on both knees 10 years previously. She was diagnosed with an intertrochanteric fracture of the left femur and fracture of the symphysis pubis 4 years previously after slipdown. For intertrochanteric fractures, internal fixation with proximal femoral nail has been performed in another institution. She complained that the left lower limb was shortened after the previous surgery. Besides osteoporosis, she had never been diagnosed with any disease that might affect the bones.\n\nOn physical examination, there was moderate tenderness in the right thigh. There was no clinical sign of infection. Results of routine laboratory tests revealed no specific abnormality. Radiographs showed transverse radiolucent line in the lateral cortex of the mid‐shaft of the femur (Fig. 6), but there was no abnormality on the contralateral side of the femur. The curvature of the femur was marked, the lateral bowing angle was 15°, and the anterior bowing angle was 20°. Bone SPECT showed hot uptake in the right femoral shaft and symphysis pubis (Fig. 7). On DEXA, BMD of the lumbar spine (L2‐4, 0.718 g/cm2, T‐score: ‐2.7) and proximal femur (0.413 g/cm2, T‐score: ‐3.8) was obtained.\n\nFig. 6 Radiographs of patient 2. Plain radiographs showed transverse radiolucent line in the lateral cortex of the mid‐shaft of the femur.\n\nFig. 7 Bone single photon emission CT of patient 2. (A) Preoperative nuclear medical images showed hot uptake in the mid‐shaft of the right femur shaft and around the symphysis pubis (arrowhead). (B) Sixteen months after surgery, uptake in the mid‐shaft of the right femur was decreased, but hot uptake was still observed around the symphysis pubis (arrowhead).\n\nThe patient was advised to discontinue alendronate use and start teriparatide injection. Based on the scoring system to evaluate impending complete fractures, the patient scored 9 points, which was an indication for prophylactic surgery. Because the curvature of the affected femur was marked, we planned prophylactic surgery using PC‐WBP. We performed CT to obtain the morphologic features of the affected femur, and the bone model was reconstructed using 3DP RP. A locking compression plate (DePuySynthes, Oberdorf, Switzerland) was molded preoperatively according to the shape of the bone model (Fig. 8). The bone model was sterilized and used intraoperatively to assist the MIPO technique (Fig. 9A). Three additional cannulated screws were fixed using the same incision at the entry site to decrease the potential risk of femoral neck fracture (Fig. 9B). The patient was encouraged to start full weight‐bearing and return to their preinjury activity level in daily life immediately after surgery.\n\nFig. 8 Precontoured plate for patient 2. The locking compression plate was prebent to match the shape of the reconstructed bone model preoperatively. Because the curvature of the femur was more severe than that in patient 1, the proximal part of the precontoured plate was placed on the more anterior aspect of the proximal femur. (A) Anterioposterior view. (B) Lateral view.\n\nFig. 9 Surgical process of patient 2. (A) Bone model was sterilized and used intraoperatively to assist minimally invasive plate osteosynthesis (MIPO) technique. (B) Immediate postoperative plain X‐rays of the right femur.\n\nThe patient did not report pain in the right thigh and returned to complete daily life at the last follow‐up. Radiography performed at 16 months postoperatively showed ongoing union and no progression of femoral bowing or implant‐related problems (Fig. 10).\n\nFig. 10 Radiographs of patient 2 at last follow‐up. Radiography performed 16 months postoperatively showed and no progression of femoral bowing or implant‐related problems.\n\nDiscussion\nWe diagnosed incomplete ADF through physical examination and radiologic evaluation in two patients complaining of mid‐thigh pain and confirmed the indication for prophylactic surgery with a scoring system. Both patients had severely bowed femurs, and the bone model was reconstructed with 3DP RP. A locking compression plate spanning the whole femur was contoured preoperatively according to the shape of the bone model and then fixed to the bone using the MIPO technique. At 18 months postoperatively, we observed bone union, no progression of bowing, and no implant‐related problems on radiography. Furthermore, the patients did not complain of pain and were able to return to their preinjury daily lives.\n\nThe treatment choice for incomplete ADF depends on the patient's symptoms and radiological findings. If there is no pain, conservative treatment can be attempted initially for an incomplete ADF without a radiolucent fracture line\n1\n. Recently, Min et al. (2017) developed a scoring system to determine the necessity of prophylactic surgery for incomplete ADF\n10\n. Both cases in the present study corresponded to the indication for surgery. Prophylactic surgery foe incomplete ADF, if indicated, has been reported to reduce pain and prevent progression to complete fracture\n1\n. Moreover, compared to the surgery for complete ADF, prophylactic fixation for incomplete ADF has advantages, such as shorter time for union, shorter hospital stay and fewer complications\n2\n.\n\nReconstruction IMN has been considered as a standard method of prophylactic fixation for incomplete subtrochanteric AFF due to its better load‐sharing capacity and less bending moment\n1\n, \n2\n. However, prophylactic nailing for incomplete ADF, which is usually combined with a bowed femur, remains a challenge. Various methods for ADF have been proposed to overcome the significant anterolateral bowing of the femur, including far lateral entry point, use of the contralateral side of the nail, and external rotation of the nail\n3\n. However, in cases combined with severe anterolateral bowing, IMN may cause iatrogenic progression to complete fracture, which may lead to delayed union or non‐union\n1\n, \n2\n. Moreover, if femoral bowing occurs bilaterally, which is common in patients with ADF, IMN with iatrogenic or intentional complete fractures may straighten the curved femur and make the affected side longer than the contralateral side, leading to limb length discrepancy (LLD). Because both patients in our report complained of LLD due to a shortened contralateral lower limb after previous fixation for an intertrochanteric fracture, there was a potential risk of worsening LLD when complete fracture occurred during IMN.\n\nBiomechanically, tensile loading is concentrated in the lateral cortex of the curved femur in daily life, such as walking, and ADF occur in the region where maximal tensile loading is applied\n2\n. By placing the plate on the lateral side, the tensile force is reduced to prevent crack propagation, and the strain that prohibits bone formation is reduced to promote the healing process\n6\n. It can also prevent the progression to complete fracture that may occur during nail insertion and maintain lower limb length. Biologically, a previous study reported that lateral plate fixation had advantages over nailing in terms of less intramedullary damage and faster bone union in incomplete ADF\n5\n. Nevertheless, long‐term follow up might be necessary to identify further progression of deformity and subsequent hardware failure.\n\nRecently, some case reports using plates in an incomplete ADF demonstrated good clinical and radiological results\n5\n, \n6\n. Nevertheless, we are concerned about peri‐implant fractures due to stress concentration around the proximal or distal end of the plate by introducing a plate with insufficient length to span the whole length of the femur, as in previous case series. Our speculation for the use of a short plate in previous studies was that, although it was difficult to perform IMN in a severely bowed femur, it was also difficult and required time to contour the longer plate spanning the whole length of the femur during surgery due to the three‐dimensional complex structure of the deformed femur. Moreover, conventional open or mini‐open plating might require extensive incision for placement of the long plate. Thus, we precontoured the plate preoperatively using 3DP RP, and the reconstructed bone model was able to facilitate MIPO during surgery to reduce the operative time. In addition, prophylactic screw fixation toward the femoral neck was performed through the same incision as for plate entry to prevent potential femoral neck fractures due to stress concentration around the tip of the plate. As well as plate fixation in situ according the shape of 3DP RP, we can use this for planning and simulating corrective osteotomy and then fix the osteotomy site with IMN, which might be more sound from a biomechanical point of view. However, this corrective osteotomy may lead to delayed union, non‐union, and limb lengthening. Moreover, both patients had undergone internal fixation for intertrochanteric fractures and had subsequent limb shortening on the contralateral side. Thus, simple valgus osteotomy may aggravate the limb length discrepancy. Even combined shortening osteotomy still has risks for nonunion, delayed union, longer operation time, and more bleeding in patients who are 75 and 78 years of age. Because reduced bone turnover rate and decreased potential for direct bone healing have been reported as characteristics of bisphosphonate‐related ADF\n1\n, we believe that PCP fixation using MIPO technique could preserve periosteal bone blood supply and subsequent indirect bone healing, similar to that in IMN.\n\nConclusion\nAlthough IMN is the standard surgical treatment for ADF, we obtained satisfactory results after use of PCP with 3DP RP in incomplete ADF with severe bowing. Based on our experience, PCP fixation using 3DP RP could be an effective treatment option for incomplete ADF with severe bowing.\n==== Refs\nReferences\n1 \n\nKoh \nA \n, \nGuerado \nE \n, \nGiannoudis \nPV \n. Atypical femoral fractures related to bisphosphonate treatment: issues and controversies related to their surgical management\n. Bone Joint J , 2017 , 99 : 295 –302\n.28249967 \n2 \n\nStarr \nJ \n, \nTay \nYKD \n, \nShane \nE \n. Current understanding of epidemiology, pathophysiology, and Management of Atypical Femur Fractures\n. Curr Osteoporos Rep , 2018 , 16 : 519 –529\n.29951870 \n3 \n\nLee \nKJ \n, \nMin \nBW \n. Surgical treatment of the atypical femoral fracture: overcoming femoral bowing\n. Hip Pelvis , 2018 , 30 : 202 –209\n.30534538 \n4 \n\nYun \nHH \n, \nOh \nCH \n, \nYi \nJW \n. Subtrochanteric femoral fracture during trochanteric nailing for the treatment of femoral shaft fracture\n. Clin Orthop Surg , 2013 , 5 : 230 –234\n.24009910 \n5 \n\nTsuchie \nH \n, \nMiyakoshi \nN \n, \nNishi \nT \n, \nAbe \nH \n, \nSegawa \nT \n, \nShimada \nY \n. Combined effect of a locking plate and Teriparatide for incomplete atypical femoral fracture: two case reports of curved femurs\n. Case Rep Orthop , 2015 , 2015 : 213614.26101679 \n6 \n\nKharazmi \nM \n, \nMichaelsson \nK \n, \nHallberg \nP \n, \nSchilcher \nJ \n. Lateral fixation: an alternative surgical approach in the prevention of complete atypical femoral fractures\n. Eur J Orthop Surg Traumatol , 2018 , 28 : 299 –304\n.28924690 \n7 \n\nLee \nJY \n, \nSoh \nT \n, \nHowe \nTS \n, \nKoh \nJS \n, \nKwek \nEB \n, \nChua \nDT \n. Bisphosphonate‐associated peri‐implant fractures: a new clinical entity? A series of 10 patients with 11 fractures\n. Acta Orthop , 2015 , 86 : 622 –626\n.25817305 \n8 \n\nSasaki \nS \n, \nMiyakoshi \nN \n, \nHongo \nM \n, \nKasukawa \nY \n, \nShimada \nY \n. Low‐energy diaphyseal femoral fractures associated with bisphosphonate use and severe curved femur: a case series\n. J Bone Miner Metab , 2012 , 30 : 561 –567\n.22610061 \n9 \n\nShane \nE \n, \nBurr \nD \n, \nAbrahamsen \nB \n, et al\nAtypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research\n. J Bone Miner Res , 2014 , 29 : 1 –23\n.23712442 \n10 \n\nMin \nBW \n, \nKoo \nKH \n, \nPark \nYS \n, et al\nScoring system for identifying impending complete fractures in incomplete atypical femoral fractures\n. J Clin Endocrinol Metab , 2017 , 102 : 545 –550\n.27802096\n\n",
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"issue": "13(1)",
"journal": "Orthopaedic surgery",
"keywords": "Diaphyseal femoral fracture; Incomplete fracture; Minimally invasive surgery; Precontoured plate; Three-dimensional printing",
"medline_ta": "Orthop Surg",
"mesh_terms": "D000368:Aged; D001858:Bone Nails; D001860:Bone Plates; D018483:Diaphyses; D005260:Female; D005264:Femoral Fractures; D005593:Fracture Fixation, Internal; D006801:Humans; D066230:Patient-Specific Modeling; D066330:Printing, Three-Dimensional",
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"title": "Precontoured Plate Fixation for Incomplete Atypical Diaphyseal Fracture of Femur using Three-Dimensional Printing Rapid Prototyping: Two Cases Reports.",
"title_normalized": "precontoured plate fixation for incomplete atypical diaphyseal fracture of femur using three dimensional printing rapid prototyping two cases reports"
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"literaturereference": "Won H, Baek S-H, Kim C-H, Kim D-H, Yoon J-W, Kim S-Y. Precontoured Plate Fixation for Incomplete Atypical Diaphyseal Fracture of Femur using Three-Dimensional Printing Rapid Prototyping: Two Cases Reports. Orthop Surg. 2021;13(1):353-359",
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{
"abstract": "Acute severe recurrence of hepatitis C virus (HCV) after solid organ transplant is associated with high mortality. Pegylated interferon and ribavirin are suboptimal in treatment of this severe form of recurrence. We report 4 cases of acute severe HCV recurrence (within 6 months after transplant), including 3 cases with fibrosing cholestatic hepatitis treated with sofosbuvir and ribavirin. All four patients achieved a rapid suppression of HCV RNA with a normalization of liver function tests within 4 weeks of starting therapy. All patients were HCV RNA negative at 12 weeks after stopping therapy. The combination was found to be safe as anemia was the only adverse effect, which developed in 2 patients (1 patient required blood transfusion, while another managed with erythropoietin). Sofosbuvir and ribavirin appear to be safe and efficacious in treatment of acute severe HCV recurrence after organ transplant.",
"affiliations": "Department of Gastroenterology & Hepatology, Fortis Escorts Liver & Digestive Diseases Institute, Delhi/NCR, India.;Department of Surgical Gastroenterology & Liver Transplant, Fortis Hospitals (Escorts & Noida), Delhi/NCR, India.;Department of Surgical Gastroenterology & Liver Transplant, Fortis Hospitals (Escorts & Noida), Delhi/NCR, India.;Department of Pathology, Fortis Escorts Hospital, Delhi, India.;Department of Gastroenterology & Hepatology, Fortis Escorts Liver & Digestive Diseases Institute, Delhi/NCR, India.",
"authors": "Wadhawan|Manav|M|;Vij|Vivek|V|;Makki|Kausar|K|;Bansal|Nalini|N|;Kumar|Ajay|A|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.1016/j.jceh.2016.10.004",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0973-6883",
"issue": "7(1)",
"journal": "Journal of clinical and experimental hepatology",
"keywords": "ALT, alanine aminotransferase; AST, aspartate aminotransferase; DAA's, sofosbuvir; FCH, fibrosing cholestatic hepatitis; Fibrosing cholestatic hepatitis; GGTP, gamma glutamyl transpeptidase; HCV, hepatitis C virus; IHBR, intrahepatic biliary radicals; Kidney transplant; LFT, liver function tests; LRLT, living-related liver transplant; Liver transplant; MMF, mycophenolate mofetil; MRCP, magnetic resonance cholangiopancreatography; POD, postoperative day; TND, target not detected",
"medline_ta": "J Clin Exp Hepatol",
"mesh_terms": null,
"nlm_unique_id": "101574137",
"other_id": null,
"pages": "28-32",
"pmc": null,
"pmid": "28348468",
"pubdate": "2017-03",
"publication_types": "D016428:Journal Article",
"references": "21031537;17164125;25557906;21486625;26907736;23432435;26889372;23081888;22613001;20960380;11870384;26044317;24767401;21426450",
"title": "Early Acute Severe HCV Recurrence After Transplantation: From Universal Mortality to Cure.",
"title_normalized": "early acute severe hcv recurrence after transplantation from universal mortality to cure"
} | [
{
"companynumb": "IN-ASTELLAS-2017US014738",
"fulfillexpeditecriteria": "1",
"occurcountry": "IN",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLIC ACID"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "FORMULATION UNKNOWN",
"drugdosagetext": "UNK UNK, UNKNOWN FREQ.",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "LIVER TRANSPLANT",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MYCOPHENOLATE"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "050708",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "FORMULATION UNKNOWN",
"drugdosagetext": "UNK UNK, UNKNOWN FREQ.",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "LIVER TRANSPLANT",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TACROLIMUS."
}
],
"patientagegroup": null,
"patientonsetage": "56",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Hepatitis cholestatic",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hepatitis C",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WADHAWAN M, VIJ V, MAKKI K, BANSAL N, KUMAR A. EARLY ACUTE SEVERE HCV RECURRENCE AFTER TRANSPLANTATION: FROM UNIVERSAL MORTALITY TO CURE. JOURNAL OF CLINICAL AND EXPERIMENTAL HEPATOLOGY. 2017;7(1):28-32",
"literaturereference_normalized": "early acute severe hcv recurrence after transplantation from universal mortality to cure",
"qualification": "3",
"reportercountry": "IN"
},
"primarysourcecountry": "IN",
"receiptdate": "20170420",
"receivedate": "20170420",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13461000,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170830"
}
] |
{
"abstract": "To compare long-term efficacy of remission-maintenance regimens in patients with newly diagnosed or relapsing antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides.\n\n\n\nThe 28-month Maintenance of Remission using Rituximab in Systemic ANCA-associated Vasculitis trial compared rituximab with azathioprine to maintain remission in patients with newly diagnosed or relapsing granulomatosis with polyangiitis, microscopic polyangiitis or renal-limited ANCA-associated vasculitis. Thereafter, prospective patient follow-up lasted until month 60. The primary endpoint was the major-relapse rate at month 60. Relapse and serious adverse event-free survival were also assessed.\n\n\n\nAmong the 115 enrolled patients, only one was lost to follow-up at month 60. For the azathioprine and rituximab groups, respectively, at month 60, the major relapse-free survival rates were 49.4% (95% CI 38.0% to 64.3%) and 71.9% (95% CI 61.2% to 84.6%) (p=0.003); minor and major relapse-free survival rates were 37.2% (95% CI 26.5% to 52.2%) and 57.9% (95% CI 46.4% to 72.2%) (p=0.012); overall survival rates were 93.0% (95% CI 86.7% to 99.9%) and 100% (p=0.045) and cumulative glucocorticoid use was comparable. Quality-adjusted time without symptoms and toxicity analysis showed that rituximab-treated patients had 12.6 months more without relapse or toxicity than those given azathioprine (p<0.001). Antiproteinase-3-ANCA positivity and azathioprine arm were independently associated with higher risk of relapse. HRs of positive ANCA to predict relapse increased over time.\n\n\n\nThe rate of sustained remission for ANCA-associated vasculitis patients, following rituximab-based or azathioprine-based maintenance regimens, remained superior over 60 months with rituximab, with better overall survival.\n\n\n\nNCT00748644.",
"affiliations": "Department of Internal Medicine, Hôpital Cochin, Université Paris Descartes, Sorbonne Paris Cité, INSERM Unité 1016, Centre de Référence pour les Maladies Auto-immunes Rares, Paris, France.;Department of Internal Medicine, Hôpital Cochin, Université Paris Descartes, Sorbonne Paris Cité, INSERM Unité 1016, Centre de Référence pour les Maladies Auto-immunes Rares, Paris, France.;Centre d'Epidémiologie Clinique, Hôpital Hôtel-Dieu, Université Paris Descartes, INSERM Unité 738, Paris, France.;Unité de Néphrologie, Hôpital Européen Georges-Pompidou, Université Paris Descartea, Paris, France.;Service de Pneumologie, Centre de Référence pour Maladies Pulmonaires Rares, Hôpital Universitaire Louis Pradel, Lyon, France.;Service de Médecine Interne, Centre Hospitalier Universitaire, Hôpital Gabriel Montpied, Clermont-Ferrand, France.;Department of Internal Medicine, Hôpital Cochin, Université Paris Descartes, Sorbonne Paris Cité, INSERM Unité 1016, Centre de Référence pour les Maladies Auto-immunes Rares, Paris, France.;Département de Médecine Interne, Hôpitaux Universitaires de Rennes, Hôpital Sud, Université Rennes I, IGDR-UMR 6290, Rennes, France.;Service de Médecine Interne, Hôpital Edouard Herriot, Lyon, France.;Service de Médecine Interne et d'Immunologie Clinique, Site Belle Isle, HPM, Metz, France.;Département de Médecine Interne, Centre Hospitalier Bretagne Atlantique de Vannes, Vannes, France.;Département de Néphrologie and Département de Médecine Interne, Centre Hospitalier de Valenciennes, Valenciennes, France.;Service de Médecine Interne, Centre Hospitalier Général de Niort, Niort, France.;Service de Médecine Interne et d'Immunologie Clinique, Centre Hospitalier Universitaire de Dijon, Université de Bourgogne, IFR100, Dijon, France.;Service de Néphrologie, Dialyse et Transplantation, Centre Hospitalier Universitaire de Grenoble, Grenoble, France.;Service de Néphrologie, INSERM Unité 699, Département Hospitalo-Universitaire FIRE, Hôpital Bichat, Université Paris Diderot, Paris, France.;Département de Néphrologie, Hôpital d'Annecy, Annecy, France.;Service de Médecine Interne, Clinique Rhône Durance, Avignon, France.;Département de Médecine Interne, Centre Hospitalier Universitaire Hôtel-Dieu, Nantes, France.;Département de Médecine Interne, Hôpital La Croix Saint-Simon, Paris, France.;Service de Médecine Interne, Centre de Référence Labellisé pour la Prise en Charge des Cytopénies Auto-immunes de l'Adulte, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Vasculitis Clinic, Créteil, France.;Department of Internal Medicine, Hôpital Cochin, Université Paris Descartes, Sorbonne Paris Cité, INSERM Unité 1016, Centre de Référence pour les Maladies Auto-immunes Rares, Paris, France.;Department of Internal Medicine, Hôpital Cochin, Université Paris Descartes, Sorbonne Paris Cité, INSERM Unité 1016, Centre de Référence pour les Maladies Auto-immunes Rares, Paris, France.;Centre d'Epidémiologie Clinique, Hôpital Hôtel-Dieu, Université Paris Descartes, INSERM Unité 738, Paris, France.;Department of Internal Medicine, Hôpital Cochin, Université Paris Descartes, Sorbonne Paris Cité, INSERM Unité 1016, Centre de Référence pour les Maladies Auto-immunes Rares, Paris, France.",
"authors": "Terrier|Benjamin|B|;Pagnoux|Christian|C|;Perrodeau|Élodie|É|;Karras|Adexandre|A|;Khouatra|Chahera|C|;Aumaître|Olivier|O|;Cohen|Pascal|P|;Decaux|Olivier|O|;Desmurs-Clavel|Hélène|H|;Maurier|François|F|;Gobert|Pierre|P|;Quémeneur|Thomas|T|;Blanchard-Delaunay|Claire|C|;Bonnotte|Bernard|B|;Carron|Pierre-Louis|PL|;Daugas|Eric|E|;Ducret|Marize|M|;Godmer|Pascal|P|;Hamidou|Mohamed|M|;Lidove|Olivier|O|;Limal|Nicolas|N|;Puéchal|Xavier|X|;Mouthon|Luc|L|;Ravaud|Philippe|P|;Guillevin|Loïc|L|;|||",
"chemical_list": "D019268:Antibodies, Antineutrophil Cytoplasmic; D018501:Antirheumatic Agents; D005938:Glucocorticoids; D007166:Immunosuppressive Agents; D000069283:Rituximab; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1136/annrheumdis-2017-212768",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-4967",
"issue": "77(8)",
"journal": "Annals of the rheumatic diseases",
"keywords": "granulomatosis with polyangiitis; systemic vasculitis; treatment",
"medline_ta": "Ann Rheum Dis",
"mesh_terms": "D000328:Adult; D000368:Aged; D056648:Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; D019268:Antibodies, Antineutrophil Cytoplasmic; D018501:Antirheumatic Agents; D001379:Azathioprine; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007166:Immunosuppressive Agents; D053208:Kaplan-Meier Estimate; D018655:Lymphocyte Count; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D012074:Remission Induction; D012307:Risk Factors; D000069283:Rituximab; D012720:Severity of Illness Index; D016896:Treatment Outcome",
"nlm_unique_id": "0372355",
"other_id": null,
"pages": "1150-1156",
"pmc": null,
"pmid": "29724729",
"pubdate": "2018-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial",
"references": null,
"title": "Long-term efficacy of remission-maintenance regimens for ANCA-associated vasculitides.",
"title_normalized": "long term efficacy of remission maintenance regimens for anca associated vasculitides"
} | [
{
"companynumb": "FR-MYLANLABS-2019M1013530",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "080292",
"drugbatchnumb": "UNK",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLET",
"drugdosagetext": "UNK",
"drugenddate": null,
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"drugindication": "VASCULITIS",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"medicinalproduct": "PREDNISONE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": "3",
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"drugindication": "VASCULITIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
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"medicinalproduct": "RITUXIMAB."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
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"drugenddate": null,
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"drugindication": "VASCULITIS",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
"drugrecurrence": null,
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"medicinalproduct": "AZATHIOPRINE."
}
],
"patientagegroup": null,
"patientonsetage": "72",
"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Drug effect incomplete",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BENJAMIN T, CHRISTIAN P, ELODIE P, ADEXANDRE K, CHAHERA K, OLIVIER A ET.AL. LONG-TERM EFFICACY OF REMISSION-MAINTENANCE REGIMENS FOR ANCA-ASSOCIATED VASCULITIDES.. ANNALS OF THE RHEUMATIC DISEASES. 2018?1151-1157",
"literaturereference_normalized": "long term efficacy of remission maintenance regimens for anca associated vasculitides",
"qualification": "1",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20190218",
"receivedate": "20190218",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15976572,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190418"
},
{
"companynumb": "FR-MYLANLABS-2019M1013516",
"fulfillexpeditecriteria": "1",
"occurcountry": "FR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "RITUXIMAB"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNK",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
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"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MICROSCOPIC POLYANGIITIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "RITUXIMAB."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": "UNK",
"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "VASCULITIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "AZATHIOPRINE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "080292",
"drugbatchnumb": "UNK",
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLET",
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "MICROSCOPIC POLYANGIITIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
}
],
"patientagegroup": null,
"patientonsetage": "68",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug effect incomplete",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BENJAMIN TERRIER, CHRISTIAN PAGNOUX, ELODIE PERRODEAU, ADEXANDRE KARRAS, CHAHERA KHOUATRA, OLIVIER AUMAITRE ET AL. LONG-TERM EFFICACY OF REMISSION-MAINTENANCE REGIMENS FOR ANCA-ASSOCIATED VASCULITIDES.. ANNALS OF THE RHEUMATIC DISEASES. 2018?77:1151-1157",
"literaturereference_normalized": "long term efficacy of remission maintenance regimens for anca associated vasculitides",
"qualification": "1",
"reportercountry": "FR"
},
"primarysourcecountry": "FR",
"receiptdate": "20190218",
"receivedate": "20190218",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15976921,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190418"
}
] |
{
"abstract": "BACKGROUND\nAcute myeloid leukemia (AML) can develop secondary to drug treatment. This phenomenon has been placed under the title \"Therapy Related Acute Myeloid Leukemias and Myelodysplastic Syndromes\" in the WHO classification of AML. Cyclophosphamide, which is used in various malignancies and rheumatological diseases, is an alkylating agent that plays a significant role in therapy related AML.\n\n\nMETHODS\nA patient treated with cyclophosphamide due to vasculitis, subsequently developed AML months after treatment.\n\n\nCONCLUSIONS\nCyclophosphamide related AML is seen, in most cases, many years after exposure to the drug. The significance of this report lies in the fact that, to our knowledge, this is the most rapidly arising case of cyclophosphamide related AML.",
"affiliations": "Ic Hastaliklari ABD, Gazi Universitesi Hastanesi, 06500, Besevler, Ankara, Turkey, hayretdink@gmail.com.",
"authors": "Koklu|Hayretdin|H|;Tufan|Abdurrahman|A|;Erkul|Yusuf|Y|;Akyurek|Nalan|N|;Civelek|Ramazan|R|",
"chemical_list": "D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11096-015-0069-4",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "37(2)",
"journal": "International journal of clinical pharmacy",
"keywords": null,
"medline_ta": "Int J Clin Pharm",
"mesh_terms": "D000328:Adult; D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D016609:Neoplasms, Second Primary",
"nlm_unique_id": "101554912",
"other_id": null,
"pages": "289-91",
"pmc": null,
"pmid": "25612567",
"pubdate": "2015-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "19155067;20039416;16231966;10509043;19357394;18176988;2885581;22180424;12623843;23507056;19717383;9065658;11921271;14651772",
"title": "Secondary acute myeloid leukemia arising early after cyclophosphamide treatment.",
"title_normalized": "secondary acute myeloid leukemia arising early after cyclophosphamide treatment"
} | [
{
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"abstract": "BACKGROUND\nAntipsychotics are drugs that can produce transient elevations of hepatic enzymes. Clozapine is an atypical antipsychotic used in treatment-resistant schizophrenia and there is evidence that it can produce elevations of hepatic transaminases, expression of liver damage in a hepatocellular pattern.\n\n\nMETHODS\nCase report and non-systematic review of the relevant literature.\n\n\nMETHODS\nA 39-year-old woman with a diagnosis of paranoid schizophrenia attended the emergency department of a general hospital for nausea, vomiting and jaundice that appeared after the initiation of clozapine. There was no clinical improvement during hospitalisation, and death occurred after 44 days.\n\n\nMETHODS\nClozapine can increase the liver enzyme levels transiently and asymptomatically; however, there are clinical criteria that recommend the withdrawal of the antipsychotic.\n\n\nCONCLUSIONS\nThis is the third case reported in the literature of a fatal outcome of clozapine-induced hepatotoxicity.",
"affiliations": "Instituto Nacional de Salud Mental Honorio Delgado-Hideyo Noguchi, Lima, Perú; Universidad Peruana Cayetano Heredia, Lima, Perú. Electronic address: joshep.revilla.z@upch.pe.;Hospital Carlos Lanfranco La Hoz, Lima, Perú.;Instituto Nacional de Salud Mental Honorio Delgado-Hideyo Noguchi, Lima, Perú; Universidad Peruana Cayetano Heredia, Lima, Perú.",
"authors": "Revilla-Zúñiga|Joshep|J|;Cornejo-Del Carpio|Joise|J|;Cruzado|Lizardo|L|",
"chemical_list": null,
"country": "Spain",
"delete": false,
"doi": "10.1016/j.rcp.2021.04.010",
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"issue": null,
"journal": "Revista Colombiana de psiquiatria (English ed.)",
"keywords": "Adverse event; Antipsicóticos; Antipsychotic agents; Drug-induced liver disease; Enfermedad hepática inducida por medicamento; Evento adverso",
"medline_ta": "Rev Colomb Psiquiatr (Engl Ed)",
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"nlm_unique_id": "101778593",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "34167791",
"pubdate": "2021-06-08",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Hepatoxicity Induced by Clozapine: Case Report and Brief Review.",
"title_normalized": "hepatoxicity induced by clozapine case report and brief review"
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},
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{
"abstract": "OBJECTIVE\nAddition of either nab-paclitaxel or erlotinib to gemcitabine to treat advanced pancreatic cancer has demonstrated overall survival benefit. This study was conducted to evaluate the tolerability and safety of combining all three drugs and assess preliminary evidence of efficacy.\n\n\nMETHODS\nIn this open-label, phase 1b study, patients with previously untreated, advanced pancreatic cancer were treated in 28-day cycles with intravenous gemcitabine/nab-paclitaxel on days 1, 8, and 15, and once daily oral erlotinib. A standard \"3 + 3\" design was used. Dose level 1 (DL1) for gemcitabine (mg/m(2))/nab-paclitaxel (mg/m(2))/erlotinib (mg) was 1000/125/100, respectively, with de-escalation to DL-1 (1000/100/100), DL-2b (1000/75/100), and DL-3 (1000/75/75). The maximum tolerated dose (MTD) was defined by occurrence of dose-limiting toxicity (DLT) in ≤1 of six patients within the first cycle. Efficacy was assessed with CT scans performed at two-cycle intervals.\n\n\nRESULTS\nNineteen patients were enrolled. DLTs occurred in two patients at DL1, three patients at DL-1, two patients at DL-2b, and one patient at DL-3. The MTD for the combination of gemcitabine/nab-paclitaxel/erlotinib was DL-3 (1000/75/75). In analyses of efficacy among 14 evaluable patients, partial responses were observed in four of six patients at DL1, one of two patients at DL-2b, and two of six patients at DL-3.\n\n\nCONCLUSIONS\nThe addition of erlotinib to gemcitabine and nab-paclitaxel is not tolerable at standard single-agent dosing of all drugs. However, significant clinical activity was noted, even at DL-3. Further study of the combination will need to incorporate reduced dosing.",
"affiliations": "Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111-2497, USA. steven.cohen@fccc.edu.;Indiana University Simon Cancer Center, Indianapolis, IN, USA.;Vanderbilt-Ingram Cancer Center, Nashville, TN, USA.;Abrazo Community Health Network, Phoenix, AZ, USA.;Aptium Oncology, Criterium, Inc., Los Angeles, CA, USA.;Novella Clinical, Boulder, CO, USA.;Novella Clinical, Boulder, CO, USA.;Champions Oncology, Hackensack, NJ, USA.;University of Colorado School of Medicine, Aurora, CO, USA.;New York University, New York, NY, USA.",
"authors": "Cohen|Steven J|SJ|;O'Neil|Bert H|BH|;Berlin|Jordan|J|;Ames|Patricia|P|;McKinley|Marti|M|;Horan|Julie|J|;Catalano|Patricia M|PM|;Davies|Angela|A|;Weekes|Colin D|CD|;Leichman|Lawrence|L|",
"chemical_list": "C520255:130-nm albumin-bound paclitaxel; D000418:Albumins; D003841:Deoxycytidine; C056507:gemcitabine; D000069347:Erlotinib Hydrochloride; D017239:Paclitaxel",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-016-2981-2",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "77(4)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Combination; Erlotinib; Gemcitabine; Nab-paclitaxel; Pancreatic cancer",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000368:Aged; D000418:Albumins; D000971:Antineoplastic Combined Chemotherapy Protocols; D003841:Deoxycytidine; D000069347:Erlotinib Hydrochloride; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D017239:Paclitaxel; D010190:Pancreatic Neoplasms",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "693-701",
"pmc": null,
"pmid": "26886016",
"pubdate": "2016-04",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "A phase 1b study of erlotinib in combination with gemcitabine and nab-paclitaxel in patients with previously untreated advanced pancreatic cancer: an Academic Oncology GI Cancer Consortium study.",
"title_normalized": "a phase 1b study of erlotinib in combination with gemcitabine and nab paclitaxel in patients with previously untreated advanced pancreatic cancer an academic oncology gi cancer consortium study"
} | [
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{
"abstract": "The incidence of breast cancer diagnosed during pregnancy is increasing. We sought to characterize patient, treatment, pregnancy and lactation factors among young women with newly diagnosed breast cancer during pregnancy in a prospective cohort study. We identified all women who were pregnant when diagnosed with invasive breast cancer among those enrolled in the Young Women's Breast Cancer Study (NCT01468246), and collected details on pregnancy, birth and lactation from surveys, and treatment information medical record review. Of 1302 enrolled participants, 976 women with invasive breast cancer completed full baseline surveys, among whom 39 (4.0%) patients reported being pregnant at diagnosis. Median age at diagnosis was 34 years (range: 25-40), with stage distribution: I, 28%; II, 44%; III, 23%; and IV, 5%. 74% of patients (29/39) had grade 3 tumors, 59% (23/39) ER-positive, and 31% (12/39) HER2-positive disease. 23 (59%) had surgery during pregnancy, 4 (17%) during the first trimester. Among the women who had surgery during pregnancy, 61% (14/23) underwent lumpectomy, 35% (8/23) unilateral, and 4% (1/23) bilateral mastectomy. All patients who had chemotherapy (51%, 20/39) received it in second and third trimesters, and had ACx4. There were 31 live births, 2 spontaneous, and 5 therapeutic abortions. Among live births, 16 (41%) were before 37 weeks of gestation. Three women reported breastfeeding. Within 6 months after delivery, comprehensive staging in 13 patients showed upstaging in four patients. In a contemporary cohort of young women with breast cancer, pregnancy at diagnosis is relatively uncommon. Treatment during pregnancy can generally be consistent with standard surgical and chemotherapy approaches, with attention to timing of therapies. Longer-term outcomes including effects of some timing issues including delayed use of anti-HER2 therapy on patient outcomes warrant further research.",
"affiliations": "Medical Oncology, National Cancer Centre Singapore (NCCS), Singapore.;Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;School of Medicine, University of Colorado, Denver, Colorado.;Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.;Department of Medicine, Stanford University Medical Center, Palo Alto, California.;Department of Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts.;Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.",
"authors": "Lee|Guek Eng|GE|;Rosenberg|Shoshana M|SM|;Mayer|Erica L|EL|;Borges|Virginia|V|;Meyer|Meghan E|ME|;Schapira|Lidia|L|;Come|Steven E|SE|;Partridge|Ann H|AH|",
"chemical_list": "D000970:Antineoplastic Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/tbj.13431",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1075-122X",
"issue": "25(6)",
"journal": "The breast journal",
"keywords": "breast cancer; pregnancy; pregnancy-associated breast cancer; young women",
"medline_ta": "Breast J",
"mesh_terms": "D000328:Adult; D000970:Antineoplastic Agents; D001942:Breast Feeding; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D007774:Lactation; D008408:Mastectomy; D009367:Neoplasm Staging; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D011256:Pregnancy Outcome; D011446:Prospective Studies; D011795:Surveys and Questionnaires",
"nlm_unique_id": "9505539",
"other_id": null,
"pages": "1104-1110",
"pmc": null,
"pmid": "31318125",
"pubdate": "2019-11",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Contemporary management of breast cancer during pregnancy and subsequent lactation in a multicenter cohort of young women with breast cancer.",
"title_normalized": "contemporary management of breast cancer during pregnancy and subsequent lactation in a multicenter cohort of young women with breast cancer"
} | [
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{
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},
{
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},
{
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{
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"abstract": "BACKGROUND\nWe report the development of asymptomatic progressive multifocal leukoencephalopathy in a patient with multiple sclerosis on natalizumab therapy. Progressive multifocal leukoencephalopathy often presents with debilitating neurologic symptoms. Very few cases have documented a completely asymptomatic course of the disease.\n\n\nMETHODS\nA 26-year-old white woman with multiple sclerosis was treated with natalizumab. She was diagnosed as having progressive multifocal leukoencephalopathy based on characteristic magnetic resonance imaging lesions after 27 infusions of natalizumab. She had no neurologic deficits at the time of diagnosis and John Cunningham virus in cerebrospinal fluid was detected at 15 copies/ml. She was initially treated with mefloquine and mirtazapine and remained asymptomatic for 3 months. She later developed worsening magnetic resonance imaging lesions related to immune reconstitution inflammatory syndrome. At that time, she received intravenously administered immunoglobulin and high-dose intravenously administered methylprednisolone with radiologic improvement of the lesions.\n\n\nCONCLUSIONS\nOur case report illustrates that early detection of asymptomatic progressive multifocal leukoencephalopathy and its subsequent treatment resulted in a benign clinical course. In consideration of the additional small number of cases of asymptomatic progressive multifocal leukoencephalopathy that have been reported, we conclude that routine magnetic resonance imaging surveillance is important for patients with multiple sclerosis who are at high risk for developing natalizumab-associated progressive multifocal leukoencephalopathy.",
"affiliations": "Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA. yinan.zhang@phhs.org.;Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.;Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX, 75390, USA.",
"authors": "Zhang|Yinan|Y|http://orcid.org/0000-0001-9934-4564;Wright|Crystal|C|;Flores|Angela|A|",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central London 172710.1186/s13256-018-1727-7Case ReportAsymptomatic progressive multifocal leukoencephalopathy: a case report and review of the literature http://orcid.org/0000-0001-9934-4564Zhang Yinan yinan.zhang@phhs.org Wright Crystal crystal.wright@utsouthwestern.edu Flores Angela angela.flores@utsouthwestern.edu 0000 0000 9482 7121grid.267313.2Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd, Dallas, TX 75390 USA 1 7 2018 1 7 2018 2018 12 18717 1 2018 28 5 2018 © The Author(s). 2018Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nWe report the development of asymptomatic progressive multifocal leukoencephalopathy in a patient with multiple sclerosis on natalizumab therapy. Progressive multifocal leukoencephalopathy often presents with debilitating neurologic symptoms. Very few cases have documented a completely asymptomatic course of the disease.\n\nCase presentation\nA 26-year-old white woman with multiple sclerosis was treated with natalizumab. She was diagnosed as having progressive multifocal leukoencephalopathy based on characteristic magnetic resonance imaging lesions after 27 infusions of natalizumab. She had no neurologic deficits at the time of diagnosis and John Cunningham virus in cerebrospinal fluid was detected at 15 copies/ml. She was initially treated with mefloquine and mirtazapine and remained asymptomatic for 3 months. She later developed worsening magnetic resonance imaging lesions related to immune reconstitution inflammatory syndrome. At that time, she received intravenously administered immunoglobulin and high-dose intravenously administered methylprednisolone with radiologic improvement of the lesions.\n\nConclusions\nOur case report illustrates that early detection of asymptomatic progressive multifocal leukoencephalopathy and its subsequent treatment resulted in a benign clinical course. In consideration of the additional small number of cases of asymptomatic progressive multifocal leukoencephalopathy that have been reported, we conclude that routine magnetic resonance imaging surveillance is important for patients with multiple sclerosis who are at high risk for developing natalizumab-associated progressive multifocal leukoencephalopathy.\n\nKeywords\nMultiple sclerosisNatalizumabProgressive multifocal leukoencephalopathyMagnetic resonance imagingissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nProgressive multifocal leukoencephalopathy (PML) is the leading adverse effect from using natalizumab in the treatment of multiple sclerosis (MS). PML is a progressive multifocal disease involving the white matter and typically presents with subacute onset of symptoms including altered mental status, visual and motor deficits, and ataxia [1]. Natalizumab-associated PML carries an average mortality of 23% and survivors often develop debilitating neurologic deficits from the disease and its treatment sequelae, such as immune reconstitution inflammatory syndrome (IRIS), in which there is a paradoxical worsening of the infection due to overwhelming inflammatory reaction by the recovering immune system after discontinuing the immunosuppressing agent [2]. PML is caused by John Cunningham virus (JCV), and patients on natalizumab therapy receive serum JCV antibody index testing and surveillance with interval magnetic resonance imagings (MRIs) to assess PML risk and detect early stages of the disease. PML is seen on MRI as multifocal, asymmetric periventricular and subcortical lesions with minimal mass effect or enhancement [3]. Despite measures of clinical vigilance, PML often presents with new neurologic deficits prior to its diagnosis.\n\nWe report the case of a patient diagnosed as having PML based on characteristic MRI lesions from a routine surveillance scan who was clinically asymptomatic at the time of diagnosis and continued to have minimal disability throughout the course of the disease.\n\nCase presentation\nA 26-year-old right-handed white woman with no significant medical history was diagnosed as having MS in 2013 at age 22 and experienced ongoing radiologic activity on both glatiramer acetate and dimethyl fumarate. She transitioned to natalizumab in July 2014 to stabilize disease activity, and her JCV antibody index was positive at 3.58 prior to starting natalizumab. She became clinically and radiologically stable with the initiation of natalizumab until November 2016 when a surveillance MRI of her brain showed asymmetric confluent non-enhancing hyperintensities in the bilateral subcortical precentral gyri consistent with PML (Fig. 1a, b). Cerebral spinal fluid (CSF) showed quantitative polymerase chain reaction (PCR) for JCV of 15 copies/ml, and other CSF studies were within normal limits. A diagnosis of PML was made based on the compatible neuroimaging findings along with the presence of JCV DNA in the CSF. Natalizumab was discontinued after 27 total treatments. Our patient was asymptomatic at the time of PML diagnosis, and she was highly functioning with an Expanded Disability Status Scale (EDSS) of 0. A decision was made to defer plasmapheresis at the time of diagnosis given her high functional status, subtle radiological change, and low viral titer. She was treated with orally administered mefloquine loading dose followed by 250 mg weekly and mirtazapine 15 mg daily.Fig. 1 (a-h) Magnetic resonance imaging T2 fluid-attenuated inversion recovery and post-contrast T1 images of the patient at time of progressive multifocal leukoencephalopathy diagnosis showing bilateral asymmetric confluent non-enhancing hyperintensities in the subcortical precentral gyri (a, b), at 3 months showing a few small enhancing lesions in the left frontal lobe suggestive of immune reconstitution inflammatory syndrome (c, d), at 5 months showing interval development of T2 signal abnormality with mild enhancement (e, f), and at 1 year showing further decrease in T2 hyperintensities and resolution of enhancement (g, h)\n\n\n\nRepeat MRI at 2 months following diagnosis showed no changes in her brain lesions. She remained asymptomatic until 3 months after diagnosis when she noticed mild dysmetria of her left hand that progressed to a tremor. The following month a repeat brain MRI revealed a few small enhancing lesions in her left frontal lobe suggestive of IRIS (Fig. 1c, d). The hyperintensities in the bilateral precentral gyri remained stable. Imaging of her cervical spine revealed a new non-enhancing cord lesion. She was then treated for 5 days with intravenously administered immunoglobulin and restarted on glatiramer acetate for MS treatment. A repeat CSF examination in February 2017 showed JCV PCR of 31 copies/ml.\n\nFive months following her diagnosis, a repeat brain MRI showed interval development of T2 signal abnormality with mild enhancement in multiple areas including the brainstem, cerebellum, and bilateral cerebral hemispheres (Fig. 1e, f). A repeat lumbar puncture was performed. JCV PCR in the CSF was undetectable. Mefloquine and mirtazapine were discontinued. Given the MRI findings, she was treated for ongoing inflammation associated with IRIS versus a possible exacerbation of her underlying MS with high-dose intravenously administered methylprednisolone (IVMP) 1500 mg daily for 3 days. She was then transitioned from glatiramer acetate to ocrelizumab for treatment of MS. Six months following her diagnosis she reported changes in left hand dexterity and right upper extremity phasic spasms. A repeat lumbar puncture was performed and JCV PCR remained undetectable. She continued MRI surveillance followed by treatment with high-dose IVMP for a total of six courses until there was significant resolution of enhancement on her brain MRI (Fig. 1g, h). Following treatment, she has residual left hand dysmetria and tremor as well as right upper extremity phasic spasms. At 1-year follow-up, her EDSS is 2.0.\n\nDiscussion\nThe patient described in this case report underwent an asymptomatic course of PML treated with mefloquine and mirtazapine. Due to the early discovery of PML in our patient and her intact neurologic examination at the time of diagnosis, we chose not to treat with plasma exchange (PLEX) in order to decrease the speed of immune reconstitution, which has been associated with stronger inflammation in patients with HIV-PML [4]. Further studies showed PLEX conferred no additional benefit of reduced mortality or improved outcome in patients who received PLEX (n = 184) versus those who did not (n = 35) for treatment of natalizumab-associated PML [5]. The neurologic deficits sustained toward the end of this patient’s treatment were thought to be from IRIS rather than the progression of PML lesions. While there is no definitive method of distinguishing PML lesions from those caused by IRIS [6], the presence of gadolinium enhancement on brain MRI along with undetectable JCV favored the diagnosis of IRIS rather than development of new PML lesions.\n\nAlthough PML usually presents with clinical symptoms at the time of diagnosis, around 8% of patients with natalizumab-associated PML were asymptomatic at diagnosis, and PML lesions have been reported to present up to 6 months prior to onset of clinical symptoms [7, 8]. Almost all patients diagnosed as having PML develop neurologic deficits throughout the course of the disease with varying levels of severity. A retrospective case series of 336 patients with natalizumab-associated PML identified factors corresponding to improved survival and favorable outcomes including younger age and lower JCV count at diagnosis, low baseline disability at diagnosis, and localized MRI lesions [9]. Only a few cases have documented an asymptomatic disease course of PML (Table 1). While data from these reports are insufficient to conclude patterns leading to asymptomatic PML course, they illustrate the importance of MRI surveillance in detecting early radiologic evidence of PML prior to the development of clinical symptoms. The frequency of MRI monitoring has been debated and arguments against more frequent use cited the increased cost and limited imaging resources. However, reports have suggested 3–4 months as the optimal surveillance interval for patients at high risk of developing PML [10].Table 1 Case reports of natalizumab-associated progressive multifocal leukoencephalopathy with asymptomatic disease course\n\nAuthors and Reference number\tAge (years)/sex\tEDSS at diagnosis\tMRI findings\tDevelopment of IRIS\tPML treatment\tCSF JCV (copies/ml)\tRisk factors [11]\t\nThis case report\t26/F\t0\tBilateral asymmetric confluent non-enhancing hyperintensities in the bilateral subcortical precentral gyri\tYes\tMefloquine and mirtazapine\t15\t27 natalizumab infusions, JCV-positive, JCV index 3.58\t\nBlinkenberg et al. [12]\t50/F\t3.5\tRight cerebellar peduncle hyperintense lesions\tYes\tNone, PML undiagnosed until presentation of PML-IRIS following natalizumab cessation\t552\t47 natalizumab infusions, JCV-positive\t\nFabis-Pedrini et al. [13]\t24/F\t6\tMildly enhancing small patchy lesions in left brainstem, cerebral peduncle, pontine tegmentum, and left brachium points\tYes\tPLEX, mefloquine, mirtazapine, prednisone\t63,910\tTreatment with natalizumab for 54 months, JCV-positive\t\nMc Govern and Hennessay [14]\t61/F\t0\tLeft posterior parietal non-enhancing hyperintensity\tNo\tPLEX, mirtazapine\t12\tTreatment with natalizumab for 3 years\t\nCSF cerebrospinal fluid, EDSS Expanded Disability Status Scale, F female, IRIS immune reconstitution inflammatory syndrome, JCV John Cunningham virus, MRI magnetic resonance imaging, PLEX plasma exchange, PML progressive multifocal leukoencephalopathy\n\n\n\nConclusions\nWhen diagnosed early and treated, PML can present with a mild or even asymptomatic disease course. Clinical vigilance and routine MRI surveillance is important for patients with MS who are at high risk for developing natalizumab-associated PML.\n\nAcknowledgements\nWe wish to thank the patient for consenting to the publication of this case report.\n\nAuthors’ contributions\nCW and YZ wrote the case presentation section of the manuscript. YZ also wrote all other sections of the manuscript. AF revised the first draft of the manuscript. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThis case report was approved by the internal research ethics committee of University of Texas Southwestern Medical Center in accordance with the code of ethics of the Declaration of Helsinki.\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nYinan Zhang has no conflict of interests to declare. Crystal Wright is a speaker for Genzyme and Novartis and is involved in a clinical trial with MED Day. Angela Flores is a speaker and consultant for Biogen and Genentech. The authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. Tan CS Koralnik IJ Progressive multifocal leukoencephalopathy and other disorders caused by JC virus: clinical features and pathogenesis Lancet Neurol 2010 9 425 437 10.1016/S1474-4422(10)70040-5 20298966 \n2. Clerico M Artusi CA Di Liberto A Rolla S Bardina V Barbero P De Mercanti SF Durelli L Long-term safety evaluation of natalizumab for the treatment of multiple sclerosis Expert Opin Drug Saf 2017 16 963 972 10.1080/14740338.2017.1346082 28641055 \n3. Garrels K Kucharczyk W Wortzman G Shandling M Progressive multifocal leukoencephalopathy: clinical and MR response to treatment AJNR Am J Neuroradiol 1996 17 597 600 8881262 \n4. Murdoch DM Suchard MS Venter WD Mhlangu P Ottinger JS Feldman C Van Rie A Glencross DK Stevens WS Weinhold KJ Polychromatic immunophenotypic characterization of T cell profiles among HIV-infected patients experiencing immune reconstitution inflammatory syndrome (IRIS) AIDS Res Ther 2009 6 16 10.1186/1742-6405-6-16 19607684 \n5. Landi D De Rossi N Zagaglia S Scarpazza C Prosperini L Albanese M Buttari F Mori F Marfia GA Sormani MP Capra R Centonze D Italian PML study group No evidence of beneficial effects of plasmapheresis in natalizumab-associated PML Neurology 2017 88 1144 1152 10.1212/WNL.0000000000003740 28228569 \n6. Honce JM Nagae L Nyberg E Neuroimaging of Natalizumab complications in multiple sclerosis: PML and other associated entities Mult Scler Int 2015 2015 809252 26483978 \n7. Dong-Si T Richman S Wattjes MP Wenten M Gheuens S Philip J Datta S McIninch J Bozic C Bloomgren G Richert N Outcome and survival of asymptomatic PML in natalizumab-treated MS patients Ann Clin Transl Neurol 2014 1 755 764 10.1002/acn3.114 25493267 \n8. Blair NF Brew BJ Halpern JP Natalizumab-associated PML identified in the presymptomatic phase using MRI surveillance Neurology 2012 78 507 508 10.1212/WNL.0b013e318246d6d8 22302545 \n9. Dong-Si T Gheuens S Gangadharan A Wenten M Philip J McIninch J Datta S Richert N Bozic C Bloomgren G Richman S Weber T Clifford DB Predictors of survival and functional outcomes in natalizumab-associated progressive multifocal leukoencephalopathy J Neuro-Oncol 2015 21 637 644 \n10. McGuigan C Craner M Guadagno J Kapoor R Mazibrada G Molyneux P Nicholas R Palace J Pearson OR Rog D Young CA Stratification and monitoring of natalizumab-associated progressive multifocal leukoencephalopathy risk: recommendations from an expert group J Neurol Neurosurg Psychiatry 2016 87 117 125 10.1136/jnnp-2016-315106.113 26492930 \n11. Bloomgren G Richman S Hotermans C Subramanyam M Goelz S Natarajan A Lee S Plavina T Scanlon JV Sandrock A Bozic C Risk of natalizumab-associated progressive multifocal leukoencephalopathy N Engl J Med 2012 366 1870 1880 10.1056/NEJMoa1107829 22591293 \n12. Blinkenberg M Sellebjerg F Leffers AM Madsen CG Sorensen PS Clinically silent PML and prolonged immune reconstitution inflammatory syndrome in a patient with multiple sclerosis treated with natalizumab Mult Scler 2013 19 1226 1229 10.1177/1352458513481010 23508652 \n13. Fabis-Pedrini MJ Xu W Burton J Carroll WM Kermode AG Asymptomatic progressive multifocal leukoencephalopathy during natalizumab therapy with treatment J Clin Neurosci 2016 25 145 147 10.1016/j.jocn.2015.08.027 26541323 \n14. Mc Govern EM Hennessy MJ Asymptomatic progressive multifocal leukoencephalopathy associated with natalizumab J Neurol 2013 260 665 667 10.1007/s00415-012-6759-0 23212753\n\n",
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"abstract": "Ten percent to 20% of children with autoimmune hepatitis (AIH) require second-line therapy to achieve remission. Although current guidelines exist on first-line management, evidence for second-line therapy in treatment-refractory patients is lacking. Our aim was to perform a systematic review and meta-analysis of the efficacy and safety of second-line treatments used in this population.\n\n\n\nElectronic and manual searches were used to identify potential studies for inclusion. Studies were selected based on reported response rates to second-line therapies in children who failed response to prednisone and azathioprine. Data extraction and risk of bias assessment were performed independently by 2 reviewers. Meta-analysis using weighted estimate of response rates at 6 months was performed for each treatment option. Heterogeneity was assessed.\n\n\n\nFifteen studies of 76 pediatric patients with AIH were included in the review. Overall response rates at 6 months were estimated as 36% for mycophenolate mofetil (MMF) (N = 34, 95% confidence interval [CI] (16-57)), and 50% for tacrolimus (N = 4, 95% CI (0-100%)) and 83% for cyclosporine (N = 15, 95% CI (66%-100%)). Adverse effects were most frequent with cyclosporine (64% experiencing at least 1 adverse effect) followed by tacrolimus (54%) and MMF (48%). Pooled estimates of adverse events were 78% for cyclosporine (95% CI (54%-100%)), 42% for tacrolimus (95% CI (0%-85%)) and 45% for MMF (95% CI (25%-68%)). Sensitivity analyses were not performed due to small sample size.\n\n\n\nCyclosporine had the highest response rate at 6 months in children with standard-treatment-refractory AIH; however, it also had the highest rate of adverse events. MMF was the second most efficacious option with a low adverse effect rate.",
"affiliations": "*The Hospital for Sick Children †University of Toronto, Toronto, Ontario, Canada ‡Yale University School of Medicine, New Haven, CT §Mount Sinai Hospital, Toronto ||London Health Sciences Centre, Western University, London, Ontario, Canada.",
"authors": "Zizzo|Andréanne N|AN|;Valentino|Pamela L|PL|;Shah|Prakesh S|PS|;Kamath|Binita M|BM|",
"chemical_list": "D007166:Immunosuppressive Agents; D016572:Cyclosporine; D009173:Mycophenolic Acid; D001379:Azathioprine; D011241:Prednisone; D016559:Tacrolimus",
"country": "United States",
"delete": false,
"doi": "10.1097/MPG.0000000000001530",
"fulltext": null,
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"issn_linking": "0277-2116",
"issue": "65(1)",
"journal": "Journal of pediatric gastroenterology and nutrition",
"keywords": null,
"medline_ta": "J Pediatr Gastroenterol Nutr",
"mesh_terms": "D001379:Azathioprine; D002648:Child; D016572:Cyclosporine; D019693:Hepatitis, Autoimmune; D006801:Humans; D007166:Immunosuppressive Agents; D060828:Induction Chemotherapy; D015233:Models, Statistical; D009173:Mycophenolic Acid; D010372:Pediatrics; D011241:Prednisone; D016559:Tacrolimus; D016896:Treatment Outcome",
"nlm_unique_id": "8211545",
"other_id": null,
"pages": "6-15",
"pmc": null,
"pmid": "28644343",
"pubdate": "2017-07",
"publication_types": "D016428:Journal Article; D017418:Meta-Analysis; D016454:Review",
"references": null,
"title": "Second-line Agents in Pediatric Patients With Autoimmune Hepatitis: A Systematic Review and Meta-analysis.",
"title_normalized": "second line agents in pediatric patients with autoimmune hepatitis a systematic review and meta analysis"
} | [
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{
"abstract": "BACKGROUND Risk factors for venous thromboembolism can include a combination of genetic, anatomic, and physiologic factors, some of which are modifiable. Patients presenting to the hospital with venous thromboembolism may have multiple risk factors that require testing beyond the initial admission labs and hypercoagulability screening panel. CASE REPORT We describe a right-handed patient who lifts weights for exercise, who presented with pulmonary infarcts and clot in the right superior vena cava/subclavian vein. These were due to a combination of 1) an acquired hypercoagulability from minimal change disease and 2) dynamic anatomic narrowing of the subclavian vein, which is known as Paget-Schroetter syndrome. Despite normal serum levels of antithrombin, protein C and S, his serum albumin was low, which prompted workup for proteinuria. Testing revealed nephrotic range proteinuria as well as dynamic occlusion of the right subclavian vein on magnetic resonance venography only when the patient lifted and externally rotated his arms. CONCLUSIONS This case report highlights the need for a thorough history and physical examination, as well as additional testing in some patients beyond the initial admission laboratory tests and screening panel for hypercoagulability. Tests could include diagnostic imaging testing with provoking maneuvers, which can help elucidate dynamic physiology. Such testing, when appropriate, can help to inform the treatment plan and prevent recurrent thromboses.",
"affiliations": "Division of Pulmonary/Critical Care, Massachusetts General Hospital, Boston, MA, USA.;Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.;Department of Radiology, Massachusetts General Hospital, Boston, MA, USA.;Division of Pulmonary/Critical Care, Massachusetts General Hospital, Boston, MA, USA.",
"authors": "Myers|Laura C|LC|;Li|Matthew D|MD|;Kalva|Sanjeeva|S|;Lai|Peggy S|PS|",
"chemical_list": "D000925:Anticoagulants",
"country": "United States",
"delete": false,
"doi": "10.12659/AJCR.919141",
"fulltext": "\n==== Front\nAm J Case RepAm J Case RepamjcaserepThe American Journal of Case Reports1941-5923International Scientific Literature, Inc. 3172787010.12659/AJCR.919141919141ArticlesPulmonary Infarction due to Paget-Schroetter Syndrome and Nephrotic Syndrome Myers Laura C. ABDEF1Li Matthew D. ABDE2Kalva Sanjeeva ABDE2Lai Peggy S. ABDE1\n1 Division of Pulmonary/Critical Care, Massachusetts General Hospital, Boston, MA, U.S.A.\n2 Department of Radiology, Massachusetts General Hospital, Boston, MA, 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: Laura C. Myers, e-mail: lcmyers@partners.org2019 15 11 2019 20 1679 1683 02 8 2019 03 9 2019 © Am J Case Rep, 20192019This work is licensed under Creative Common Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)Patient: Male, 23\n\nFinal Diagnosis: Minimal change disease\n\nSymptoms: Right arm and neck swelling\n\nMedication: —\n\nClinical Procedure: Catheter-directed thrombolysis\n\nSpecialty: Cardiology\n\nObjective:\nRare co-existance of disease or pathology\n\nBackground:\nRisk factors for venous thromboembolism can include a combination of genetic, anatomic, and physiologic factors, some of which are modifiable. Patients presenting to the hospital with venous thromboembolism may have multiple risk factors that require testing beyond the initial admission labs and hypercoagulability screening panel.\n\nCase Report:\nWe describe a right-handed patient who lifts weights for exercise, who presented with pulmonary infarcts and clot in the right superior vena cava/subclavian vein. These were due to a combination of 1) an acquired hypercoagulability from minimal change disease and 2) dynamic anatomic narrowing of the subclavian vein, which is known as Paget-Schroetter syndrome. Despite normal serum levels of antithrombin, protein C and S, his serum albumin was low, which prompted workup for proteinuria. Testing revealed nephrotic range proteinuria as well as dynamic occlusion of the right subclavian vein on magnetic resonance venography only when the patient lifted and externally rotated his arms.\n\nConclusions:\nThis case report highlights the need for a thorough history and physical examination, as well as additional testing in some patients beyond the initial admission laboratory tests and screening panel for hypercoagulability. Tests could include diagnostic imaging testing with provoking maneuvers, which can help elucidate dynamic physiology. Such testing, when appropriate, can help to inform the treatment plan and prevent recurrent thromboses.\n\nMeSH Keywords:\nNephrotic SyndromePulmonary EmbolismThrombophiliaUpper Extremity Deep Vein Thrombosis\n==== Body\nBackground\nThe Centers for Disease Control and Prevention estimate that there are over 500 000 hospitalizations in the United States for venous thromboembolism per year [1]. The risk factors for venous thromboembolism are well studied [2]. They include factors that are genetic, physiologic, and anatomic [3]. Given how common an admission is for venous thromboembolism, many hospitals have implemented a standardized panel to test the blood for suspected hypercoagulability. These panels can be abnormal in up to 50% of those tested [4]. However, not all risk factors can be identified through laboratory testing. A thorough history and physical examination is needed to determine if additional laboratory and radiographic testing is needed beyond the typical admission labs and hypercoagulability screening panel.\n\nWe present a case of a young, active, right-handed patient with a large obstructing clot in the superior vena cava and right subclavian vein, as well as pulmonary infarcts. Workup revealed that he had a combination of 2 rare predisposing factors for venous thromboembolism, including nephrotic range proteinuria due to minimal change disease and dynamic anatomic occlusion of the subclavian vein due to Paget-Schroetter syndrome [5]. This syndrome develops most commonly in patients who do repetitive overhead movements for exercise or their job. In this particular case, multiple tests beyond typical admission laboratory tests and the screening panel for hypercoagulability were required to make the diagnoses, including a urine protein level and magnetic resonance venography with dynamic provoking maneuvers.\n\nThis case highlights the need for practicing physicians to 1) formulate a broad differential diagnosis for venous thromboembolism after taking a thorough history and 2) consider obtaining additional tests, including tests with dynamic provoking maneuvers, in order to elicit dynamic pathology that would otherwise remain elusive.\n\nCase Report\nThe patient was a 23-year-old male who presented with several days of right arm and neck swelling, scapular discomfort that was worse with inspiration and new onset exertional dyspnea. He denied recent immobilization, air travel, smoking or a personal or family history of vascular thrombosis. He lifted weights regularly for exercise but did not do repeated overhead lifting for his job. He is right-handed. Physical examination was notable for generalized swelling of the right arm and neck but the superficial veins in the area were not noted to be engorged. Computed tomographic angiography showed a filling defect in the superior vena cava with right arm/chest wall edema, suggestive of upstream thrombosis (Figure 1A) as well as multiple pulmonary emboli with infarcts (Figure 1B). Upper extremity ultrasound confirmed occlusive right axillosubclavian thrombosis. Ultrasound did not reveal thrombosis in the veins of the lower extremities. Transthoracic echocardiogram showed no right heart strain. He was treated with a standard dose intravenous heparin drip.\n\nThe hypercoagulability panel revealed normal levels of anti-thrombin, protein C, protein S as well as cardiolipin and beta2-glycoprotein I antibodies. He did not carry the Factor V Leiden or prothrombin G20210A mutations. Testing for lupus anticoagulant was negative. Other laboratory workup was notable for normal renal function. However, he was found to have a low serum albumin level of 1.7 g/dL (reference 3.3–5 g/dL). Given the low serum albumin, urine protein level was checked, and he was found to have nephrotic range proteinuria (urine total protein 1121 mg/dL, reference 0–13.5 mg/dL).\n\nThe patient underwent catheter-directed thrombolysis, thrombectomy, and angioplasty of the right subclavian and axillary veins. Given the location of the clot, venous thoracic outlet syndrome was suspected. Magnetic resonance venography showed stenosis of the right subclavian vein between the clavicle anteriorly and the anterior scalene posteriorly only with abduction and external rotation of the patient’s arms (Figure 1C, 1D). Stenosis was not seen in the left subclavian vein with the same arm movement. This finding was consistent with unilateral thoracic outlet syndrome, which is also known as Paget-Schroetter syndrome in the presence of upper extremity clot [5].\n\nHe was transitioned from the intravenous heparin drip to rivaroxaban (15 mg twice daily for the first 3 weeks then 10 mg daily). Anticoagulation was planned for at least 6 months. At the time of discharge, the most likely renal diagnosis was primary minimal change disease given his age. He was started on glucocorticoid therapy (1 mg/kg daily) and lisinopril (40 mg daily). Renal biopsy was deferred given his need for anticoagulation. Three months later, he underwent right supraclavicular first rib resection, brachial plexus neuroplasty, subclavian venolysis, and scalenectomy. He recovered well from the surgery. As an outpatient, his renal disease was found to be resistant to glucocorticoids so was tapered to prednisone 5 mg daily and started on monthly injections of rituximab 1000 mg.\n\nDiscussion\nThis is an unusual case of a young adult who developed life-threatening venous thromboembolism due to a combination of rare anatomic and physiologic risk factors. This patient had 2 conditions, including 1) acquired hypercoagulability from nephrotic syndrome and 2) dynamic anatomic occlusion of the right subclavian vein, which is called Paget-Schroetter syndrome in the presence of upper extremity clot. This case highlights an important lesson for practicing physicians. In patients with venous thromboembolism, additional testing may be needed beyond the initial admission labs and screening hypercoagulability panel. Despite a normal hypercoagulability panel, this patient’s low serum albumin level prompted providers to check for proteinuria. Furthermore, the location of the right subclavian vein thrombosis prompted providers to check for dynamic occlusion of the subclavian vein via magnetic resonance venography.\n\nApproximately 7% of patients with nephrotic syndrome have a venous thromboembolism event, although the risk of venous thromboembolism varies depending on the underlying pathology [6,7]. The risk is highest at the time of diagnosis of nephrotic syndrome and increases as the serum albumin decreases. If the serum albumin is <2.5 g/dL [8], patients with nephrotic syndrome have ∼4% absolute risk of a venous thromboembolic event. This patient’s serum albumin was in fact below this threshold. However, patients with nephrotic syndrome are particularly prone to deep vein thromboses in the legs and renal veins [9,10], not upper extremities.\n\nStudies of the mechanism underlying the hypercoagulable state in patients with nephrotic syndrome point toward changes in the levels of antithrombin, protein C, protein S secondary to loss in the urine. Interestingly, these levels can be normal, as they were in this patient, despite being functionally hypercoagulable [11].\n\nQuantifying the urine protein is not part of the standard laboratory workup for an unprovoked venous thromboembolism [11,12]. In this particular case, it was the low serum albumin that prompted providers to check for proteinuria. Additionally, not all patients with nephrotic syndrome have abnormal serum creatinine at the time of diagnosis, such as was true in this case. The other signs or symptoms that should prompt an evaluation of the urine include new or unexplained hypertension, hypercholesterolemia, and edema. Performing a thorough review of systems and physical examination would hopefully prevent clinicians from missing these signs.\n\nRenal biopsy is typically recommended in adults with new onset nephrotic syndrome. Unfortunately, biopsy was not possible for this patient, given his risk of recurrent clot if taken off anticoagulation. In terms of his response to therapy, we are hopeful that he will have a favorable response to rituximab despite not being steroid responsive. Adults have ∼80% chance of remission at 7 months with immunosuppressive therapy [13].\n\nThe name Paget-Schroetter syndrome refers to the specific clinical situation in which a patient with venous thoracic outlet syndrome develops an upper extremity clot. The pathogenesis of venous thoracic outlet syndrome is thought to relate to repetitive overhead movements causing trauma and inflammation to the thoracic bundle [5]. Because not everyone who routinely does overhead lifting develops this syndrome, people with certain anatomy of the shoulder are thought to be predisposed to this syndrome. While this patient did do some overhead weightlifting for exercise, he did not do daily overhead lifting for his job, for instance. He was right-handed, however, so likely favored his right arm to perform single arm tasks.\n\nTimely surgical decompression is recommended for patients with Paget-Schroetter syndrome [14]. However, the type of surgical intervention often depends on the exact anatomic abnormality. The procedure can involve first rib resection, cervical rib resection, division of anomalous bands or musculotendinous insertion, and scalenectomy. This patient underwent successful surgical decompression within 3 months of diagnosis.\n\nThis case highlights the important lesson that 3-dimensional, dynamic vascular imaging can be helpful to diagnose a vascular occlusion that occurs only with certain arm positioning. This patient’s right subclavian vein stenosis was not appreciated on computed tomography. The axial image from magnetic resonance venography was required for the diagnosis, specifically when the patient lifted and externally rotated his arms. Although Paget-Schroetter syndrome is rare (1–2/100 000 people per year) [5], this key concept about provoking maneuvers could be applied in other contexts as a universal lesson in clinical diagnosis.\n\nAfter careful review of the literature, we have not found an association between proteinuria and Paget-Schroetter syndrome. Thus, we believe that this patient had 2 unrelated, uncommon conditions. In terms of timing, the onset of minimal change disease likely prompted the clot to form at the location that was anatomically vulnerable to venous stasis due to repetitive movement of the right arm during exercise and daily living. In this particular case, advanced laboratory and imaging tests were necessary to fully appreciate his risk factors for venous thromboembolism, treat him appropriately and arrange for proper follow-up.\n\nConclusions\nThis case highlights 2 important lessons for practicing physicians. First, clinicians should formulate a broad differential diagnosis for venous thromboembolism and consider combinations of rare genetic, anatomic, and physiologic risk factors. Second, additional diagnostic testing beyond the initial admission labs and screening panel for hypercoagulability should be considered in patients with venous thromboembolism when there is enough clinical suspicion. This may include laboratory tests to check for proteinuria as well as imaging tests with dynamic provoking maneuvers.\n\nDepartment and Institution where work was done\n\nMassachusetts General Hospital in Boston, MA, USA as a collaboration between the Division of Pulmonary/Critical Care and the Department of Radiology.\n\nConflicts of interest\n\nNone.\n\nFigure 1. (A) Venous thromboses in the superior vena cava and right brachiocephalic/subclavian veins with associated arm/chest edema. Coronal reformatted computed tomographic angiography of the chest shows filling defect in the superior vena cava (arrowhead), right brachiocephalic and subclavian veins with associated right arm/chest edema, suggestive of upstream thrombosis. (B) Pulmonary infarcts in a patient with Paget-Schroetter syndrome and nephrotic syndrome. Axial computed tomography of the chest shows multiple pulmonary infarcts in the peripheral right lower lobe. (C, D) Dynamic compression of right subclavian vein with patient’s arms raised. Following endovascular treatment of venous thrombosis, magnetic resonance venography of the chest (T1-weighted fat saturated post-contrast images) with the arms down (C) and arms up (D) shows dynamic severe compression of the right subclavian vein between the clavicle anteriorly and the anterior scalene muscle posteriorly at its insertion near the first rib (arrow).\n==== Refs\nReferences:\n1. Centers for Disease Control and Prevention (CDC) Venous thromboembolism in adult hospitalizations – United States, 2007–2009 MMWR Morb Mortal Wkly Rep 2012 61 401 4 22672974 \n2. Lijfering WM Rosendaal FR Cannegieter SC Risk factors for venous thrombosis – current understanding from an epidemiological point of view Br J Haematol 2010 149 824 33 20456358 \n3. Moheimani F Jackson DE Venous thromboembolism: Classification, risk factors, diagnosis, and management ISRN Hematol 2011 2011 124610 22084692 \n4. Deitcher SR Gomes MP Hypercoagulable state testing and malignancy screening following venous thromboembolic events Vasc Med 2003 8 33 46 12866610 \n5. Illig KA Doyle AJ A comprehensive review of Paget-Schroetter syndrome J Vasc Surg 2010 51 1538 47 20304578 \n6. Barbour SJ Greenwald A Djurdjev O Disease-specific risk of venous thromboembolic events is increased in idiopathic glomerulonephritis Kidney Int 2012 81 190 95 21918501 \n7. Lionaki S Derebail VK Hogan SL Venous thromboembolism in patients with membranous nephropathy Clin J Am Soc Nephrol 2012 7 43 51 22076873 \n8. Gyamlani G Molnar MZ Lu JL Association of serum albumin level and venous thromboembolic events in a large cohort of patients with nephrotic syndrome Nephrol Dial Transplant 2017 32 157 64 28391310 \n9. Mahmoodi BK ten Kate MK Waanders F High absolute risks and predictors of venous and arterial thromboembolic events in patients with nephrotic syndrome: Results from a large retrospective cohort study Circulation 2008 117 224 30 18158362 \n10. Chugh KS Malik N Uberoi HS Renal vein thrombosis in nephrotic syndrome – a prospective study and review Postgrad Med J 1981 57 566 70 7329894 \n11. Khor B Van Cott EM Laboratory evaluation of hypercoagulability Clin Lab Med 2009 29 339 66 19665682 \n12. Bauer KA Rosendaal FR Heit JA Hypercoagulability: Too many tests, too much conflicting data Hematology Am Soc Hematol Educ Program 2002 353 68 12446432 \n13. Nakayama M Katafuchi R Yanase T Steroid responsiveness and frequency of relapse in adult-onset minimal change nephrotic syndrome Am J Kidney Dis 2002 39 503 12 11877569 \n14. Urschel HC Jr Patel AN Surgery remains the most effective treatment for Paget-Schroetter syndrome: 50 years’ experience Ann Thorac Surg 2008 86 254 60 18573433\n\n",
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"keywords": null,
"medline_ta": "Am J Case Rep",
"mesh_terms": "D000925:Anticoagulants; D003131:Combined Modality Therapy; D003937:Diagnosis, Differential; D006801:Humans; D008297:Male; D061185:Mechanical Thrombolysis; D009404:Nephrotic Syndrome; D054060:Pulmonary Infarction; D056824:Upper Extremity Deep Vein Thrombosis; D055815:Young Adult",
"nlm_unique_id": "101489566",
"other_id": null,
"pages": "1679-1683",
"pmc": null,
"pmid": "31727870",
"pubdate": "2019-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21918501;11877569;20456358;19665682;12866610;20304578;22672974;12446432;18158362;22084692;18573433;28391310;22076873;7329894",
"title": "Pulmonary Infarction due to Paget-Schroetter Syndrome and Nephrotic Syndrome.",
"title_normalized": "pulmonary infarction due to paget schroetter syndrome and nephrotic syndrome"
} | [
{
"companynumb": "US-009507513-1912USA008712",
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"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "HEPARIN SODIUM"
},
"drugadditional": null,
"drugadministrationroute": "042",
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"drugindication": "PULMONARY INFARCTION",
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"medicinalproduct": "HEPARIN"
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{
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"drugdosagetext": "10 MILLIGRAM, QD",
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"medicinalproduct": "RIVAROXABAN"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
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"drugdosageform": "TABLET",
"drugdosagetext": "40 MILLIGRAM, DAILY",
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"drugindication": "PULMONARY INFARCTION",
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"medicinalproduct": "PRINIVIL"
},
{
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"activesubstance": {
"activesubstancename": "RIVAROXABAN"
},
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"drugadministrationroute": null,
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"drugcharacterization": "2",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "15 MILLIGRAM, BID",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PULMONARY INFARCTION",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": "2",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "15",
"drugstructuredosageunit": "003",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "RIVAROXABAN"
}
],
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"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MYERS LC, LI MD, KALVE S AND LAI PS.. PULMONARY INFARCTION DUE TO PAGET-SCHROETTER SYNDROME AND NEPHROTIC SYNDROME. AMERICAN JOURNAL OF CASE REPORTS. 2019?20:1679-83",
"literaturereference_normalized": "pulmonary infarction due to paget schroetter syndrome and nephrotic syndrome",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200102",
"receivedate": "20200102",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17223062,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200409"
}
] |
{
"abstract": "Fluorquinolone-prophylaxis has proven useful in preventing infections in high risk neutropenic patients. The objective of this study was to describe the clinical, microbiological and therapeutic characteristics, and outcome of patients in the first episode of febrile neutropenia, comparing those who received levofloxacin prophylaxis with those who didn't. It was a prospective observational study that included all the episodes of inpatients with febrile neutropenia (February 1997- November 2014), also including the first episode in a same patient in different hospitalizations. Of 946 episodes here included, 821 presented high risk febrile neutropenia. A total of 264 cases (27.9%) received levofloxacin prophylaxis. This group consisted of a higher proportion of high risk febrile neutropenia (99.2% vs. 82.3%, p = 0.0001) and patients that had received an hematopoietic stem cell transplant (67.8% vs. 29.3%, p = 0.0001) compared to those who didn't receive prophylaxis. Those who received levofloxacin prophylaxis presented a similar frequency of clinically diagnosed but a lower proportion of microbiologically documented infections (28.8% vs. 37.5%, p = 0.012) than those who didn't receive prophylaxis. The episodes of bacteremia that occurred in the first group were more frequently caused by multidrug resistant bacteria (MDRB) (34.5% vs. 17.3%, p = 0.007) and by extended spectrum beta lactamase producing Enterobacteriaceae (19% vs. 3.8%, p = 0.0001). The group that received prophylaxis had a lower proportion of adequate empirical antibiotic treatment (69.7% vs. 83.7%, p = 0.009), with similar outcomes in both groups. We suggest that levofloxacin prophylaxis should be stopped whenever there is a rise in the frequency of MDRB infections in this population.",
"affiliations": "Sección Infectología, Departamento de Medicina Interna, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno (CEMIC), Buenos Aires, Argentina. E-mail: albertocarena@yahoo.com.ar.;Sección Infectología, Departamento de Medicina Interna, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno (CEMIC), Buenos Aires, Argentina.;Sección Infectología, Departamento de Medicina Interna, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno (CEMIC), Buenos Aires, Argentina.;Sección Infectología, Departamento de Medicina Interna, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno (CEMIC), Buenos Aires, Argentina.;Sección Bacteriología, Micología y Parasitología, Departamento de Análisis Clínicos, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno (CEMIC), Buenos Aires, Argentina.;Sección Infectología, Departamento de Medicina Interna, Centro de Educación Médica e Investigaciones Clínicas Norberto Quirno (CEMIC), Buenos Aires, Argentina.",
"authors": "Carena|Alberto A|AA|;Jorge|Laura|L|;Bonvehí|Pablo|P|;Temporiti|Elena|E|;Zárate|Mariela S|MS|;Herrera|Fabián|F|",
"chemical_list": "D000900:Anti-Bacterial Agents; D024841:Fluoroquinolones; D064704:Levofloxacin",
"country": "Argentina",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-7680",
"issue": "76(5)",
"journal": "Medicina",
"keywords": "leukemia; levofloxacin prophylaxis; neutropenia",
"medline_ta": "Medicina (B Aires)",
"mesh_terms": "D000328:Adult; D000900:Anti-Bacterial Agents; D019072:Antibiotic Prophylaxis; D016470:Bacteremia; D024881:Drug Resistance, Bacterial; D004755:Enterobacteriaceae; D064147:Febrile Neutropenia; D024841:Fluoroquinolones; D006801:Humans; D064704:Levofloxacin; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D015203:Reproducibility of Results; D012307:Risk Factors; D016896:Treatment Outcome",
"nlm_unique_id": "0204271",
"other_id": null,
"pages": "295-303",
"pmc": null,
"pmid": "27723617",
"pubdate": "2016",
"publication_types": "D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "Levofloxacin prophylaxis in neutropenic patients.",
"title_normalized": "levofloxacin prophylaxis in neutropenic patients"
} | [
{
"companynumb": "AR-JNJFOC-20161024460",
"fulfillexpeditecriteria": "1",
"occurcountry": "AR",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LEVOFLOXACIN"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "020634",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FEBRILE NEUTROPENIA",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "2",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "500",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LEVOFLOXACIN."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Infection",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Multiple organ dysfunction syndrome",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Shock",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Bacteraemia",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "CARENA AA, JORGE L, BONVEHI P, TENIPORITI E, ZARATE MS, HERRERA F. LEVOFLOXACIN PROPHYLAXIS IN NEUTROPENIC PATIENTS. MEDICINA (BUENOS AIRES) 2016;76(5):295-302.",
"literaturereference_normalized": "levofloxacin prophylaxis in neutropenic patients",
"qualification": "1",
"reportercountry": "AR"
},
"primarysourcecountry": "AR",
"receiptdate": "20161123",
"receivedate": "20161028",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12894047,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170207"
}
] |
{
"abstract": "BACKGROUND\nMembranoproliferative glomerulonephritis (MPGN) is an uncommon form of glomerulonephritis and it can be particularly difficult to predict outcomes and manage women with this disorder during pregnancy.\n\n\nMETHODS\nThe management of 3 successful pregnancies in women with MPGN from 1 center and previously described cases from the world literature are reviewed. This includes a number of large studies of pregnancy in women with underlying glomerular disease as well as small case series and individual reports. Courses of these pregnancies, maternal and fetal outcomes, and management, when described, were included in this review.\n\n\nRESULTS\nSome successful outcomes used antiplatelet therapy and plasmapheresis, but high-dose intravenous, followed by oral, corticosteroid therapy was used most frequently in patients with successful outcomes.\n\n\nCONCLUSIONS\nThe data provided is meant as a guide for clinicians who provide care for women with MPGN who are considering pregnancy or women who present with this disorder while pregnant.",
"affiliations": "Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana; Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana.;Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana; Department of Pathology, Tulane University School of Medicine, New Orleans, Louisiana.;Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana. Electronic address: kkrane@tulane.edu.",
"authors": "Nair|Devika|D|;Kidd|Laura|L|;Krane|N Kevin|NK|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1016/j.amjms.2017.01.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0002-9629",
"issue": "353(4)",
"journal": "The American journal of the medical sciences",
"keywords": "Membranoproliferative glomerulonephritis; Pregnancy",
"medline_ta": "Am J Med Sci",
"mesh_terms": "D000328:Adult; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative; D006801:Humans; D011247:Pregnancy; D011248:Pregnancy Complications; D055815:Young Adult",
"nlm_unique_id": "0370506",
"other_id": null,
"pages": "320-328",
"pmc": null,
"pmid": "28317619",
"pubdate": "2017-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Membranoproliferative Glomerulonephritis in Pregnancy.",
"title_normalized": "membranoproliferative glomerulonephritis in pregnancy"
} | [
{
"companynumb": "PHHY2017US092633",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": null,
"drugadministrationroute": "064",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "MATERNAL DOSE: 1G DAILY FOR 3 DAYS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FOETAL EXPOSURE DURING PREGNANCY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "METHYLPREDNISOLONE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": null,
"drugadministrationroute": "064",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "MATERNAL DOSE: 2 MG/KG/DAY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FOETAL EXPOSURE DURING PREGNANCY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "AZATHIOPRINE."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LABETALOL\\LABETALOL HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "064",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
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"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FOETAL EXPOSURE DURING PREGNANCY",
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"drugintervaldosageunitnumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LABETALOL"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "HYDRALAZINE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": "064",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FOETAL EXPOSURE DURING PREGNANCY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
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"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "HYDRALAZINE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLDOPA"
},
"drugadditional": null,
"drugadministrationroute": "064",
"drugauthorizationnumb": "018934",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FOETAL EXPOSURE DURING PREGNANCY",
"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": "METHYLDOPA."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drugadministrationroute": "064",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "MATERNAL DOSE: 1 MG/KG/DAY",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "FOETAL EXPOSURE DURING PREGNANCY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": null,
"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "PREDNISONE."
}
],
"patientagegroup": "1",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Nonreassuring foetal heart rate pattern",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Low birth weight baby",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Premature baby",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Apgar score low",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "NAIR D, KIDD L, KRANE NK. MEMBRANOPROLIFERATIVE GLOMERULONEPHRITIS IN PREGNANCY. AMERICAN JOURNAL OF THE MEDICAL SCIENCES. 2017;353 (4):320-8",
"literaturereference_normalized": "membranoproliferative glomerulonephritis in pregnancy",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170705",
"receivedate": "20170705",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13718182,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20171127"
}
] |
{
"abstract": "BACKGROUND\nPerineural spread of malignant melanoma (MM) along cranial nerves is a rare complication of MM of the head and neck.\n\n\nMETHODS\nA 78-year-old man presented with untreatable facial pain and cutaneous hypoesthesia in V2/V3 branches of right trigeminal nerve. Six months earlier patient removed a lentigo maligna melanoma in his right upper lip and a MM in his right gingiva. Brain magnetic resonance imaging showed pathologic thickening of the right maxillary and mandibular nerves and of the intracranial trigeminal nerve. Infraorbital nerve biopsy confirms MM neural metastasis. BRAFV600E mutation was identified only in the lentigo maligna melanoma. Patient was treated with brain proton therapy but 5 months later developed sensorimotor deficit of his right arm because of a cervical metastasis.\n\n\nCONCLUSIONS\nIn patients presenting with atypical facial pain and history of head and neck melanoma a trigeminal spreading should be considered. Magnetic resonance imaging can detect early perineural spread and target biopsy.",
"affiliations": "Neurological Clinic.;Oncology Clinic.;Institute of Surgical Pathology, Ospedale dell'Angelo, Mestre Venice, Italy.",
"authors": "Pompanin|Sara|S|;De Rossi|Costanza|C|;La Marra|Francesco|F|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1097/NRL.0000000000000336",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1074-7931",
"issue": "26(5)",
"journal": "The neurologist",
"keywords": null,
"medline_ta": "Neurologist",
"mesh_terms": "D000368:Aged; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008545:Melanoma; D012878:Skin Neoplasms; D014276:Trigeminal Nerve",
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"title": "Trigeminal Metastasis of Malignant Melanoma: Clinical, Neuroradiological, and Pathological Features. A Case Report.",
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"abstract": "Herein we describe four patients with acquired hemophilia A (AHA) caused by factor VIII (FVIII) inhibitor and histories of dipeptidyl peptidase-4 inhibitor (DPP4-I) treatment for diabetes mellitus (DM). Drug exposure can cause a breakdown of immune tolerance to FVIII associated with CD4 T cells, resulting in the induction of autoantibodies against FVIII. In patient 1 in the present series, FVIII inhibitor disappeared after DPP4-I treatment. The DPP4-I treatment was stopped faster in patient 1 than it was in patient 2, whose FVIII inhibitor titer was higher than patient 1's. Two patients died: patient 3 due to brain infarction after recurrence associated with the development of sigmoid colon rupture, and patient 4 due to multiple organ failure associated with Clostridium difficile colitis. DPP4-I treatment may create an ideal environment for the induction of new antibodies and AHA onset associated with tumor necrosis factor-α reduction. These are the first reported cases of the potential development and/or prolonging of AHA after DDP4-I treatment for DM, and they suggest possible disease associations.",
"affiliations": "Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-Ku, Fukuoka, 810-8563, Japan. yamas009@gmail.com.;Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-Ku, Fukuoka, 810-8563, Japan.;Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-Ku, Fukuoka, 810-8563, Japan.;Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-Ku, Fukuoka, 810-8563, Japan.;Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-Ku, Fukuoka, 810-8563, Japan.",
"authors": "Yamasaki|Satoshi|S|;Kadowaki|Masanori|M|;Jiromaru|Takashi|T|;Takase|Ken|K|;Iwasaki|Hiromi|H|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1007/s13300-019-0609-3",
"fulltext": "\n==== Front\nDiabetes Ther\nDiabetes Ther\nDiabetes Therapy\n1869-6953\n1869-6961\nSpringer Healthcare Cheshire\n\n30927215\n609\n10.1007/s13300-019-0609-3\nCase Series\nAcquired Hemophilia A Associated with Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Type 2 Diabetes Mellitus: A Single-Center Case Series in Japan\nYamasaki Satoshi yamas009@gmail.com\n\nKadowaki Masanori\nJiromaru Takashi\nTakase Ken\nIwasaki Hiromi\ngrid.415613.4 Department of Hematology and Clinical Research Institute, National Hospital Organization Kyushu Medical Center, 1-8-1 Jigyohama, Chuo-Ku, Fukuoka, 810-8563 Japan\n29 3 2019\n29 3 2019\n6 2019\n10 3 11391143\n21 2 2019\n© The Author(s) 2019\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\nHerein we describe four patients with acquired hemophilia A (AHA) caused by factor VIII (FVIII) inhibitor and histories of dipeptidyl peptidase-4 inhibitor (DPP4-I) treatment for diabetes mellitus (DM). Drug exposure can cause a breakdown of immune tolerance to FVIII associated with CD4 T cells, resulting in the induction of autoantibodies against FVIII. In patient 1 in the present series, FVIII inhibitor disappeared after DPP4-I treatment. The DPP4-I treatment was stopped faster in patient 1 than it was in patient 2, whose FVIII inhibitor titer was higher than patient 1’s. Two patients died: patient 3 due to brain infarction after recurrence associated with the development of sigmoid colon rupture, and patient 4 due to multiple organ failure associated with Clostridium difficile colitis. DPP4-I treatment may create an ideal environment for the induction of new antibodies and AHA onset associated with tumor necrosis factor-α reduction. These are the first reported cases of the potential development and/or prolonging of AHA after DDP4-I treatment for DM, and they suggest possible disease associations.\n\nElectronic supplementary material\n\nThe online version of this article (10.1007/s13300-019-0609-3) contains supplementary material, which is available to authorized users.\n\nKeywords\n\nAcquired hemophilia A\nDiabetes mellitus\nDipeptidyl peptidase-4 inhibitors\nTumor necrosis factor-α\nissue-copyright-statement© The Author(s) 2019\n==== Body\nIntroduction\n\nAcquired hemophilia A (AHA) is caused by autoantibodies that inhibit factor VIII (FVIII) activity and lead to life-threatening hemorrhage [1]. It can be associated with autoimmune conditions, underlying malignancies, or drug allergies, but no specific cause is identified in an estimated 50% of patients [2, 3]. Diabetes mellitus (DM) is a highly prevalent condition diagnosed via well-established criteria, but the main causes of DM have not been well characterized. Genetics, environmental factors, poor diet, obesity, medications, infections, and a sedentary lifestyle are variably associated with DM in some cases [4]. Dipeptidyl peptidase-4 inhibitors (DPP4-Is) are relatively new oral antidiabetic drugs that have various effects on the immune system, including plasma tumor necrosis factor (TNF)-α reduction [5] and the inhibition of pathogenic T cells [6]. In patients with type 2 DM, DDP4-Is reportedly reduced the risk of rheumatoid arthritis [7] but increased the risk of inflammatory bowel disease [8]. Currently, there are no reports on associations between AHA and DDP4-I administration in type 2 DM patients.\n\nCases\n\nHerein we describe four patients with AHA and histories of DDP4-I treatment for DM (Table 1). Two were male and two were female, and their ages ranged from 61 to 84 years. Activated partial thromboplastin times (APTTs) ranged from 71.1 to 115.5 s (normal range = 21–33 s), which is markedly prolonged (see figures in the Electronic supplementary material, ESM). Anemia progressed to 5.2–6.0 g/dL of hemoglobin (normal range = 13.5–17.0 g/dL), necessitating red blood cell transfusions of 16–24 units. FVIII activity levels were < 1% in all cases (normal range = 60–150%), and FVIII inhibitor titers ranged from 14 to 100 Bethesda units/mL (normal titer = 0 Bethesda units/mL). Serum glycoprotein levels ranged from 15 to 20% (normal range = 12.4–16.3%) and all patients received a DDP4-I (sitagliptin phosphate hydrate in three cases and alogliptin benzonate in one case). Due to limitations on the use of FVIII imposed by the Japanese health insurance system, AHA patients can receive recombinant activated factor VII but not FVIII. Therefore, recombinant activated factor VII was administered to all four patients (three at diagnosis, one at recurrence) to control bleeding after bleeding diathesis, an isolated prolonged APTT, detection of low coagulation factor activity in mixing studies, or failure to exhibit APTT normalization after mixing of the patient’s serum with a nonhemophiliac donor’s serum. Mixing studies are performed to determine the presence of factor deficiency or factor inhibitors, or the presence of nonspecific inhibitors such as lupus anticoagulants, if APTT is prolonged in the specimen. With regard to immunological treatments for the eradication of inhibitors, prednisolone was administered to all four patients, cyclophosphamide was administered to patient 1, and rituximab was administered to patient 4. In patient 1, FVIII inhibitor disappeared after DPP4-I treatment. The DPP4-I treatment was stopped faster in patient 1 than it was in patient 2, whose FVIII inhibitor titer was higher than patient 1’s. In patient 2, FVIII inhibitor decreased from 27 Bethesda units/mL to 1 Bethesda unit/mL with the use of recombinant activated factor VII and the administration of prednisolone (daily dose of 1 mg/kg/day), and hemostasis was achieved. Prednisolone was tapered off and the FVIII inhibitor titer was negative after approximately 18 months. Two patients died: patient 3 due to brain infarction after recurrence associated with the development of sigmoid colon rupture, and patient 4 due to multiple organ failure associated with Clostridium difficile colitis. The present case series was retrospective and did not involve any experimental intervention. Accordingly, no institutional ethical approval was required or sought. Informed consent was obtained from all individual participants included in the study.Table 1 Patient characteristics and treatment outcomes\n\nCase\tAge\tSex\tUnderlying conditions (duration of diseases)\tSite of bleeding\tMinimal Hb (g/dL)\tRBC transfusions (total amount in units)\tGlycoprotein (%)\tFVIII inhibitor titer (BU/mL)\t\nAt diagnosis\tAt recurrence\tAt diagnosis\tAt recurrence\t\n1\t61\tM\tDM (5 years), HT (5 years), OMI (5 years)\tSubcutaneous\t5.2\t16\t15\t–\t35\t–\t\n2\t70\tM\tDM (2 months)\tSubcutaneous, intramuscular\t6\t16\t16\t–\t27\t–\t\n3\t71\tF\tDM (1 years 6 months), CKD (1.5 years)\tSubcutaneous\t5.4\t16\t18\t14\t14\t3\t\n4\t84\tF\tDM (5 years)\tSubcutaneous\t6\t24\t20\t24\t100\t20\t\nCase\tTotal dose of rFVIIa administered (mg)\tImmunological treatments (dose)\tDuration of PSL\tAnti-DM treatment\tOutcome\tOS (days)\tCause of death\t\nAt diagnosis (dose, duration of treatment)\tAfter diagnosis\t\n1\t160\tPSL (1 mg/kg) + CPA (50 mg/days)\t4 months\tSitagliptin phosphate hydrate (50 mg/days, 5 years)\tInsulin → none\tSurviving without recurrence\t3225\tNone\t\n2\t90\tPSL (1 mg/kg)\t19 months\tSitagliptin phosphate hydrate (50 mg/days, 2 months)\tSitagliptin phosphate hydrate\tSurviving without recurrence\t687\tNone\t\n3\t120\tPSL (1 mg/kg)\tUntil death (21 months)\tAlogliptin benzonate (6.25 mg/days, 1 year 6 months)\tAlogliptin benzonate + insuline → liraglutide\tDeath after recurrence\t158\tBrain infarction\t\n4\t400\tPSL (1 mg/kg) + RIT (375 mg/m2 × 3)\tUntil death (1 months)\tSitagliptin (25 mg, 5 years) phosphate hydrate\tSitagliptin phosphate hydrate + insulin\tDeath after recurrence\t30\tMultiple organ failure\t\nHb hemoglobin, RBC red blood cell, FVIII factor VIII, BU Bethesda units, M male, F female, DM diabetes mellitus, HT hypertension, OMI old myocardial infarction, CKD chronic kidney disease, PSL prednisolone, CPA cyclophosphamide, rFVIIa activated recombinant factor VII, d days, RIT rituximab, OS overall survival\n\nDiscussion\n\nAHA is characterized by the presence of an autoimmune mechanism that either alone or accompanied by autoimmune disease, aging, or drug exposure causes a breakdown in immune tolerance to FVIII autoantibodies involving CD4 T cells and results in the development of autoantibodies against FVIII. DPP4-I may be responsible for the impaired proliferative response of CD4 T cells to antigens and mitogens observed in hemophiliacs [9]. Although immunosuppressive treatment should eradicate inhibitors as soon as a diagnosis of AHA is confirmed, immunosuppression is associated with significant side effects including sepsis and colitis in older DM patients. TNF-α inhibitors may activate autoimmune reactions and the production of autoantibodies, and in 2/4 of the present cases AHA may have been induced by TNF-α inhibitors, as has previously been reported [10, 11]. DPP4-I treatment may create an ideal environment for new antibody formation and AHA onset associated with TNF-α reduction.\n\nCases of the onset of AHA associated with hypersensitivity to drugs such as antibiotics (penicillin, sulfonamides, and chloramphenicol), anticonvulsants (phenytoin), antihypertensive agents (methyldopa), and vaccination have been reported [12]. As increasing titers of FVIII inhibitors due to drug hypersensitivity disappear after termination of the responsible drug [13], immunological treatments to eradicate FVIII autoantibodies may not be required in patients who experience drug hypersensitivity.\n\nWhile the observations in the present case series are suggestive of associations, there are substantial limitations to the conclusions that can be drawn from it. The study was a retrospective case series that only included four patients, and low patient numbers can hinder the recognition of small differences in outcomes. Notwithstanding this, the results are concordant with an association between AHA and DPP4-I. Current AHA therapeutic strategies in DM patients who have undergone DDP4-I administration may not improve outcomes in patients who are resistant to immunological treatments to eradicate FVIII autoantibodies. Because the analysis of various comorbidities in DM patients was beyond the scope of the current study, and the best immunological treatments to use in DM patients with AHA remain uncertain, carefully designed prospective trials are essential to determine the contribution of immunological treatments to the successful eradication of FVIII autoantibodies. Another consideration that limits the interpretation of the present study is a lack of knowledge pertaining to predisposing factors for AHA. Lastly, a longer follow-up period may be needed to better evaluate eligibility criteria for DDP4-I administration in DM patients with AHA.\n\nIn conclusion, data derived from the present case series suggest that DDP4-I treatment for DM may induce and/or prolong AHA. Prospective observations and studies with larger numbers of patients are needed to improve the safety and efficacy of DDP4-I treatment in DM patients with AHA.\n\nElectronic supplementary material\n\nBelow is the link to the electronic supplementary material. Supplementary file1 (DOCX 267 kb)\n\nAcknowledgements\n\nWe thank the patients and clinical staff for their participation in the study.\n\nFunding\n\nNo funding or sponsorship was received for this study or publication of this article. The article processing charges were funded by the authors.\n\nEditorial Assistance\n\nThe authors acknowledge The Clinical Research Institute, Kyushu Medical Hospital for editorial support. The authors also thank Dr. Owen Proudfoot from Edanz Group (http://www.edanzediting.com/ac) for editing a draft of this manuscript. Editorial assistance was funded by the authors.\n\nAuthorship\n\nAll named authors meet the International Committee of Medical Journal Editors criteria for authorship of this article, take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.\n\nAuthorship Contributions\n\nSatoshi Yamasaki designed the study, analyzed the data, and prepared the manuscript. Masanori Kadowaki, Takashi Jiromaru, Ken Takase, and Hiromi Iwasaki prepared and reviewed the manuscript. All authors have approved the final manuscript.\n\nDisclosures\n\nSatoshi Yamasaki, Masanori Kadowaki, Takashi Jiromaru, Ken Takase and Hiromi Iwasaki have nothing to disclose.\n\nCompliance with Ethics Guidelines\n\nThe present case series was retrospective and did not involve any experimental intervention. Accordingly, no institutional ethical approval was required or sought. Informed consent was obtained from all individual participants included in the study.\n\nOpen Access\n\nThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International License (http://creativecommons.org/licenses/by-nc/4.0/), which permits any noncommercial use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.\n\nEnhanced Digital Features\n\nTo view enhanced digital features for this article go to 10.6084/m9.figshare.7873700.\n==== Refs\nReferences\n\n1. Kruse-Jarres R Kempton CL Baudo F Collins PW Knoebl P Leissinger CA Tiede A Kessler CM Acquired hemophilia A: updated review of evidence and treatment guidance Am J Hematol 2017 92 695 705 10.1002/ajh.24777 28470674\n2. Baudo F. Collins P. Huth-Kuhne A. Levesque H. Marco P. Nemes L. Pellegrini F. Tengborn L. Knoebl P. Management of bleeding in acquired hemophilia A: results from the European Acquired Haemophilia (EACH2) Registry Blood 2012 120 1 39 46 10.1182/blood-2012-02-408930 22618709\n3. Shetty Shrimati Bhave Manali Ghosh Kanjaksha Acquired hemophilia A: Diagnosis, aetiology, clinical spectrum and treatment options Autoimmunity Reviews 2011 10 6 311 316 10.1016/j.autrev.2010.11.005 21115138\n4. American Diabetes Association 2. Classification and diagnosis of diabetes: standards of medical care in diabetes—2018 Diabetes Care 2018 41 Suppl 1 S13 S27 10.2337/dc18-S002 29222373\n5. Atkin SL Katsiki N Banach M Mikhailidis DP Pirro M Sahebkar A Effect of dipeptidyl peptidase-4 inhibitors on circulating tumor necrosis factor-α concentrations: a systematic review and meta-analysis of controlled trials J Diabetes Complicat 2017 31 1458 1464 10.1016/j.jdiacomp.2017.05.016\n6. Zhao Y Yang L Wang X Zhou Z The new insights of DPP-4 inhibitors: their potential immune modulatory function in autoimmune diabetes Diabetes Metab Res Rev 2014 30 646 653 10.1002/dmrr.2530 24446278\n7. Kim SC Schneeweiss S Glynn RJ Doherty M Goldfine AB Solomon DH Dipeptidyl peptidase-4 inhibitors in type 2 diabetes may reduce the risk of autoimmune diseases: a population-based cohort study Ann Rheum Dis 2015 74 1968 1975 10.1136/annrheumdis-2014-205216 24919467\n8. Abrahami D, Douros A, Yin H, Yu OHY, Renoux C, Bitton A, Azoulay L. Dipeptidyl peptidase-4 inhibitors and incidence of inflammatory bowel disease among patients with type 2 diabetes: population based cohort study. BMJ. 2018;360:k872.\n9. Invernizzi R Montani N Giusto M Mosconi E Lorenzutti F Comolli G Pecci A Gamba G Expression of dipeptidylaminopeptidase IV/CD26 in peripheral blood lymphocytes of hemophilic subjects Eur J Haematol 1998 60 145 152 10.1111/j.1600-0609.1998.tb01015.x 9548412\n10. Arthanari S Ahmad H Nisar M Fatal acquired hemophilia A in a patient with rheumatoid arthritis treated with adalimumab J Clin Rheumatol 2012 18 50 51 10.1097/RHU.0b013e31823ee3cd 22157274\n11. Banse C Benhamou Y Lequerré T Le Cam-Duchez V Lévesque H Vittecoq O Acquired hemophilia possibly induced by etanercept in a patient with rheumatoid arthritis Jt Bone Spine 2015 82 200 202 10.1016/j.jbspin.2014.12.003\n12. Franchini M Gandini G Di Paolantonio T Mariani G Acquired hemophilia A: a concise review Am J Hematol 2005 80 55 63 10.1002/ajh.20390 16138334\n13. Delgado J Jimenez-Yuste V Hernandez-Navarro F Villar A Acquired haemophilia: review and meta-analysis focused on therapy and prognostic factors Br J Haematol 2003 121 21 35 10.1046/j.1365-2141.2003.04162.x 12670328\n\n",
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"title": "Acquired Hemophilia A Associated with Dipeptidyl Peptidase-4 Inhibitors for the Treatment of Type 2 Diabetes Mellitus: A Single-Center Case Series in Japan.",
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{
"abstract": "We describe a child initially diagnosed with multi-focal infantile hemangioma (cutaneous, hepatic, pulmonary), a benign vascular lesion, which underwent malignant transformation to angiosarcoma. The use of anti-angiogenic agents, such as bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, has been reported in adults with angiosarcoma. Treatment with chemotherapy (gemcitabine and docetaxel) and bevacizumab resulted in disease response with progression free survival of 12 months. This report describes the response to chemotherapy and bevacizumab in a child with angiosarcoma and highlights the potential for malignant transformation of benign vascular lesions and the need for careful monitoring.",
"affiliations": "Division of Pediatric Hematology/Oncology/Stem Cell Transplantation/Cancer Biology, Stanford University School of Medicine, Palo Alto, California.",
"authors": "Jeng|Michael R|MR|;Fuh|Beng|B|;Blatt|Julie|J|;Gupta|Anita|A|;Merrow|Arnold C|AC|;Hammill|Adrienne|A|;Adams|Denise|D|",
"chemical_list": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab",
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.25067",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "61(11)",
"journal": "Pediatric blood & cancer",
"keywords": "KRAS L19F; angiosarcoma; bevacizumab; malignant transformation",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": "D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D000068258:Bevacizumab; D002471:Cell Transformation, Neoplastic; D006391:Hemangioma; D006394:Hemangiosarcoma; D006801:Humans; D007223:Infant; D008297:Male; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "2115-7",
"pmc": null,
"pmid": "24740626",
"pubdate": "2014-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Malignant transformation of infantile hemangioma to angiosarcoma: response to chemotherapy with bevacizumab.",
"title_normalized": "malignant transformation of infantile hemangioma to angiosarcoma response to chemotherapy with bevacizumab"
} | [
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{
"abstract": "This case report describes the possible benefit of intravenous lipid emulsion in two patients surviving a severe intoxication with hydroxychloroquine in a dose that was previously considered to be lethal. The first case involves a 25-year-old female who ingested 17.5 grams of hydroxychloroquine, approximately one hour before presentation. An ECG showed QRS widening and the lab results showed hypokalaemia. She became unconscious, and developed hypotension and eventually apnoea. After intubation, supportive care consisted of norepinephrine and supplementation of potassium. Moreover, sodium bicarbonate and intravenous lipid emulsion were started to prevent cardiac toxicity. After these interventions, haemodynamic stability was established within a few hours. Although cardiomyopathy was confirmed, the patient recovered after two weeks. The second case concerns a 25-year-old male who took 5 grams of hydroxychloroquine. At presentation, two hours after intake, he showed QTc prolongation and hypokalaemia. The patient was treated with the usual supportive care and, although presentation to hospital was later, with intravenous lipid emulsion. Also this patient recovered. In conclusion, these cases show the benefit of supplemental intravenous lipid emulsion to prevent cardiac toxicity after a severe intoxication with hydroxychloroquine.",
"affiliations": "Department of Clinical Pharmacy, Catharina Hospital Eindhoven, Eindhoven, the Netherlands.",
"authors": "Ten Broeke|R|R|;Mestrom|E|E|;Woo|L|L|;Kreeftenberg|H|H|",
"chemical_list": "D005217:Fat Emulsions, Intravenous; D014662:Vasoconstrictor Agents; D006886:Hydroxychloroquine; D011189:Potassium Chloride; D017693:Sodium Bicarbonate; D009638:Norepinephrine",
"country": "Netherlands",
"delete": false,
"doi": null,
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"issn_linking": "0300-2977",
"issue": "74(5)",
"journal": "The Netherlands journal of medicine",
"keywords": null,
"medline_ta": "Neth J Med",
"mesh_terms": "D000328:Adult; D001145:Arrhythmias, Cardiac; D002853:Chromatography, Liquid; D062787:Drug Overdose; D004562:Electrocardiography; D005217:Fat Emulsions, Intravenous; D005260:Female; D006801:Humans; D006886:Hydroxychloroquine; D007008:Hypokalemia; D007022:Hypotension; D008297:Male; D009638:Norepinephrine; D011189:Potassium Chloride; D017693:Sodium Bicarbonate; D013406:Suicide, Attempted; D053719:Tandem Mass Spectrometry; D014662:Vasoconstrictor Agents",
"nlm_unique_id": "0356133",
"other_id": null,
"pages": "210-4",
"pmc": null,
"pmid": "27323674",
"pubdate": "2016-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Early treatment with intravenous lipid emulsion in a potentially lethal hydroxychloroquine intoxication.",
"title_normalized": "early treatment with intravenous lipid emulsion in a potentially lethal hydroxychloroquine intoxication"
} | [
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"abstract": "Central nervous system (CNS) toxicity has been reported in approximately 10-30% of patients receiving intravenous infusions of ifosfamide. Encephalopathy is a rare but serious CNS adverse reaction in these patients, and although usually transient and reversible, may cause persistent neurological dysfunction or death. Clinical features range from fatigue and confusion to coma and death. Although methylene blue can be used to treat ifosfamide-induced neurotoxicity, including encephalopathy, its mechanism of action remains poorly defined. We describe here two patients with recurrent epithelial ovarian cancer who experienced fatal encephalopathy following ifosfamide/mesna treatment.",
"affiliations": "Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.",
"authors": "Shin|You-Jung|YJ|;Kim|Ji-Young|JY|;Moon|Jei-Won|JW|;You|Rae-Mi|RM|;Park|Jeong-Yeol|JY|;Nam|Joo-Hyun|JH|",
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"fulltext": "\n==== Front\nCancer Res TreatCRTCancer Research and Treatment : Official Journal of Korean Cancer Association1598-29982005-9256Korean Cancer Association 10.4143/crt.2011.43.4.260Case ReportFatal Ifosfamide-Induced Metabolic Encephalopathy in Patients with Recurrent Epithelial Ovarian Cancer: Report of Two Cases Shin You-Jung MDKim Ji-Young MDMoon Jei-Won MDYou Rae-Mi MDPark Jeong-Yeol MDPhDNam Joo-Hyun MDPhDDepartment of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.Correspondence: Jeong-Yeol Park, MD, PhD. Department of Obstetrics and Gynecology, Asan Medical Center, University of Ulsan College of Medicine, Pungnap 2-dong, Songpa-gu, Seoul 138-736, Korea. Tel: 82-2-3010-3646, Fax: 82-2-477-7331, catgut1-0@hanmail.net12 2011 27 12 2011 43 4 260 263 07 7 2010 29 9 2010 Copyright © 2011 by the Korean Cancer Association2011This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.Central nervous system (CNS) toxicity has been reported in approximately 10-30% of patients receiving intravenous infusions of ifosfamide. Encephalopathy is a rare but serious CNS adverse reaction in these patients, and although usually transient and reversible, may cause persistent neurological dysfunction or death. Clinical features range from fatigue and confusion to coma and death. Although methylene blue can be used to treat ifosfamide-induced neurotoxicity, including encephalopathy, its mechanism of action remains poorly defined. We describe here two patients with recurrent epithelial ovarian cancer who experienced fatal encephalopathy following ifosfamide/mesna treatment.\n\nEncephalopathyOvarian epithelial cancerIfosfamideMesnaMethylene blue\n==== Body\nIntroduction\nIfosfamide is an alkylating agent frequently used to treat ovarian, testicular, cervical, and head and neck cancers, as well as lymphomas and soft tissue sarcomas. Frequent side effects of ifosfamide include myelotoxicity, hemorrhagic cystitis and neurotoxicity (mental confusion, drowsiness, hallucinations, disorientation, and coma) [1]. Although the use of ifosfamide was initially limited by severe hemorrhagic cystitis, this problem was resolved by the concurrent administration of sodium 2-mercaptoethane sulfonate (mesna), a synthetic thiol compound that binds to toxic species of ifosfamide in the bladder to form stable nontoxic thioether compounds. Ifosfamide and mesna can both have adverse effects in the central nervous system (CNS), with 10-30% of ifosfamide-treated patients experiencing CNS toxicity [2-6]. These neurotoxicities are dose dependent and may be fatal. Furthermore, the mechanism of action and factors predisposing to ifosfamide-induced encephalopathy are poorly understood. Methylene blue (MB) can be used to treat these encephalopathies, but its mechanism of action is unclear. In this report, we describe two patients with recurrent epithelial ovarian cancer who experienced fatal ifosfamide-induced encephalopathy, as well as a review of the proposed pathophysiology of ifosfamide-induced encephalopathy and the use of MB in its management.\n\nCase Reports\n1. Case 1\nA 54-year-old, gravida 2, para 2, married woman presented with recurrent epithelial ovarian cancer (endometrioid adenocarcinoma). She had noninsulin dependent diabetes mellitus, diabetic retinopathy, and hypertension. Seven years earlier, she underwent coronary artery bypass grafting due to coronary artery disease.\n\nThree years ago, she was transferred to our center after laparoscopic bilateral salpingo-oophorectomy which led to a diagnosis of epithelial ovarian cancer. She underwent a debulking operation, including total abdominal hysterectomy and pelvic and paraaortic lymph node dissection, total omentectomy, appendectomy, peritoneal mass excision, and left ureter resection and anastomosis. The tumor was categorized as International Federation of Obstetrics and Gynecology (FIGO) stage IIIc and cytoreductive surgery was suboptimal. Following the surgery, she received 6 cycles of adjuvant chemotherapy with paclitaxel/carboplatin. However, because there was disease progression in this patient, she was further treated with 3 cycles of topotecan, followed by 3 cycles of docetaxel. An abdomino-pelvic computed tomography (CT) scan showed aggravation of disease and her serum carbohydrate antigen 125 (CA-125) concentration was elevated from 534 to 1,270 U/mL. We decided to change her chemotherapy regimen to ifosfamide monotherapy.\n\nShe was started on ifosfamide 1,200 mg/m2/day, administered via continuous infusion on days 1-3 of each 4 week cycle, along with mesna 300 mg/m2/day. On the third day she received ifosfamide, her mental status worsened, with a change from drowsiness to stupor, followed by disorientation, stereotyped movements, and emotional instability. She had no lateralizing neurologic signs. Her blood test results, including measurements of serum glucose, brain natriuretic peptide, and electrolytes, were normal, and her cerebrospinal fluid was negative for malignant cells. In addition, brain magnetic resonance imaging (MRI) findings were normal. An electroencephalogram showed frequent 1-1.5 Hz periodic or single triphasic waves on both hemispheres (Fig. 1). She was diagnosed with ifosfamide-induced encephalopathy, and her chemotherapy was discontinued immediately. Her neurologic symptoms and signs did not improve. Despite the supportive care, her encephalopathy became aggravated, and she developed ifosfamide-induced acute tubular necrosis. She was discharged without any hope for recovery and died within 1 month.\n\n2. Case 2\nA 46-year-old, gravida 2, para 2, married woman with recurrent epithelial ovarian cancer (serous adenocarcinoma) was referred to our institution for further management. She had no specific medical history.\n\nAt initial diagnosis of epithelial ovarian cancer, she underwent bilateral salpingo-oophorectomy, partial omentectomy and incidental appendectomy at another hospital, and cytoreductive surgery was suboptimal. She received 12 cycles of adjuvant chemotherapy with paclitaxel and carboplatin. However, an abdomino-pelvic CT scan showed residual peritoneal carcinomatosis and her serum CA-125 concentration was elevated, from 517 to 1,020 U/mL. After referral to our center, she underwent optimal cytoreductive surgery, including total abdominal hysterectomy, pelvic and paraaortic lymph node dissection, low anterior resection, and right diaphragmatic stripping. After surgery, she received 3 cycles of adjuvant chemotherapy with topotecan and cisplatin. Due to disease progression, her regimen was switched to 3 cycles of docetaxel and carboplatin. Due to the disease progression on this regimen, we changed her chemotherapy regimen to a combination of ifosfamide and etoposide. She received the first cycle of etoposide (75 mg/m2/day in 3-hour infusions on days 1-5) and ifosfamide (1,200 mg/m2/day in 3-hour infusions on days 1-5), along with 300 mg/m2/day mesna, without any complications. On day 6, her speech became unintelligible but her orientation was intact. On day 7, she developed delirium, disorientation, visual and auditory hallucinations, stereotyped movements, and emotional instability. At that time, her estimated glomerular filtration rate, serum creatinine and blood urea nitrogen were 27 mL/min (normal, >60 mL/min), 2.3 mg/dL (normal, 0.7 to 1.4 mg/dL) and 33 mg/dL (normal, 10 to 26 mg/dL), respectively, and her renal function decreased gradually. Brain MRI was normal. After referral to a nephrologist, her electrolyte imbalance was corrected and her uremia was improved by hemodialysis. However, her mental impairments showed no improvement. She was diagnosed as having severe ifosfamide-induced encephalopathy. She never recovered and was discharged in a hopeless condition on day 10 and died within 1 month.\n\nDiscussion\nIfosfamide is an oxazaphosphorine antineoplastic agent (a nitrogen mustard derivative) and is a structural analog of cyclophosphamide [3,7]. Ifosfamide is a prodrug that requires hepatic activation to its cytotoxic metabolite, ifosfamide mustard [7,8]. The latter is metabolized by cytochrome p450 to generate the active alkylating agents, 4-hydroxy-ifosfamide and isophosphoramide mustard [8]. Ifosfamide and its metabolites can penetrate the blood brain barrier (BBB), with CNS toxicity occurring in 10-40% of patients receiving high doses of the drug [2-6].\n\nThe exact pathophysiological mechanisms responsible for the development of ifosfamide-induced encephalopathy are unclear, but one of the causes is thought to be the dechloroethylation of Ifosfamide to form chloroacetaldehyde (CAA) [8-10]. Hypotheses for the possible pathophysiological pathways leading to the development of ifosfamide-induced encephalopathy [2,11,12] were based on the finding of glutaric acid and sarcosine in the urine of a patient with ifosfamide-induced encephalopathy (Fig. 2) [11,13]. The accumulation of glutaric acid may lead to an increase in chloroethyl amine, the metabolism of which may in turn disturb the mitochondrial respiratory chain. Thus, the accumulation of nicotinamide adenine dinucleotide hydrogen (NADH) may prevent the dehydrogenation of aldehydes such as the ifosfamide metabolite CAA, a potentially neurotoxic substance [9]. CAA, which is structurally similar to both chloral hydrate and acetaldehyde, can cross the BBB and therefore be responsible for ifosfamide-induced encephalopathy [7]. The neurotoxic effects of CAA may be due to 1) a direct neurotoxic effect, 2) depletion from the CNS of glutathione, and/or 3) the inhibition of mitochondrial oxidative phosphorylation resulting in impaired fatty acid metabolism [2].\n\nCNS toxicity displays a wide spectrum of signs and symptoms. Manifestations of ifosfamide-induced encephalopathy include cerebellar ataxia, mental confusion, complex visual hallucinations, extrapyramidal signs, seizures and/or mutism. Less common CNS manifestations of ifosfamide are asterixis, nonconvulsive status epilepticus, manic episodes and cerebellar and temporo-frontal cortical degeneration [6].\n\nAccording to the National Cancer Institute Toxicity Grading for Encephalopathy [14], there are five grades of encephalopathy. Most patients with ifosfamide-induced encephalopathy show grade 1 or 2 symptoms. Many patients with ifosfamide-induced encephalopathy recover spontaneously and completely within 48-72 hours following the onset of discontinuation of ifosfamide and conservative management such as adequate hydration. Some patients with ifosfamide-induced encephalopathy present with grade 3 or 4 symptoms. However, most patients with grade 3 or 4 symptoms can also recover spontaneously and completely. In rare cases, grade 3 or 4 encephalopathy leads to death. Because ifosfamide-induced encephalopathy research is limited to case reports and small retrospective case series, the prognosis and sequelae according to the toxicity grade, has not been clearly established [10].\n\nAlthough factors predisposing to ifosfamide-induced encephalopathy have not yet been revealed, rates of neurotoxicity may be increased by pre-existing renal or hepatic failure, low albumin and poor performance status [4,15]. These two cases were considered as grade 4 ifosfamide-induced encephalopathy according to the National Cancer Institute Toxicity Grading for Encephalopathy [14] and both resulted in death within 1 month. In case 1, the electroencephalogram (EEG) finding was also revealed as Meanwell grade IV [5]. Both patients' clinical courses may have been aggravated by their decreased renal function [10].\n\nIfosfamide-induced encephalopathy is a clinical diagnosis. The differential diagnoses of ifosfamide-induced encephalopathy include infection, metabolic abnormalities and concomitant drug-induced syndromes. It is supported by normal brain imaging, EEG findings of metabolic encephalopathy and the absence of other causes [6]. EEG characteristics have been correlated with the clinical grading of ifosfamide-induced encephalopathy [5]. For example, Meanwell grade 3 toxicity has been associated predominantly with delta wave activity, with or without sharp complex waveforms, whereas patients with grade 4 toxicity exhibit continuous delta activity, complex waveforms and triphasic waves. The EEG recording in case 1 showed evidence of grade 4 toxicity (Fig. 1).\n\nIn patients experiencing acute ifosfamide-induced encephalopathy, the mainstays of management include the prompt cessation of ifosfamide infusion and intravenous hydration. Although ifosfamide-induced encephalopathy usually reverses completely within 2-3 days after the cessation of drug administration, it may not in some patients with high grade toxicity.\n\nBecause ifosfamide-induced encephalopathy can resolve spontaneously 48-72 hours following its onset, patients with mild symptoms may not need treatment with MB. Patients with more severe symptoms and with grade 3-4 toxicity may derive greater benefit from MB. However, as the encephalopathy resolves spontaneously in most cases, even in patients with severe symptoms, and since controlled clinical trials have not been conducted to determine the efficacy of MB in severe ifosfamide-induced encephalopathy, the evidence to support its use is not strong [10]. In most cases, MB is considered for use in the management of acute symptoms [12]. While some patients have experienced improvements in CNS function as rapidly as within 10 minutes, others have required several days to recover [10].\n\nMB has been increasingly used both for the treatment and prevention of ifosfamide-induced encephalopathy [8,11]. MB is thought to counteract some of the metabolic pathways of ifosfamide [11]. It may act as an alternative electron acceptor, replacing the inhibited flavoproteins and thus restoring the mitochondrial respiratory chain. It may also oxidize NADH, allowing the dehydrogenation of aldehydes. MB has also been found to inhibit plasma and extrahepatic monoamine oxidases (Fig. 2) [3,8,13]. The recommended dose of intravenous MB for treatment of ifosfamide-induced encephalopathy is 50 mg every 4 hours (1% aqueous solution over 5 minutes), whereas the dose for secondary prophylaxis of ifosfamide-induced encephalopathy is 50 mg every 6 hours, either intravenously or orally [8]. However, the efficacy of MB in patients with severe ifosfamide-induced encephalopathy is still controversial.\n\nConflict of interest relevant to this article was not reported.\n\nFig. 1 Electroencephalogram (EEG) recording in case 1, showing frequent diffuse 1 Hz periodic triphasic waves and rhythmic delta slowing (EEG recording parameters: amplitude, 1 cm=70 µV; interval between two thick vertical lines=1 sec).\n\nFig. 2 Proposed pathogenesis pathways involved in ifosfamide neurotoxicity and the proposed sites of action of methylene blue: (1) Inhibition of extrahepatic mono-amine oxidation of chloroethylamine to chloroacetaldehyde; (2) Restoration of hepatic nicotinamide adenine dinucleomide hydrogen (NADH) oxidative functions; (3) Substitute for electron transport flavoprotein (ETF) enzyme (electron acceptor) (ada-pted from Donegan S. J Oncol Pharm Pract. 2001; 6:153-65 [13], with permission).\n==== Refs\n1 Giovanis P Garna A Marcante M Nardi K Giusto M Ifosfamide encephalopathy and use of methylene blue: a case report of different sequential neurotoxicity Tumori 2009 95 545 546 19856674 \n2 Ajithkumar T Parkinson C Shamshad F Murray P Ifosfamide encephalopathy Clin Oncol (R Coll Radiol) 2007 19 108 114 17355105 \n3 Alici-Evcimen Y Breitbart WS Ifosfamide neuropsychiatric toxicity in patients with cancer Psychooncology 2007 16 956 960 17278152 \n4 Rieger C Fiegl M Tischer J Ostermann H Schiel X Incidence and severity of ifosfamide-induced encephalopathy Anticancer Drugs 2004 15 347 350 15057138 \n5 Meanwell CA Blake AE Kelly KA Honigsberger L Blackledge G Prediction of ifosfamide/mesna associated encephalopathy Eur J Cancer Clin Oncol 1986 22 815 819 3095121 \n6 Klastersky J Side effects of ifosfamide Oncology 2003 65 Suppl 2 7 10 14586140 \n7 McVay JI Wood AM Suspected ifosfamide-induced neurotoxicity Pharmacotherapy 1999 19 1450 1455 10600096 \n8 Pelgrims J De Vos F Van den Brande J Schrijvers D Prové A Vermorken JB Methylene blue in the treatment and prevention of ifosfamide-induced encephalopathy: report of 12 cases and a review of the literature Br J Cancer 2000 82 291 294 10646879 \n9 David KA Picus J Evaluating risk factors for the development of ifosfamide encephalopathy Am J Clin Oncol 2005 28 277 280 15923801 \n10 Patel PN Methylene blue for management of Ifosfamide-induced encephalopathy Ann Pharmacother 2006 40 299 303 16391008 \n11 Küpfer A Aeschlimann C Cerny T Methylene blue and the neurotoxic mechanisms of ifosfamide encephalopathy Eur J Clin Pharmacol 1996 50 249 252 8803513 \n12 Turner AR Duong CD Good DJ Methylene blue for the treatment and prophylaxis of ifosfamide-induced encephalopathy Clin Oncol (R Coll Radiol) 2003 15 435 439 14570094 \n13 Donegan S Novel treatment for the management of ifosfamide neurotoxicity: rationale for the use of methylene blue J Oncol Pharm Pract 2001 6 153 165 \n14 National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 3.0 2003 Bethesda, MD National Cancer Institute \n15 Brunello A Basso U Rossi E Stefani M Ghiotto C Marino D Ifosfamide-related encephalopathy in elderly patients: report of five cases and review of the literature Drugs Aging 2007 24 967 973 17953463\n\n",
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{
"abstract": "The case is presented of a 52-year-old woman with scleroderma, mixed connective tissue disease, and interstitial lung disease, who developed chronic cytomegalovirus necrotizing retinitis while on treatment with prednisone, mycophenolate, and hydroxychloroquine. Initially diagnosed as macular hole, the patient underwent a pars plana vitrectomy. Two months after surgery, due to progressive worsening, the diagnosis was made and treatment started (intravenous and intravitreal ganciclovir). The patient developed severe macular atrophy with final visual acuity of counting fingers. A chronic retinal necrosis can be caused by cytomegalovirus infection in non-HIV patients with partial immune dysfunction from other causes, characterized by a slowly progressive granular retinitis with occlusive vasculitis.",
"affiliations": "Unidad de Gestión Clínica de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, Spain.;Unidad de Gestión Clínica de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, Spain.;Unidad de Gestión Clínica de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, Spain. Electronic address: mariangeles.esp@gmail.com.;Unidad de Gestión Clínica de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, Spain.;Unidad de Gestión Clínica de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, Spain.;Unidad de Gestión Clínica de Oftalmología, Hospital Universitario Virgen del Rocío, Sevilla, Spain.",
"authors": "López-Herrero|F|F|;Sánchez-Vicente|J L|JL|;Espiñeira-Periñán|M A|MA|;de Las Morenas-Iglesias|J|J|;Franco-Ruedas|C|C|;Rueda-Rueda|T|T|",
"chemical_list": "D015774:Ganciclovir",
"country": "Spain",
"delete": false,
"doi": "10.1016/j.oftale.2020.06.006",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2173-5794",
"issue": "96(7)",
"journal": "Archivos de la Sociedad Espanola de Oftalmologia",
"keywords": "Cytomegalovirus retinitis; Enfermedad mixta del tejido conectivo; Esclerodermia; Mixed connective tissue disease; Necrosis retiniana vírica; Retinal vasculitis; Retinitis por citomegalovirus; Scleroderma; Vasculitis retiniana; Viral retinal necrosis",
"medline_ta": "Arch Soc Esp Oftalmol (Engl Ed)",
"mesh_terms": "D003587:Cytomegalovirus; D017726:Cytomegalovirus Retinitis; D005260:Female; D015774:Ganciclovir; D006801:Humans; D008875:Middle Aged; D008947:Mixed Connective Tissue Disease; D014821:Vitrectomy",
"nlm_unique_id": "101715860",
"other_id": null,
"pages": "392-396",
"pmc": null,
"pmid": "34217479",
"pubdate": "2021-07",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Chronic cytomegalovirus necrotizing retinitis in a patient with scleroderma and mixed connective tissue disease.",
"title_normalized": "chronic cytomegalovirus necrotizing retinitis in a patient with scleroderma and mixed connective tissue disease"
} | [
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{
"abstract": "BACKGROUND\nSeveral adverse events have been associated with the use of bevacizumab during the treatment of neoplasms such as colorectal cancer, breast cancer, non-small cell lung cancer, pancreatic cancer and renal cell carcinoma. The present case demonstrates how focal neurological symptoms lead to the magnetic resonance imaging-based differential diagnosis between focal parenchymal metastases and microischemic phenomena, with crucial implications for patient management.\n\n\nMETHODS\nWe describe the case of a 37-year-old Italian Caucasian woman with metastatic colon cancer who developed focal neurological symptoms during a chemotherapy regimen involving the use of bevacizumab. Brain magnetic resonance imaging examination revealed millimetric lesions with restricted diffusion without perilesional edema or contrast enhancement after gadodiamide intravenous injection, suggestive of acute microischemic phenomena. This complication is very rare but clinically significant.\n\n\nCONCLUSIONS\nThe differential diagnosis in patients with cancer undergoing bevacizumab treatment should include microischemic phenomena.",
"affiliations": "Interdisciplinary Center for Biomedical Research, Department of Radiology, University Campus Bio-Medico of Rome, via Longoni, 47 I-00155 Rome, Italy. c.quattrocchi@unicampus.it.",
"authors": "Quattrocchi|Carlo C|CC|;Alexandre|Andrea M|AM|;Tonini|Giuseppe|G|;Errante|Yuri|Y|;Grasso|Rosario F|RF|;Zobel|Bruno Beomonte|BB|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/1752-1947-5-84",
"fulltext": "\n==== Front\nJ Med Case ReportsJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-5-842135258010.1186/1752-1947-5-84Case ReportBrain microischemic phenomena in a woman receiving bevacizumab treatment: a case report Quattrocchi Carlo C 1c.quattrocchi@unicampus.itAlexandre Andrea M 2andrea.alexandre@libero.itTonini Giuseppe 3not@valid.comErrante Yuri 1not@valid.comGrasso Rosario F 1andrea.alexandre@libero.itZobel Bruno Beomonte 1andrea.alexandre@libero.it1 Interdisciplinary Center for Biomedical Research, Department of Radiology, University Campus Bio-Medico of Rome, via Longoni, 47 I-00155 Rome, Italy2 Department of Bio-imaging and Radiological Sciences, Catholic University of Sacred Heart, Policlinico A. Gemelli. Largo F. Vito, I-00100 Rome, Italy3 Interdisciplinary Center for Biomedical Research, Oncology, University Campus Bio-Medico of Rome, via Longoni, 47 I-00155 Rome, Italy2011 27 2 2011 5 84 84 1 4 2010 27 2 2011 Copyright ©2011 Quattrocchi et al; licensee BioMed Central Ltd.2011Quattrocchi 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.Introduction\nSeveral adverse events have been associated with the use of bevacizumab during the treatment of neoplasms such as colorectal cancer, breast cancer, non-small cell lung cancer, pancreatic cancer and renal cell carcinoma. The present case demonstrates how focal neurological symptoms lead to the magnetic resonance imaging-based differential diagnosis between focal parenchymal metastases and microischemic phenomena, with crucial implications for patient management.\n\nCase presentation\nWe describe the case of a 37-year-old Italian Caucasian woman with metastatic colon cancer who developed focal neurological symptoms during a chemotherapy regimen involving the use of bevacizumab. Brain magnetic resonance imaging examination revealed millimetric lesions with restricted diffusion without perilesional edema or contrast enhancement after gadodiamide intravenous injection, suggestive of acute microischemic phenomena. This complication is very rare but clinically significant.\n\nConclusion\nThe differential diagnosis in patients with cancer undergoing bevacizumab treatment should include microischemic phenomena.\n==== Body\nIntroduction\nWe describe the case of a patient with metastatic colon cancer who developed focal neurological symptoms during a chemotherapy regimen including bevacizumab. Some millimetric lesions were detected by a first magnetic resonance imaging (MRI) examination and were not detectable on the MRI examination performed six months later. In patients with cancer undergoing bevacizumab treatment, the occurrence of neurological focal symptoms leads to an MRI differential diagnosis between focal parenchymal metastases and microischemic phenomena, with crucial decisions that must be made for patient management.\n\nCase presentation\nA 37-year-old Italian Caucasian woman underwent a colonscopy that revealed a polypoid formation 28cm from the external anal margin. The biopsy showed areas of adenocarcinoma in the context of tubulovillous and villous adenoma with mild to severe dysplasia. Computed tomography (CT) staging was negative for regional or distant metastases. Surgical removal was performed by partial colectomy. The tumor histology confirmed the diagnosis of adenocarcinoma with infiltration of the serosa and pathological TNM staging of pT4pN1M0.\n\nA follow-up CT examination three months later revealed eight focal hepatic lesions distributed throughout both lobes. Chemotherapy treatment with the folinic acid, fluorouracil and oxaliplatin (FOLFOX) scheme was started, and the patient showed a partial response after the fourth course of treatment. She underwent surgical resection of metastases localized at hepatic segments IV and V. CT examination showed disease progression in the lung and liver parenchyma six months later. Several lines of treatment were started, including XELOX (capecitabine plus oxaliplatin), FOLFIRI (folinic acid, fluorouracil and irinotecan) and radiofrequency thermoablation, with no response. CT showed a partial hepatic response after 12 courses of cetuximab and irinotecan therapy, but hepatic progression was observed after 24 courses. Therefore, chemoimmunotherapy with bevacizumab (Avastin; Genentech, South San Francisco, CA, USA) and FOLFOX was started, but it was suspended after nine cycles as the patient developed left hemiparesis, hemifacial left anesthesia and right-hand paresthesia.\n\nA brain MRI scan showed three millimetric lesions located in the right temporooccipital lobe (Figure 1A), the left pontine region (Figure 2B) and the right parietal lobe (Figure 2C) with restricted diffusion (Figures 1A to 1C) and no enhancement after gadodiamide injection. These findings, that is, hyperintensity on fluid attenuated inversion recovery (FLAIR) images, slight enhancement on postgadolinium T1-weighted images, restricted diffusion and no contrast enhancement, were suggestive of areas of acute microischemic strokes. Although unusual in the context of stroke, the subcortical lesion at the level of the right temporooccipital white matter was confirmed to be unchanged with regard to size and signal intensity on FLAIR images obtained at the one-year follow-up examination (Figure 3). Moreover, other bilateral centrum semiovale lesions not detected on diffusion-weighted images and not showing contrast enhancement were hypointense with a hyperintense gliotic peripheral ring visualized on FLAIR images, suggestive of areas of chronic microischemic origin (Figure 2D). These lesions appeared as millimetric spots of hyperintensity on T2-weighted images obtained at the one-year follow-up examination. No other risk factors for thromboembolic events were recognized: the patient's clinical history was negative for hypertension, hypercholesterolemia, hypertriglyceridemia, diabetes, obesity, smoking, atrial fibrillation, heart disease, atrial or ventricular septal defects and previous episodes of thrombosis or symptoms correlated to thrombosis. Her pharmacological history was negative for anticoagulant or procoagulant drugs. Her platelets were 161 × 103/μL (normal range, 150 to 450), her International Normalized Ratio was 1.08 (normal range, 0.85 to 1.16) and her activated partial thromboplastin time ratio was 0.84 (normal range, 0.82 to 1.20).\n\nFigure 1 (A) Right temporooccipital lesion can be easily detected as a hyperintense spot in T1-weighted sequences . (B) The lesion shows restricted diffusion, an absence of perilesional edema. (C) No enhancement is observed after gadodiamide injection. These findings are suggestive of areas of microischemic phenomena.\n\nFigure 2 Other lesions suggestive of areas of acute embolic strokes are (A) the right parietal lobe, (B) the left pontine region and (C) the right parietal lobe (alternate view) . (D) Another bilateral centrum semiovale lesion not detected on diffusion-weighted images, without contrast enhancement, is hypointense in this fluid attenuated inversion recovery (FLAIR) image with a hyperintense gliotic peripheral ring, suggestive of small vascular ischemic microlacunae.\n\nFigure 3 FLAIR image obtained at the patient's one-year follow-up magnetic resonance imaging (MRI) examination demonstrating the subcortical lesion at the level of the right temporooccipital white matter . The lesion was unchanged with regard to size and signal intensity compared with the previous MRI (see Figure 1A).\n\nAn ultrasound Doppler study was obtained, which showed normal morphology of supraaortic vessels. In addition, the patient's electrocardiogram and echocardiogram were normal.\n\nLow-molecular-weight heparin (6,000 IU twice daily), edema therapy (8 mg of dexamethasone twice daily) and antiplatelet therapy (200 mg/day aspirin) were administered, resulting in complete resolution of the patient's neurological symptoms.\n\nDiscussion\nBevacizumab, a humanized antibody directed against the vascular endothelial growth factor (VEGF) that is used as an angiogenesis inhibitor, has been examined in combination with chemotherapeutic agents in several clinical trials in patients with advanced colorectal cancer [1], even as a first-line treatment [2]. The addition of bevacizumab increased the overall response rate and extended median survival. In the past four years, bevacizumab has been used with increasing frequency for the treatment of other neoplasms, such as breast cancer, non-small cell lung cancer, pancreatic cancer and renal cell carcinoma.\n\nSeveral adverse events have been associated with the use of bevacizumab: hypertension (the most common side effect), gastrointestinal perforation, wound-healing complications, hemorrhage, arterial thomboembolic events, proteinuria, congestive heart failure, leukopenia and diarrhea [3]. Arterial thromboembolic events have been observed in 0.9% of the cases in the BEATrial [3] and in 2.1% of the cases in the BRiTE Registry [4]. The mechanism of concurrent thrombosis and bleeding during bevacizumab treatment is not clear, being related to the role of VEGF in maintaining a healthy endothelium.\n\nConclusion\nVascular events involving the central nervous system have been reported as reversible posterior leukoencephalopathy syndrome following a bevacizumab or FOLFIRI treatment regimen for metastatic colon cancer, which are likely related to high systolic blood pressure levels [5]. Furthermore, as thromboembolic events and microischemic phenomena are a well-known complication of bevacizumab chemotherapeutic treatment [6], the occurrence of neurological focal symptoms leads to an MRI-based differential diagnosis between focal parenchymal metastases and microischemic phenomena, which lead to crucial decisions for patient management.\n\nConsent\nWritten informed consent was obtained from the patient for publication of this case report and accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nAuthors' contributions\nGT and YE analyzed and interpreted the patient data regarding the primary disease (colon cancer) and decided on the therapeutic strategy. CCQ, RFG and BBZ performed the brain magnetic resonance imaging. CCQ and AMA were the major contributors in writing the manuscript. All authors read and approved the final manuscript.\n==== Refs\nMeyerhardt JA Mayer RJ Systemic therapy for colorectal cancer N Engl J Med 2005 352 476 487 10.1056/NEJMra040958 15689586 \nSaif MW Merritt J Robbins J Stewart J Schupp Phase III multicenter randomized clinical trial to evaluate the safety and efficacy of CoFactor/5-fluorouracil/bevacizumab versus leucovorin/5-fluorouracil/bevacizumab as initial treatment for metastatic colorectal carcinoma Clin Colorectal Cancer 2006 6 229 234 10.3816/CCC.2006.n.042 17026795 \nVan Cutsem E Michael M Berry S Dibartolomeo M Rivera F Kretzschmar A Mazier M Lutiger B Cunningham D Preliminary safety and efficacy of bevacizumab with first-line FOLFOX, XELOX, FOLFIRI, and capecitabine for mCRC: First BEATrial Presented at the 2007 Gastrointestinal Cancers Symposium, Orlando, FL, USA [Abstract 346] \nKozloff M Hainsworth J Badarinath S Cohn A Flynn P Steis R Dong W Suzuki S Sugrue M Grothey A Efficacy of bevacizumab plus chemotherapy as first-line treatment of patients with metastatic colorectal cancer: updated results from a large observational registry in the US (BRiTE). Presented at the 2006 ASCO annual meeting proceedings, Part I (Abstract 3537) J Clin Oncol 2006 24 18S \nGlusker P Recht L Lane B Reversible posterior leukoencephalopathy syndrome and bevacizumab N Engl J Med 2006 354 980 981 10.1056/NEJMc052954 16510760 \nFriedman HS Prados MD Wen PY Mikkelsen T Schiff D Abrey LE Yung WK Paleologos N Nicholas MK Jensen R Vredenburgh J Huang J Zheng M Cloughesy T Bevacizumab alone and in combination with irinotecan in recurrent glioblastoma J Clin Oncol 2009 27 4733 4740 10.1200/JCO.2008.19.8721 19720927\n\n",
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{
"abstract": "The effect of recombinant human granulocyte colony-stimulating factor (rhG-CSF) administration at 10 microg/kg/day for 15-30 min over 3 consecutive days in 3 preterm neonates with allo-immune neonatal neutropenia (ANN) is reported. Patients 1 and 2 had antibodies against antigen NA2, while patient 3 had antibodies against NA1. All neonates developed a rapid increase in absolute neutrophil count which reached the normal range within 48 h (from 75-640/mm(3) to 2,520-4,700/mm(3)). However, 23-25 days later, all 3 neonates relapsed into a second phase of severe neutropenia (408-870/mm(3)). Antibodies against neutrophil antigens were still positive during this period. This second-phase neutropenia persisted for 20-30 days and resolved spontaneously. It may be possible that when rhG-CSF is administered within a short time after birth in neonates with ANN, its effect is exhausted before the concentration of circulating antibodies decreases, with the result that a second phase of neutropenia can be expected.",
"affiliations": "Division of Neonatology, Department of Paediatrics, Catholic University of the Sacred Heart, Rome, Italy. catneo@rm.unicatt.it",
"authors": "Girlando|P|P|;Zuppa|A A|AA|;Romagnoli|C|C|;Tortorolo|G|G|",
"chemical_list": "D007518:Isoantibodies; D007519:Isoantigens; D011994:Recombinant Proteins; C067704:neutrophil-specific antigen NA1, human; C072753:neutrophil-specific antigen NA2; D016179:Granulocyte Colony-Stimulating Factor",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000014279",
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"issn_linking": "0006-3126",
"issue": "78(4)",
"journal": "Biology of the neonate",
"keywords": null,
"medline_ta": "Biol Neonate",
"mesh_terms": "D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D007231:Infant, Newborn; D007234:Infant, Premature; D007518:Isoantibodies; D007519:Isoantigens; D007958:Leukocyte Count; D008297:Male; D009503:Neutropenia; D009504:Neutrophils; D011994:Recombinant Proteins",
"nlm_unique_id": "0247551",
"other_id": null,
"pages": "277-80",
"pmc": null,
"pmid": "11093006",
"pubdate": "2000-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Transient effect of granulocyte colony-stimulating factor in allo-immune neonatal neutropenia.",
"title_normalized": "transient effect of granulocyte colony stimulating factor in allo immune neonatal neutropenia"
} | [
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{
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}
],
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},
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{
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{
"abstract": "His neurologic exam was normal. Family history was positive for a cousin with narcolepsy but negative for seizures and obstructive sleep apnea. Polysomnography revealed moderate OSA with minimal oxygen desaturation. Inpatient video EEG monitoring captured several of the events that the patient and his wife had described; the patient seemed \"uninhibited\" in his behavior. His EEG, cardiac telemetry, oxygen saturation, blood pressure, and serum glucose level remained normal.",
"affiliations": "Department of Neurology, Georgetown University Hospital, Washington, DC USA. Email: motamedi@georgetown.edu.;Department of Medicine, Georgetown University Hospital, Washington, DC USA.",
"authors": "Motamedi|Gholam K|GK|;Wheeler|Margot G|MG|",
"chemical_list": "D006993:Hypnotics and Sedatives; D011725:Pyridines; D000077334:Zolpidem",
"country": "United States",
"delete": false,
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"issn_linking": "0094-3509",
"issue": "64(2)",
"journal": "The Journal of family practice",
"keywords": null,
"medline_ta": "J Fam Pract",
"mesh_terms": "D003221:Confusion; D003937:Diagnosis, Differential; D006801:Humans; D006993:Hypnotics and Sedatives; D008297:Male; D008508:Medication Errors; D001523:Mental Disorders; D008875:Middle Aged; D011725:Pyridines; D012892:Sleep Deprivation; D000077334:Zolpidem",
"nlm_unique_id": "7502590",
"other_id": null,
"pages": "92-6",
"pmc": null,
"pmid": "25671536",
"pubdate": "2015-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Daily episodes of confusion · altered behavior · chronic sleep deprivation · Dx?",
"title_normalized": "daily episodes of confusion altered behavior chronic sleep deprivation dx"
} | [
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"drugindication": "HYPERLIPIDAEMIA",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "SIMVASTATIN."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ZOLPIDEM TARTRATE"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": "077884",
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugdosageform": "TABLET",
"drugdosagetext": "12.5 MG, UNK",
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"drugindication": "DRUG DISPENSING ERROR",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
"drugrecurrence": null,
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"drugstructuredosagenumb": "12.5",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "ZOLPIDEM TARTRATE EXTENDED-RELEASE TABLETS"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LISINOPRIL"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "TABLET",
"drugdosagetext": null,
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "LISINOPRIL."
}
],
"patientagegroup": null,
"patientonsetage": "60",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug dispensing error",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Confusional state",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Abnormal behaviour",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Sleep attacks",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MOTAMEDI GK, WHEELER MG.. DAILY EPISODES OF CONFUSION - ALTERED BEHAVIOR - CHRONIC SLEEP DEPRIVATION - DX?.. J-FAM-PRACT. 2015?64(2):92-96",
"literaturereference_normalized": "daily episodes of confusion altered behavior chronic sleep deprivation dx",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20151104",
"receivedate": "20151104",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 11697034,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 2,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20160304"
}
] |
{
"abstract": "We aimed to determine the prevalence and incidence, and to identify the factors associated with liver abnormalities in patients with psoriatic arthritis (PsA).\n\n\n\nFrom a longitudinal cohort study, we identified PsA patients with either elevated serum transaminase or alkaline phosphatase levels or liver disease after the first visit to the PsA clinic (cases). Controls were subjects from the same cohort who never had such abnormalities or liver disease. Cases and controls were matched 1:1 by sex, age at the first clinic visit, and followup duration; variables at the onset of the first appearance of liver test abnormality associated with liver abnormalities were identified using univariate logistic and multivariate logistic regression analyses.\n\n\n\nAmong 1061 patients followed in the PsA clinic, 343 had liver abnormalities. Two hundred fifty-six patients who developed liver abnormalities after the first visit were identified as cases, and 718 patients were identified as controls. The prevalence of liver abnormalities was 32% and the incidence was 39/1000 patient-years where there were 256 cases over 6533 total person-years in the PsA cohort. Liver abnormalities were detected after a mean (SD) followup duration of 8.3 ± 7.8 years. The common causes of liver abnormalities were drug-induced hepatitis and fatty liver. Independent factors associated with liver abnormalities were higher body mass index (BMI), daily alcohol intake, higher damaged joint count, elevated C-reactive protein, and use of methotrexate, leflunomide, or tumor necrosis factor inhibitors.\n\n\n\nLiver abnormalities are common among patients with PsA and are associated with higher BMI, more severe disease, and certain therapies.",
"affiliations": "From the Psoriatic Arthritis Program, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University Health Network, Toronto; Department of Statistics and Actuarial Science, University of Waterloo, Waterloo; University of Toronto, Department of Medicine, Division of Rheumatology, University of Toronto, Toronto; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Rheumatic Disease Unit, Department of Internal Medicine, Phramongkutlao Hospital and College of Medicine, Bangkok, Thailand.;From the Psoriatic Arthritis Program, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University Health Network, Toronto; Department of Statistics and Actuarial Science, University of Waterloo, Waterloo; University of Toronto, Department of Medicine, Division of Rheumatology, University of Toronto, Toronto; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Rheumatic Disease Unit, Department of Internal Medicine, Phramongkutlao Hospital and College of Medicine, Bangkok, Thailand.;From the Psoriatic Arthritis Program, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University Health Network, Toronto; Department of Statistics and Actuarial Science, University of Waterloo, Waterloo; University of Toronto, Department of Medicine, Division of Rheumatology, University of Toronto, Toronto; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Rheumatic Disease Unit, Department of Internal Medicine, Phramongkutlao Hospital and College of Medicine, Bangkok, Thailand.;From the Psoriatic Arthritis Program, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University Health Network, Toronto; Department of Statistics and Actuarial Science, University of Waterloo, Waterloo; University of Toronto, Department of Medicine, Division of Rheumatology, University of Toronto, Toronto; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Rheumatic Disease Unit, Department of Internal Medicine, Phramongkutlao Hospital and College of Medicine, Bangkok, Thailand.;From the Psoriatic Arthritis Program, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University Health Network, Toronto; Department of Statistics and Actuarial Science, University of Waterloo, Waterloo; University of Toronto, Department of Medicine, Division of Rheumatology, University of Toronto, Toronto; Krembil Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; Rheumatic Disease Unit, Department of Internal Medicine, Phramongkutlao Hospital and College of Medicine, Bangkok, Thailand. Dafna.gladman@utoronto.ca.",
"authors": "Pakchotanon|Rattapol|R|;Ye|Justine Yang|JY|;Cook|Richard J|RJ|;Chandran|Vinod|V|;Gladman|Dafna D|DD|0000-0002-9074-0592",
"chemical_list": "D008727:Methotrexate",
"country": "Canada",
"delete": false,
"doi": "10.3899/jrheum.181312",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0315-162X",
"issue": "47(6)",
"journal": "The Journal of rheumatology",
"keywords": "BIOLOGICS; BODY MASS INDEX; DMARD; LIVER; PSORIATIC ARTHRITIS",
"medline_ta": "J Rheumatol",
"mesh_terms": "D015535:Arthritis, Psoriatic; D006801:Humans; D008107:Liver Diseases; D008137:Longitudinal Studies; D008727:Methotrexate",
"nlm_unique_id": "7501984",
"other_id": null,
"pages": "847-853",
"pmc": null,
"pmid": "31615918",
"pubdate": "2020-06-01",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Liver Abnormalities in Patients with Psoriatic Arthritis.",
"title_normalized": "liver abnormalities in patients with psoriatic arthritis"
} | [
{
"companynumb": "CA-PFIZER INC-2019469343",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IBUPROFEN"
},
"drugadditional": "1",
"drugadministrationroute": null,
"drugauthorizationnumb": "018989",
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"drugcharacterization": "1",
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"drugdosageform": null,
"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "PSORIATIC ARTHROPATHY",
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"medicinalproduct": "IBUPROFEN."
}
],
"patientagegroup": "5",
"patientonsetage": null,
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"reaction": [
{
"reactionmeddrapt": "Drug-induced liver injury",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "PAKCHOTANON, R.. LIVER ABNORMALITIES IN PATIENTS WITH PSORIATIC ARTHRITIS. THE JOURNAL OF RHEUMATOLOGY. 2020?47 (6):847-853",
"literaturereference_normalized": "liver abnormalities in patients with psoriatic arthritis",
"qualification": "1",
"reportercountry": "CA"
},
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"receiptdate": "20200625",
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},
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},
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200713"
}
] |
{
"abstract": "Carboxymethylcellulose (CMC) is a derivative of cellulose found in many food products, pharmaceuticals and cosmetics. Allergy to CMC in parenteral corticosteroid preparations leading to anaphylaxis is rare, but has previously been reported. We report a case of a 52-year-old woman with prurigo nodularis of Hyde, who reacted with anaphylaxis after intradermal injection of Kenalog 40 mg/ml. Allergy testing showed a positive skin prick test for CMC and the patient was advised to avoid future parenteral exposure to CMC. This case highlights the need to examine excipients in severe cases of drug allergy.",
"affiliations": "Hud- og Allergiafdeling, Gentofte Hospital, Niels Andersens Vej 65, 2900 Hellerup. martin.willy.meyer.01@regionh.dk.",
"authors": "Meyer|Martin Willy|MW|;Zachariae|Claus|C|;Garvey|Lene Heise|LH|",
"chemical_list": "D005938:Glucocorticoids; D014222:Triamcinolone Acetonide; D002266:Carboxymethylcellulose Sodium",
"country": "Denmark",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-5782",
"issue": "177(4)",
"journal": "Ugeskrift for laeger",
"keywords": null,
"medline_ta": "Ugeskr Laeger",
"mesh_terms": "D000707:Anaphylaxis; D002266:Carboxymethylcellulose Sodium; D004342:Drug Hypersensitivity; D005260:Female; D005938:Glucocorticoids; D006801:Humans; D007271:Injections, Intradermal; D008875:Middle Aged; D014222:Triamcinolone Acetonide",
"nlm_unique_id": "0141730",
"other_id": null,
"pages": "V10140532",
"pmc": null,
"pmid": "25613209",
"pubdate": "2015-01-19",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Anaphylactic shock after intradermal injection of corticosteroid.",
"title_normalized": "anaphylactic shock after intradermal injection of corticosteroid"
} | [
{
"companynumb": "DK-MYLANLABS-2017M1003913",
"fulfillexpeditecriteria": "1",
"occurcountry": "DK",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "TRIAMCINOLONE"
},
"drugadditional": "3",
"drugadministrationroute": "023",
"drugauthorizationnumb": "011601",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": "40 MG/ML, UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NEURODERMATITIS",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"medicinalproduct": "TRIAMCINOLONE"
}
],
"patientagegroup": null,
"patientonsetage": "52",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Anaphylactic reaction",
"reactionmeddraversionpt": "20.1",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MEYER MW, ZACHARIAE C, GARVEY LH. ANAPHYLACTIC SHOCK AFTER INTRADERMAL INJECTION OF CORTICOSTEROID. UGESKR-LAEG 2015;177(4):V10140532.",
"literaturereference_normalized": "anaphylactic shock after intradermal injection of corticosteroid",
"qualification": "3",
"reportercountry": "DK"
},
"primarysourcecountry": "DK",
"receiptdate": "20170906",
"receivedate": "20170125",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13151964,
"safetyreportversion": 3,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": 1,
"seriousnessother": 1,
"transmissiondate": "20171127"
}
] |
{
"abstract": "Reiter's syndrome is known to be a rare severe adverse of Bacillus Calmette-Guerin (BCG) therapy. We report five cases of patients with Reiter's syndrome following intravesical BCG therapy for bladder carcinoma, and review the clinical characteristics, treatments, and outcomes of these patients. Each patient developed polyarthritis after urinary tract symptoms, and developed conjunctivitis anywhere from the third to the eighth BCG induction cycle. One case presented a slight elevation of inflammatory responses in blood analysis, and the other four cases had a higher level of white blood cell (WBC) counts and C-reactive protein (CRP) values. WBC counts at the diagnosis of Reiter's syndrome had a positive correlation with the time from initial treatment to cure of the disease. In all cases, BCG therapy was discontinued, and non-steroidal anti-inflammatory drugs (NSAIDs), oral steroids, and anti-tuberculosis drugs were administered. Anti-rheumatic drugs were not used in these cases. Improvement of symptoms was reported from 1 to 13 months after initial treatment. No patients had recurrence of Reiter's syndrome, whereas 2 patients had alternative treatment 2 and 18 months later, respectively, because of cancer recurrence. For cases with conjunctivitis and joint pain occurring during intravesical BCG therapy, early clinical interventions such as NSAIDs, steroids, and anti-tuberculosis drugs should be introduced, especially in cases with a high level of inflammatory changes in blood analysis.",
"affiliations": "1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;Department of Urology, Komatsu City Hospital, Komatsu, Japan.;Department of Urology, Komatsu City Hospital, Komatsu, Japan.;1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.;1Department of Integrative Cancer Therapy and Urology, Kanazawa University Graduate School of Medical Science, 13-1, Takaramachi, Kanazawa, Ishikawa 920-8641 Japan.",
"authors": "Nakagawa|Tomomi|T|;Shigehara|Kazuyoshi|K|;Naito|Renato|R|;Yaegashi|Hiroshi|H|;Nakashima|Kazufumi|K|;Iijima|Masashi|M|;Kawaguchi|Shohei|S|;Nohara|Takahiro|T|;Kitagawa|Yasuhide|Y|;Izumi|Kouji|K|;Kadono|Yoshifumi|Y|;Mizokami|Atsushi|A|",
"chemical_list": null,
"country": "Singapore",
"delete": false,
"doi": "10.1007/s13691-018-0342-1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2192-3183",
"issue": "7(4)",
"journal": "International cancer conference journal",
"keywords": "Bacillus Calmette-Guerin; Bladder carcinoma; Reiter’s syndrome",
"medline_ta": "Int Cancer Conf J",
"mesh_terms": null,
"nlm_unique_id": "101734231",
"other_id": null,
"pages": "148-151",
"pmc": null,
"pmid": "31149535",
"pubdate": "2018-10",
"publication_types": "D002363:Case Reports",
"references": "11334488;16220289;16461205;17028812;22377450;23816569;26717781;27052489;27376122;27825571;28889718;3511286",
"title": "Reiter's syndrome following intravesical Bacillus Calmette-Guerin therapy for bladder carcinoma: a report of five cases.",
"title_normalized": "reiter s syndrome following intravesical bacillus calmette guerin therapy for bladder carcinoma a report of five cases"
} | [
{
"companynumb": "JP-SA-2018SA285277",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
"drugadditional": null,
"drugadministrationroute": "043",
"drugauthorizationnumb": "103943",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
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"drugdosagetext": "1 UNK",
"drugenddate": null,
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"medicinalproduct": "BCG FOR IMMUNOTHERAPY"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
"drugadditional": null,
"drugadministrationroute": "043",
"drugauthorizationnumb": "103943",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "1 UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "BLADDER CANCER",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "BCG FOR IMMUNOTHERAPY"
}
],
"patientagegroup": "5",
"patientonsetage": "63",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Reiter^s syndrome",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Polyarthritis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Dysuria",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Conjunctivitis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "NAKAGAWA T., SHIGEHARA K., NAITO R., YAEGASHI H., NAKASHIMA K., IIJIMA M., ETAL. REITER^S SYNDROME FOLLOWING INTRAVESICAL BACILLUS CALMETTE-GUERIN THERAPY FOR BLADDER CARCINOMA: A REPORT OF FIVE CASES. INTERNATIONAL CANCER CONFERENCE JOURNAL. 2018?7:148-151",
"literaturereference_normalized": "reiter s syndrome following intravesical bacillus calmette guerin therapy for bladder carcinoma a report of five cases",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20181018",
"receivedate": "20181018",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15526174,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190205"
},
{
"companynumb": "JP-SA-2018SA285284",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "BACILLUS CALMETTE-GUERIN ANTIGEN, UNSPECIFIED SUBSTRAIN"
},
"drugadditional": "3",
"drugadministrationroute": "043",
"drugauthorizationnumb": "103943",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "6 UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": null,
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": null,
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{
"abstract": "BACKGROUND\nBefore introduction of tenofovir/emtricitabine/efavirenz (TDF/FTC/EFV), 3-drug antiretroviral therapy (ART) was associated with increased adverse birth outcomes when used for prevention of mother-to-child HIV transmission (PMTCT) in Botswana.\n\n\nMETHODS\nWe extracted obstetric records from all women at the 2 largest maternities in Botswana from 2009-2011 when Botswana National Guidelines recommended zidovudine (ZDV) from 28 weeks gestational age (GA) for CD4 ≥350 and ART for CD4 <350, and again in 2013-2014 after implementation of TDF/FTC/EFV for prevention of mother-to-child HIV transmission regardless of CD4 or GA. We compared the use of TDF/FTC/EFV in pregnancy with other 3-drug ART regimens, and with initiation of ZDV, among women with similar CD4 cell counts. Outcomes included small for gestational age (SGA), preterm delivery (PTD) (<37 weeks GA), and stillbirths (SB).\n\n\nRESULTS\nAmong 9445 HIV-infected women delivering during the study period, 170 were on TDF/FTC/EFV at conception and 1468 initiated TDF/FTC/EFV during pregnancy. Adverse birth outcomes were high overall (3% SB, 21% PTD, and 18% SGA) and among women receiving TDF/FTC/EFV (3% SB, 22% PTD, and 12% SGA). There was no difference in PTD or SB among women initiating TDF/FTC/EFV compared with ZDV or other 3-drug ART, but initiating TDF/FTC/EFV was associated with fewer SGA infants than other 3-drug ART (adjusted odds ratio: 0.4, 95% confidence interval: 0.2 to 0.7).\n\n\nCONCLUSIONS\nAdverse birth outcomes remain high among HIV-infected women. TDF/FTC/EFV was at least as safe as other ART and associated with fewer SGA infants when initiated during pregnancy. Larger studies are needed to evaluate birth outcomes and congenital abnormalities among women on TDF/FTC/EFV at conception.",
"affiliations": "*Beth Israel Deaconess Medical Center, Boston, MA; †Botswana Harvard AIDS Institute Partnership, Gaborone, Botswana; ‡Harvard School of Public Health, Boston, MA; §Faculty of Health Sciences, University of Botswana, Gaborone, Botswana; ‖Massachusetts General Hospital, Boston, MA; and ¶Brigham and Women's Hospital, Boston, MA.",
"authors": "Zash|Rebecca|R|;Souda|Sajini|S|;Chen|Jennifer Y|JY|;Binda|Kelebogile|K|;Dryden-Peterson|Scott|S|;Lockman|Shahin|S|;Mmalane|Mompati|M|;Makhema|Joseph|J|;Essex|Max|M|;Shapiro|Roger|R|",
"chemical_list": "D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D003521:Cyclopropanes; D000068698:Tenofovir; D000068679:Emtricitabine; C098320:efavirenz",
"country": "United States",
"delete": false,
"doi": "10.1097/QAI.0000000000000847",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-4135",
"issue": "71(4)",
"journal": "Journal of acquired immune deficiency syndromes (1999)",
"keywords": null,
"medline_ta": "J Acquir Immune Defic Syndr",
"mesh_terms": "D000328:Adult; D000480:Alkynes; D019380:Anti-HIV Agents; D048588:Benzoxazines; D001902:Botswana; D003521:Cyclopropanes; D004359:Drug Therapy, Combination; D000068679:Emtricitabine; D005260:Female; D015658:HIV Infections; D006801:Humans; D007231:Infant, Newborn; D018445:Infectious Disease Transmission, Vertical; D011247:Pregnancy; D000068698:Tenofovir",
"nlm_unique_id": "100892005",
"other_id": null,
"pages": "428-36",
"pmc": null,
"pmid": "26379069",
"pubdate": "2016-04-01",
"publication_types": "D016428:Journal Article",
"references": "23066160;22384039;23846560;25030058;17597712;22176889;25030057;11590515;22460969;19273671;17314523;18753864;17057609;19214117;23043067;21237718;17299724;22892835;15752534;16327320;22910324;19424054;17624841;20032533;17079992;16421366;23358421;23317954;22253579;24069778;23351797;18370438;17457096",
"title": "Reassuring Birth Outcomes With Tenofovir/Emtricitabine/Efavirenz Used for Prevention of Mother-to-Child Transmission of HIV in Botswana.",
"title_normalized": "reassuring birth outcomes with tenofovir emtricitabine efavirenz used for prevention of mother to child transmission of hiv in botswana"
} | [
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{
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{
"abstract": "OBJECTIVE\nIn the fall of 2013, the US Centers for Disease Control and Prevention (CDC) published a preliminary report on a cluster of liver disease cases that emerged in Hawaii in the summer 2013. This report claimed a temporal association as sufficient evidence that OxyELITE Pro (OEP), a dietary supplement (DS) mainly for weight loss, was the cause of this mysterious cluster. However, the presented data were inconsistent and required a thorough reanalysis.\n\n\nMETHODS\nTo further investigate the cause(s) of this cluster, we critically evaluated redacted raw clinical data of the cluster patients, as the CDC report received tremendous publicity in local and nationwide newspapers and television. This attention put regulators and physicians from the medical center in Honolulu that reported the cluster, under enormous pressure to succeed, risking biased evaluations and hasty conclusions.\n\n\nRESULTS\nWe noted pervasive bias in the documentation, conclusions, and public statements, also poor quality of case management. Among the cases we reviewed, many causes unrelated to any DS were evident, including decompensated liver cirrhosis, acute liver failure by acetaminophen overdose, acute cholecystitis with gallstones, resolving acute hepatitis B, acute HSV and VZV hepatitis, hepatitis E suspected after consumption of wild hog meat, and hepatotoxicity by acetaminophen or ibuprofen. Causality assessments based on the updated CIOMS scale confirmed the lack of evidence for any DS including OEP as culprit for the cluster.\n\n\nCONCLUSIONS\nThus, the Hawaii liver disease cluster is now best explained by various liver diseases rather than any DS, including OEP.",
"affiliations": "Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/ Main, Germany.;Institute of Industrial, Environmental and Social Medicine, Medical Faculty, Goethe University Frankfurt/Main, Germany.;Institute of Industrial, Environmental and Social Medicine, Medical Faculty, Goethe University Frankfurt/Main, Germany.;Institute of Industrial, Environmental and Social Medicine, Medical Faculty, Goethe University Frankfurt/Main, Germany.;Department of Internal Medicine II, Division of Gastroenterology and Hepatology, Klinikum Hanau, Teaching Hospital of the Medical Faculty, Goethe University Frankfurt/ Main, Germany.;Department of Internal Medicine II, Division of Gastroenterology, Hepatology and Infectious Diseases, Friedrich Schiller University Jena, Germany.",
"authors": "Teschke|Rolf|R|;Schwarzenboeck|Alexander|A|;Frenzel|Christian|C|;Schulze|Johannes|J|;Eickhoff|Axel|A|;Wolff|Albrecht|A|",
"chemical_list": "D019440:Anti-Obesity Agents",
"country": "Mexico",
"delete": false,
"doi": "10.5604/16652681.1184237",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1665-2681",
"issue": "15(1)",
"journal": "Annals of hepatology",
"keywords": null,
"medline_ta": "Ann Hepatol",
"mesh_terms": "D000328:Adult; D019440:Anti-Obesity Agents; D015982:Bias; D002487:Centers for Disease Control and Prevention, U.S.; D056486:Chemical and Drug Induced Liver Injury; D016000:Cluster Analysis; D000068598:Data Accuracy; D016208:Databases, Factual; D019587:Dietary Supplements; D005260:Female; D006254:Hawaii; D006801:Humans; D008107:Liver Diseases; D008297:Male; D008875:Middle Aged; D033262:Narration; D011379:Prognosis; D012107:Research Design; D012189:Retrospective Studies; D018570:Risk Assessment; D012307:Risk Factors; D012621:Seasons; D013997:Time Factors; D014481:United States",
"nlm_unique_id": "101155885",
"other_id": null,
"pages": "91-109",
"pmc": null,
"pmid": "26626645",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "The mystery of the Hawaii liver disease cluster in summer 2013: A pragmatic and clinical approach to solve the problem.",
"title_normalized": "the mystery of the hawaii liver disease cluster in summer 2013 a pragmatic and clinical approach to solve the problem"
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"abstract": "Background: Lichen planus is a chronic mucocutaneous inflammatory disease. Oral manifestations are common, and may remain exclusive to the oral mucosa without involvement of the skin or other mucosae. A differential diagnosis includes oral lichenoid drug reactions. Allopurinol, which is the first line hypo-uricemic treatment, is often quoted as being a possible offending drug, though oral reactions have rarely been reported. Case presentation: We describe a 59-year-old male gout patient, successfully treated with allopurinol, who developed acute onset of oral lichenoid lesions, involving bilaterally the buccal mucosa, the tongue and the labial mucosa. Histopathology was consistent with a lichen planus or a drug-induced lichenoid reaction. Improvement of the patient's condition after withdrawal of allopurinol confirmed the lichenoid nature of the lesion. Remission was complete after a few weeks. Discussion: Although unusual, allopurinol may induce a lichenoid drug reaction. These reactions may mimic clinically and histopathologically idiopathic lichen planus. Improvement or complete regression of the lesions may be attempted to confirm the diagnosis. According to the latest WHO recommendations, these lesions have a potential for malignant transformation.",
"affiliations": "Unit of Oral Medicine and Pathology, Division of Oral Maxillofacial Surgery, Department of Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland.;Unit of Oral Medicine and Pathology, Division of Oral Maxillofacial Surgery, Department of Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland.;Unit of Oral Medicine and Pathology, Division of Oral Maxillofacial Surgery, Department of Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland.;Unit of Oral Medicine and Pathology, Division of Oral Maxillofacial Surgery, Department of Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland.",
"authors": "Perez|Alexandre|A|;Lazzarotto|Benjamin|B|;Carrel|Jean-Pierre|JP|;Lombardi|Tommaso|T|0000-0001-9347-3736",
"chemical_list": null,
"country": "Switzerland",
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"doi": "10.3390/dermatopathology7020004",
"fulltext": "\n==== Front\nDermatopathology (Basel)\nDermatopathology (Basel)\ndermatopathology\nDermatopathology\n2296-3529 MDPI \n\n32806618\n10.3390/dermatopathology7010004\ndermatopathology-07-00004\nCase Report\nAllopurinol-Induced Oral Lichenoid Drug Reaction with Complete Regression after Drug Withdrawal\nPerez Alexandre † Lazzarotto Benjamin † Carrel Jean-Pierre https://orcid.org/0000-0001-9347-3736Lombardi Tommaso * Unit of Oral Medicine and Pathology, Division of Oral Maxillofacial Surgery, Department of Surgery, University Hospitals of Geneva, 1205 Geneva, Switzerland; alexandre.perez@hcuge.ch (A.P.); benjamin.lazzarotto@hcuge.ch (B.L.); jean-pierre.carrel@unige.ch (J.-P.C.)\n* Correspondence: tommaso.lombardi@hcuge.ch; Tel.: +41-79 553-32-06† These authors are considered equally as co-First authors.\n\n\n12 8 2020 \n9 2020 \n7 2 18 25\n15 6 2020 10 8 2020 © 2020 by the authors.2020Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).Background: Lichen planus is a chronic mucocutaneous inflammatory disease. Oral manifestations are common, and may remain exclusive to the oral mucosa without involvement of the skin or other mucosae. A differential diagnosis includes oral lichenoid drug reactions. Allopurinol, which is the first line hypo-uricemic treatment, is often quoted as being a possible offending drug, though oral reactions have rarely been reported. Case presentation: We describe a 59-year-old male gout patient, successfully treated with allopurinol, who developed acute onset of oral lichenoid lesions, involving bilaterally the buccal mucosa, the tongue and the labial mucosa. Histopathology was consistent with a lichen planus or a drug-induced lichenoid reaction. Improvement of the patient’s condition after withdrawal of allopurinol confirmed the lichenoid nature of the lesion. Remission was complete after a few weeks. Discussion: Although unusual, allopurinol may induce a lichenoid drug reaction. These reactions may mimic clinically and histopathologically idiopathic lichen planus. Improvement or complete regression of the lesions may be attempted to confirm the diagnosis. According to the latest WHO recommendations, these lesions have a potential for malignant transformation.\n\noral mucosalichen planuslichenoid reactionadverse drug reactionallopurinol\n==== Body\n1. Introduction\nLichen planus is a common chronic inflammatory disorder, affecting the skin, oral and genital mucosa, scalp and nails. Oral manifestations are frequent, and may remain exclusive to the oral cavity without involvement of other organs [1].\n\nTo the contrary of cutaneous lichen planus, oral lichen planus is a long-term chronic disease with a dynamic evolution, as a result of successive waves of variably destructive activity at the epithelium–chorion interface. Thus, progressive changes of the clinical and histopathological aspects occur over time, increasing the number of possible clinical presentations, going from white keratotic dots to mucosal atrophy and hyperkeratosis in the late stage. The most characteristic and easily recognized clinical aspect being the reticular form [2].\n\nOral lichenoid drug reactions are a connected entity, the term referring to a lichen planus-like rash triggered by systemic drug exposure. Allopurinol stands beside many classes of drugs involved, such as nonsteroidal anti-inflammatory drugs (NSAIDs), B-blockers, ACE inhibitors, thiazide diuretics as well as some antibiotics [3]. This anti-gout drug is often quoted but only a few reports are described in the literature.\n\nThis article reports a clinically and histopathologically detailed case of oral lichenoid lesions associated with allopurinol therapy, that showed complete regression after the withdrawal of the drug.\n\n2. Case Presentation\nA 59-year-old man was referred due to a 4-week history of severe pain within the oral cavity. The patient give written consent for publication. Medical history revealed skin psoriasis diagnosed with a biopsy more than 30 years ago, which has since been treated by calcipotriol betamethasone gel (Daivobet®, LEO Pharmaceutical Products Ltd., Regensdorf, Switzerland) intermittently depending on the evolution of the lesions. Otherwise, the patient suffered episodic gout attacks for which he was under allopurinol for one month prior to consultation. On examination, he had multiple keratinized lesions in plaque form, involving the bilateral buccal and lingual mucosae, with some erythematous streaks and ulcerated areas (Figure 1).\n\nA biopsy of the right buccal mucosa was performed. Histopathological examination revealed a stratified squamous epithelium with focal atrophy and discreet parakeratosis. The superficial chorion contained a band-like dense inflammatory infiltrate, composed mostly of lymphocytes and macrophages, with very rare eosinophils. Apoptotic keratinocytes in the basal layer were observed (Figure 2a,b). These features were consistent with an active lichen planus or a drug-induced lichenoid reaction.\n\nGiven the suspected allopurinol involvement, the medication was withdrawn and not substituted in agreement with his general practitioner. Three weeks after discontinuation, significant regression of the lesions was observed and the patient no longer had any symptoms. The one-year postoperative examination revealed a thin keratosis of the buccal mucosa and a discreet depapillation of the dorsolingual mucosa. Follow-up after 3 years showed complete healing (Figure 3).\n\n3. Discussion\nGout is the most common form of arthritis in men over the age of 40 and its incidence keeps on increasing [4,5]. Allopurinol is an effective urate-lowering drug, working as a xanthine oxidase inhibitor. It is considered as the first line preventative treatment of chronic gout worldwide. Some infrequent adverse events are well described, mainly the hypersensitivity syndrome. Skin reactions may occur in approximately 2% of patients. Most cutaneous reactions are maculo-papular eruptions; however, severe reactions, such as toxic epidermal necrolysis, are also documented [6].\n\nOral manifestations in the form of lichenoid lesions, although frequently quoted, are rare, and have only been reported twice in the literature [7,8] (see Table 1). The clinical presentation in all reported cases was painful oral ulcerations. Patients were 1 female and 3 males, and patient age ranged from 53 to 75 years. Lesions were described as white striae, white plaques, along with erosions and ulcerations. All lesions were present bilaterally on the buccal mucosa, on the borders of the tongue, and in two cases on the mucosa of the lower lip. Clinical impression, in all reported cases, was that of erosive lichen planus. A biopsy was performed in only one case [7]. The latter was said to be consistent with lichen planus without further details.\n\nIn our case, the patient complained of pain and the buccal mucosa and tongue were affected, with erosions on the former. Histologically, our case showed a lichenoid aspect although indistinguishable from an idiopathic lichen planus. The presence of parakeratosis is not helpful in oral lesions and eosinophils were very rare, differently to drug-induced skin lesions.\n\nThe diagnosis of drug-induced lichenoid lesions may be difficult, as it may share a similar aspect to those found in the idiopathic oral lichen planus, both clinically and histopathologically. It is important to make the difference between the two conditions, because lichen planus is usually treated by corticosteroids or immunomodulatory agents, whereas drug-induced lichenoid lesions are treated by the withdrawal of the offending agent.\n\nThe difficulty of diagnosis also lies in the fact that cutaneous and/or oral lesions may occur after a variable latency period from the introduction of the offending drug [3]. In the present case, a few weeks of allopurinol therapy were sufficient to observe oral lesions, which is consistent with the two previous reports.\n\nOur diagnosis was conducted according to the updated French drug reaction assessment of imputability criteria [9]. In the present case, the chronological score was 3 (C3) whereas the semiological score was 2 (S2). Therefore, intrinsic imputability score was 5 (I5), and extrinsic imputability score was 2 (B2) considering the bibliographical data. Imputability of allopurinol on the basis of the obtained score was consistent.\n\nThe resolution after drug withdrawal seems to be spread over a variable period of time, and the literature is evasive about the degree of regression that the clinician can expect. In the present case, complete healing was observed at the 3-year follow-up. For other drugs, some authors suggest a time frame of up to 24 months before full resolution, depending on the initial extension of the lesions, their severity or the drug incriminated [3,10].\n\nAlthough the World Health Organization (WHO) classifies oral lichen planus as a precancerous disease, incidence of malignant transformation is still a matter of discussion. Discrepancies in studies may stem from variations in diagnostic criteria, insufficient knowledge or recognition of the late stage of the disease (post-lichen state), confusion with other keratotic and/or atrophic lesions, poor detection of early dysplastic changes, and too short follow-up periods in prospective studies. The latest systematic review assessed an overall transformation rate of 1.40% [11], but this was probably underestimated if one takes into account the previously discussed limitations. Nowadays, the WHO and some authors consider lichenoid reactions to have a malignant potential [3,12]. However, the exact transformation rate is unknown since diagnostic criteria are not always clear-cut. Further studies are necessary to elucidate the true premalignant role of such lesions.\n\n4. Conclusions\nThe purpose of this article is to report an unusual case of drug-induced reaction of the oral mucosa, induced by allopurinol, for which a complete healing was obtained after withdrawal of the drug. Clinicians must be aware of the recognition and management of oral lichenoid drug reactions. The diagnosis may be difficult, since a great overlap in clinical and histopathological presentation with oral idiopathic lichen planus exists. Although a matter of controversy, diagnosis and follow-up of these lichenoid lesions seems all the more important due to potential malignant transformation.\n\nAuthor Contributions\nConceptualization, A.P., B.L. and T.L.; writing—review and editing, A.P., B.L. and T.L.; patient management, J.-P.C. All authors have read and agreed to the published version of the manuscript.\n\nFunding\nThis research received no external funding. \n\nConflicts of Interest\nThe authors declare no conflict of interest. \n\nFigure 1 (a) Keratotic lesions involving the right buccal mucosa and the lower lip, with focal erythema and an ulcerated area. (b) Keratotic lesions involving the lateral border of the tongue, and the median anterior area. (c) Keratotic lesions of the left buccal mucosa and lip.\n\nFigure 2 (a) Histopathological section showing parakeratotic partly atrophic squamous epithelium with a band-like dense inflammatory infiltrate in the superficial chorion (HE stain, ×10). (b) Higher magnification showing inflammatory lymphocytic infiltrate and apoptotic bodies in the basal layer (HE stain, ×40).\n\nFigure 3 (a–c) Three-year follow-up showing complete healing of the right buccal mucosa and the lower lip (a), the lateral border of the tongue (b), and the left buccal mucosa and lip (c).\n\ndermatopathology-07-00004-t001_Table 1Table 1 Clinical and histopathological characteristics of allopurinol-induced oral lesions in patients reported in 3 publications.\n\n\n\tClinical Features\tAllopurinol Indication\tHistopathological Features\tOutcomes\t\nChau et al. \n1984 [7]\tM, Caucasian, \n53 y\tUlcerations\nKeratotic striae and plaques\tGout\tNo biopsy\tHealing of ulcers\nPersistence of the keratosis\t\nM, Caucasian, \n56 y\tUlcerations on the lip, buccal mucosa and tongue\tGout\tNo biopsy \tHealing of ulcers\nPersistence of the keratosis\t\nM, Caucasian, \n60 y\tUlcerations\nKeratotic striae on the lip, buccal mucosa and tongue\tGout\tLP versus lichenoid reaction\tPersistence of minor ulcerations \t\nNair et al. \n2005 [8]\tF, Chinese,\n75 y\tErosions and ulcerations\nKeratotic striae and plaques on the buccal mucosa and tongue\tGout\tNo biopsy\tResolution of erosions\nPersistence of faint keratosis\t\nPresent case\tM, Caucasian, \n59 y\tBuccal ulceration\nKeratotic striae on the lip, buccal mucosa and tongue\tGout\tLP versus lichenoid reaction\tComplete healing\n==== Refs\nReferences\n1. Saurat J.-H. Lipsker D. Thomas L. Borradori L. Lachapelle J.-M. Dermatologie Et Infections Sexuellement Transmissibles 6th ed. Elsevier-Masson Paris, France 2017 \n2. Lombardi T. Küffer R. Concept actuel du lichen plan oral. Le diagnostic facile au début, peut devenir très difficile dans les lichens anciens La Presse Médicale 2016 45 227 239 10.1016/j.lpm.2015.10.012 26597583 \n3. Cheng Y.-S.L. Gould A. Kurago Z. Fantasia J. Muller S. Diagnosis of oral lichen pla-nus: A position paper of the American Academy of Oral and Maxillofacial Pathology Oral Surg. Oral Med. Oral Pathol. Oral Radiol. 2016 122 332 354 10.1016/j.oooo.2016.05.004 27401683 \n4. Seth R. Kydd A.S. Buchbinder R. Bombardier C. Edwards C.J. Allopurinol for chronic gout Cochrane Database Syst. Rev. 2014 10.1002/14651858.CD006077.pub3 25314636 \n5. Smith E.U.R. Díaz-Torné C. Perez-Ruiz F. March L.M. Epidemiology of gout: An up-date Best Pract. Res. Clin. Rheumatol. 2010 24 811 827 10.1016/j.berh.2010.10.004 21665128 \n6. Atzori L. Pinna A.L. Mantovani L. Ferreli C. Pau M. Mulargia M. Aste N. Cutaneous adverse drug reactions to allopurinol: 10 year observational survey of the dermatology de-partment—Cagliari University (Italy) J. Eur. Acad. Dermatol. Venereol. 2011 26 1424 1430 10.1111/j.1468-3083.2011.04313.x 22017528 \n7. Chau N.Y. Reade P.C. Rich A.M. Hay K.D. Allopurinol-amplified lichenoid reactions of the oral mucosa Oral Surg. Oral Med. Oral Pathol. 1984 58 397 400 10.1016/0030-4220(84)90331-1 6593665 \n8. Nair R.G. Newsome P.R.H. Itthagarun A. Samaranayake L.P. Severe oral erosive lichen planus due to methyldopa and allopurinol: A case report Hong Kong Dent. J. 2005 2 122 125 \n9. Arimone Y. Bidault I. Dutertre J.-P. Gérardin M. Guy C. Haramburu F. Hillaire-Buys D. Meglio C. Penfornis C. Réactualisation de la méthode française d’imputabilité des effets indésirables des médicaments Therapie 2011 66 517 525 10.2515/therapie/2011073 22186077 \n10. Halevy S. Shai A. Lichenoid drug eruptions J. Am. Acad. Dermatol. 1993 29 249 255 10.1016/0190-9622(93)70176-T 8335745 \n11. Giuliani M. Troiano G. Cordaro M. Corsalini M. Gioco G. Muzio L.L. Pignatelli P. Lajolo C. Rate of malignant transformation of oral lichen planus: A systematic review Oral Dis. 2019 25 693 709 10.1111/odi.12885 29738106 \n12. Van der Meij E.H. Mast H. van der Waal I. The possible premalignant character of oral lichen planus and oral lichenoid lesions: A prospective five-year follow-up study of 192 patients Oral Oncol. 2007 43 742 748 10.1016/j.oraloncology.2006.09.006 17112770\n\n",
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"issn_linking": "2296-3529",
"issue": "7(2)",
"journal": "Dermatopathology (Basel, Switzerland)",
"keywords": "adverse drug reaction; allopurinol; lichen planus; lichenoid reaction; oral mucosa",
"medline_ta": "Dermatopathology (Basel)",
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"abstract": "Invasive pulmonary aspergillosis (IPA) is a rare pathology with increasing incidence mainly in critical care settings and recently in immunocompetent patients. The mortality of the disease is very high, regardless of an early diagnosis and aggressive treatment. Here, we report a case of a 56 yr old previously healthy woman who was found unconscious at home and admitted to the emergency room with mild respiratory insufficiency. In the first 24 hours she developed an acute respiratory failure with new radiographic infiltrates requiring Intensive Care Unit admission. A severe obstructive pattern with impossibility of ventilation because of bilateral atelectasis was observed, requiring emergent venovenous extracorporeal membrane oxygenator device insertion. Bronchoscopy revealed occlusion of main bronchi, demonstrating by biopsy an invasive infection by Aspergillus fumigatus and A. flavus. Despite an aggressive treatment and vital support the patient had a fatal outcome. The forensic study confirms the diagnosis of IPA but also revealed the presence of disseminated aspergillosis.",
"affiliations": "Intensive Care Unit, Bellvitge University Hospital, Feixa Llarga, S/N, Hospitalet de Llobregat, 08907 Barcelona, Spain.;Intensive Care Unit, Bellvitge University Hospital, Feixa Llarga, S/N, Hospitalet de Llobregat, 08907 Barcelona, Spain.;Bronchoscopy Department, Bellvitge University Hospital, Feixa Llarga, S/N, Hospitalet de Llobregat, 08907 Barcelona, Spain.;Forensic Laboratory, Institute of Legal Medicine of Catalunya, Gran Via de les Corts Catalanes 111, 08075 Barcelona, Spain.;Bronchoscopy Department, Bellvitge University Hospital, Feixa Llarga, S/N, Hospitalet de Llobregat, 08907 Barcelona, Spain.;Intensive Care Unit, Bellvitge University Hospital, Feixa Llarga, S/N, Hospitalet de Llobregat, 08907 Barcelona, Spain.",
"authors": "Moreno-González|Gabriel|G|;Ricart de Mesones|Antoni|A|;Tazi-Mezalek|Rachid|R|;Marron-Moya|Maria Teresa|MT|;Rosell|Antoni|A|;Mañez|Rafael|R|",
"chemical_list": "D000935:Antifungal Agents",
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"fulltext": "\n==== Front\nCan Respir JCan. Respir. JCRJCanadian Respiratory Journal1198-22411916-7245Hindawi Publishing Corporation 10.1155/2016/7984032Case ReportInvasive Pulmonary Aspergillosis with Disseminated Infection in Immunocompetent Patient Moreno-González Gabriel \n1\n\n*\nRicart de Mesones Antoni \n1\nTazi-Mezalek Rachid \n2\nMarron-Moya Maria Teresa \n3\nRosell Antoni \n2\nMañez Rafael \n1\n1Intensive Care Unit, Bellvitge University Hospital, Feixa Llarga, S/N, Hospitalet de Llobregat, 08907 Barcelona, Spain2Bronchoscopy Department, Bellvitge University Hospital, Feixa Llarga, S/N, Hospitalet de Llobregat, 08907 Barcelona, Spain3Forensic Laboratory, Institute of Legal Medicine of Catalunya, Gran Via de les Corts Catalanes 111, 08075 Barcelona, Spain*Gabriel Moreno-González: dr_gabrielmoreno@hotmail.comAcademic Editor: Elisa Giovannetti\n\n2016 5 5 2016 2016 79840323 8 2015 11 4 2016 17 4 2016 Copyright © 2016 Gabriel Moreno-González et al.2016This 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.Invasive pulmonary aspergillosis (IPA) is a rare pathology with increasing incidence mainly in critical care settings and recently in immunocompetent patients. The mortality of the disease is very high, regardless of an early diagnosis and aggressive treatment. Here, we report a case of a 56 yr old previously healthy woman who was found unconscious at home and admitted to the emergency room with mild respiratory insufficiency. In the first 24 hours she developed an acute respiratory failure with new radiographic infiltrates requiring Intensive Care Unit admission. A severe obstructive pattern with impossibility of ventilation because of bilateral atelectasis was observed, requiring emergent venovenous extracorporeal membrane oxygenator device insertion. Bronchoscopy revealed occlusion of main bronchi, demonstrating by biopsy an invasive infection by Aspergillus fumigatus and A. flavus. Despite an aggressive treatment and vital support the patient had a fatal outcome. The forensic study confirms the diagnosis of IPA but also revealed the presence of disseminated aspergillosis.\n==== Body\n1. Case Presentation\nA 56 yr old healthy woman was found at home in coma and with signs of long-standing immobilization such as pressure sores and dehydration. She had a history of 14-pack-year tobacco smoking and dyslipidemia treated with simvastatin 40 mg a day. There was no history of chronic pulmonary disease or other chronic diseases. Three days before admission she fell suffering mild head injury. The following day she was asymptomatic. After two days she was found in coma and delivered to the emergency room of our hospital. At hospital admission she had mild respiratory insufficiency with PaO2 : FIO2 ratio of 200 mmHg, bronchospasm, and mild depressed level of consciousness. Chest radiography was normal (Figure 1(a)(A)). Biochemical analysis at admission showed acute kidney injury with urea of 41 mmol/L (3.3–8 mmol/L), creatinine 120 μmol/L (0–85 μmol/L), and creatine phosphokinase of 15 mckat/L (0.05–2.3). The complete blood count showed hemoglobin of 16.6 g/L and 11,800 leucocytes, D-dimer of 680 mcg/L (<200), and normal clothing times. Brain computed tomography (CT) scan was performed and reported as normal and lumbar puncture revealed a normal cerebrospinal fluid. Thoracic CT scan ruled out pulmonary thromboembolism but a small lingula consolidation was observed (see Figure 1(a)(B)).\n\nInitial management included fluid reanimation with crystalloids, bronchodilators, and empiric antibiotics (amoxicillin/clavulanic acid) as suspicion of aspiration pneumonia. However, 24 hours later she developed severe mixed acute respiratory failure with severe hypoxemia (pO2 : FIO2 of 100 mmHg) and respiratory acidosis with pCO2 of 73 mmHg associated with new radiographic infiltrates (Figure 1(a)(C)), requiring admission to the Intensive Care Unit (ICU), emergent orotracheal intubation, and initiation of invasive mechanical ventilation. A severe obstructive pattern was observed with impossibility of ventilation and chest radiography revealed complete bilateral infiltrates (Figure 1(a)(D)). The patient persisted with severe respiratory insufficiency. Prone positioning was not effective and an ECMO was inserted within the first 24 hr. of ICU admission. Fiber-optic bronchoscopy showed a large quantity of necrotic material at the distal bronchial tree, with impossibility of progress with the bronchoscope to subsegmental bronchi (Figure 1(b)). The serology was positive for galactomannan whereas histologic studies and culture of three different samples of the mucosa revealed Aspergillus fumigatus and Aspergillus flavus. We started intravenous voriconazole, caspofungin, and nebulized liposomal amphotericin. One week later the patient presented hemodynamic instability, worsening renal function and progressive multiorgan failure, and death. A forensic autopsy was performed showing invasive pulmonary aspergillosis (IPA) with disseminated infection involving lungs (bilateral necrotizing pneumonia), brain (necrotic and hemorrhagic spots suggesting septic emboli), heart, and kidneys (see Figure 2).\n\n2. Discussion\nThe IPA is a rare pathology and the most devastating form of Aspergillus infection, characterized by invasion and necrosis of lung parenchyma [1]. There are several recognized risk factors to develop IPA, most of them related to different types of immunodeficiencies [2]. Classical risk factors associated with IPA include systemic or local radiotherapy, chemotherapy, airway constriction, prior inhaled (more than 2 weeks) or systemic (more than 3 weeks) corticosteroid use, hypoproteinaemia, prior antibiotic therapy (more than 2 weeks), neutropenia (less than 500 neutrophils/mm3 for more than 10 days), and chronic granulomatous diseases [3]. The risk of IPA correlates with the duration and degree of neutropenia and is higher following allogenic rather than autologous hematopoietic stem cell transplantation. Also, patients with severe graft versus host disease after hematopoietic stem cell transplantation, after solid organ transplantation, CMV lung infection, and CD4 count less than 100 cells/mm3 have a higher incidence of IPA [2]. In all of these conditions, IPA has a significant mortality ranging from 50% in neutropenic patients to 90% in hematopoietic stem cell transplantation patients [3, 4].\n\nPatients admitted to ICU also showed an increased frequency of IPA (ranging from 0.33% to 6.9%) [3, 5]. Risk factors identified in ICU patients include chronic obstructive pulmonary disease, cirrhosis, solid organ transplantation, and severe sepsis [6].\n\nOther factors associated with IPA in ICU include severe burns, short steroid treatment (less than 7 days), prolonged ICU stay (more than 21 days), malnutrition, and postcardiac surgery status [7]. Here, we report a previously healthy patient who developed IPA without any evidence of risk factors for this condition. The presence of IPA in nonimmunocompromised patients is growing [8–10]. Most of the reports are single cases initially treated with empiric antibiotics because of mild symptoms, some receiving antituberculosis treatment due to atypical presentation and high frequency of tuberculosis in the region, until the diagnosis of IPA [11, 12]. More than half of immunocompetent patients with invasive aspergillosis have underlying diseases (tuberculosis infection, diabetes mellitus, bronchiectasis, pulmonary sequestration, solid cancer, or chronic liver disease) [13]. However, to our knowledge dehydration and acute kidney injury, the only factors identified in this case, are not associated with IPA. In some cases IPA is related to previous colonization of the bronchial tree leading to epithelial damage and invasion [2] or to heavy inoculum of Aspergillus [10]. There is no evidence that any of these two circumstances affected our patient.\n\nThe diagnosis of IPA remains challenging and a high index of suspicion is necessary. A retrospective cohort study of nonneutropenic patients with (80%) or without (20%) underlying conditions and diagnosed with IPA demonstrated that clinical presentation (cough, dyspnea, fever, weight loss, hemoptysis, chest tightness, or chest pain) was similar [14]. Other studies suggest that hemoptysis is an important symptom present in around 60% of patients with IPA, but that in general, the clinical findings in patients without risk factors are nonspecific and do not aid in the diagnosis [13]. The typical radiological signs (presence of air crescent sign and the halo sign in CRx or CT scan) were not observed in any condition, whereas bronchoscopic findings and cultures were comparable [14]. In this case, the patient had wheezing, dyspnea, and severe respiratory insufficiency along with new radiological infiltrates nonsuggestive of IPA initially oriented as acute respiratory distress syndrome and aspiration pneumonia. The association of nonspecific clinical findings and the atypical radiological manifestations makes the diagnosis of IPA difficult and leads to a high misdiagnosis rate [13].\n\nThe histopathological examination of lung tissue by thoracoscopic or open-lung biopsy is the gold standard to diagnose IPA. Here, because of impossibility of progressing distally, we obtained a biopsy of the necrotic material in proximal bronchi, revealing the presence of two Aspergillus species. Mixed infection of different Aspergillus species is rarely reported in the literature [15] and associated with severe immunodepression and treatment failure, making our case even more exceptional.\n\nVoriconazole 6 mg/kg IV b.i.d. for 1 day, followed by 4 mg/kg IV b.i.d., is the primary therapy for IPA [16]. We added caspofungin 70 mg in the first day and 50 mg the day thereafter due to the severity of the disease and the presence of two different Aspergillus species. Finally, we added nebulized liposomal amphotericin B to the treatment as an adjuvant therapy according to previous reports [17].\n\nThe risk factors associated with disseminated aspergillosis are the same for IPA. However, there are few cases reported in the literature in immunocompetent patients [9, 11, 12, 18]. In our case the patient had no relevant past medical history, the analysis did not reveal immunocompromise, tumoral markers were negative, and the pathological findings did not show any underlying disease besides the disseminated aspergillosis. So the presence of IPA with disseminated infection and the presence of two different Aspergillus species in the same patient were unexpected. Early diagnosis and correct aggressive treatment are associated with better outcome in patients with IPA [11]. However, although we initiated early appropriate aggressive treatment, the patient developed multiorgan failure and death revealing the severity of IPA in nonimmunocompromised patients.\n\nAdditional Points\n Learning objectives are as follows:To have invasive pulmonary aspergillosis into the differential diagnostics in acute respiratory failure in emergency room or intensive care when more common etiologies are excluded and the patient has no adequate clinical response to antibiotic therapy.\n\nTo understand that in rare cases severe invasive pulmonary aspergillosis with disseminated infection can affect immunocompetent patients.\n\n\n\n\n\nCanMEDS Competency: Medical Expert\n\n\n Pretest questions are as follows:Which are the frequency and mortality rates of invasive aspergillosis infection in immunocompetent patients admitted to an Intensive Care Unit?\n\nHow to diagnose invasive pulmonary aspergillosis in nonimmunocompromised patients?\n\n\n\n\n Posttest questions are as follows:Which are the frequency and mortality rates of invasive aspergillosis infection in immunocompetent patients admitted to an Intensive Care Unit?\n\n\n The incidence of invasive aspergillosis in ICU is around 0.33 but some studies report it as high as 6.9% in ICU population. The mortality rates are around 38% in colonized patients and 67% in putative invasive aspergillosis but can be as high as 80% (almost similar to the incidence in hematopoietic stem cell transplantation recipients).\n\n\n\n\nHow to diagnose invasive pulmonary aspergillosis in nonimmunocompromised patients?\n\n\n There is no specific clinical presentation of invasive pulmonary aspergillosis in immunocompetent patients. Also, the classical radiological signs in chest X-rays or computer tomography are absent. A high index of suspicion, bronchoscopy findings, microbiological sampling, and pulmonary biopsy are the main stem for diagnosis of IPA in immunocompetent patients.\n\n\n\n\n\n\n\nCompeting Interests\nThe authors declare that they have no competing interests.\n\nAuthors' Contributions\nGabriel Moreno-González has done literature search, data collection, analysis of data, and paper preparation. Antoni Ricart de Mesones has done literature search, data collection, analysis of data, and reviewing of the paper. Rachid Tazi-Mezalek has done literature search, data collection, analysis of data, and reviewing of the paper. Maria Teresa Marron-Moya has done data collection, analysis of data, and reviewing of the paper. Antoni Rosell has done data collection, analysis of data, and reviewing of the paper. Rafael Mañez has done literature search, data collection, analysis of data, and reviewing of the paper.\n\nFigure 1 Radiological and bronchoscopic findings. (a) Radiological findings. (A) Chest radiography (CRx) at hospital admission (day 1). (B) Computed tomography revealing small lingula consolidation (day 2). (C) CRx at ICU admission with new bilateral infiltrates (day 3). (D) CRx after 24 h of ICU admittance showing bilateral atelectasis (day 4). (b) Bronchoscopic findings. (A) Necrotic detritus and pseudomembrane in the right upper lobe. (B) Right upper lobe and right carina with an extensive deposit of necrotic material. Bronchoscopic biopsy was performed and revealed the presence of fungus with hyphae suggestive of Aspergillus. (C) Involvement of intermediate bronchus. (D) The orifice of bronchus in the culmen was not visible because of a large quantity of necrotic material. Bronchial wash fluid revealed the presence of Aspergillus. (E) Necrotic detritus and pseudomembrane in the left upper lobe. (F) Involvement of culmen, left carina, and lingula.\n\nFigure 2 Pathological findings. (a) Lung. The image shows left and right lungs with bilateral necrotizing pneumonia with vascular invasion. Left lung weight: 875 gr. Right lung weight: 1040 gr. (b) Trachea. The trachea and main bronchi affected by invasive aspergillosis. (c) Heart. The white nodule in the left ventricle was reported as aspergilloma. (d) Brain. Several hemorrhagic and necrotic areas caused by septic microemboli of Aspergillus.\n==== Refs\n1 Zmeili O. S. Soubani A. O. Pulmonary aspergillosis: a clinical update QJM : Monthly Journal of the Association of Physicians 2007 100 6 317 334 10.1093/qjmed/hcm035 17525130 \n2 Kousha M. Tadi R. Soubani A. O. Pulmonary aspergillosis: a clinical review European Respiratory Review 2011 20 121 156 174 10.1183/09059180.00001011 2-s2.0-80052543114 21881144 \n3 Meersseman W. Vandecasteele S. J. Wilmer A. Verbeken E. Peetermans W. E. Van Wijngaerdert E. Invasive aspergillosis in critically ill patients without malignancy American Journal of Respiratory and Critical Care Medicine 2004 170 6 621 625 10.1164/rccm.200401-093OC 2-s2.0-4444302605 15229094 \n4 Fukuda T. Boeckh M. Carter R. A. Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning Blood 2003 102 3 827 833 10.1182/blood-2003-02-0456 2-s2.0-0042243672 12689933 \n5 Taccone F. S. Van den Abeele A.-M. Bulpa P. Epidemiology of invasive aspergillosis in critically ill patients: clinical presentation, underlying conditions, and outcomes Critical Care 2015 19 1, article 7 10.1186/s13054-014-0722-7 2-s2.0-84924559963 \n6 Dutkiewicz R. Hage C. A. Aspergillus infections in the critically ill Proceedings of the American Thoracic Society 2010 7 3 204 209 10.1513/pats.200906-050al 2-s2.0-77955478959 20463249 \n7 Meersseman W. Lagrou K. Maertens J. Van Wijngaerden E. Invasive aspergillosis in the intensive care unit Clinical Infectious Diseases 2007 45 2 205 216 10.1086/518852 2-s2.0-34447101561 17578780 \n8 Croitoru A. Melloni B. Dupuy-Grasset M. Darde M. L. Delage M. Bonnaud F. Rare form of semi-invasive aspergillosis in immunocompetent patient: case report Pneumologia 2011 60 4 222 224 2-s2.0-84555191260 22420173 \n9 Ergene U. Akcali Z. Ozbalci D. Nese N. Senol S. Disseminated aspergillosis due to Aspergillus niger in immunocompetent patient: a case report Case Reports in Infectious Diseases 2013 2013 3 385190 10.1155/2013/385190 \n10 Sridhar V. Rajagopalan N. Shivaprasad C. Patil M. Varghese J. Acute community acquired Aspergillus pneumonia in a presumed immunocompetent host BMJ Case Reports 2012 10.1136/bcr.09.2011.4866 \n11 Raja N. S. Singh N. N. Disseminated invasive aspergillosis in an apparently immunocompetent host Journal of Microbiology, Immunology and Infection 2006 39 1 73 77 2-s2.0-33645302149 \n12 Tiwari V. Khatri K. Khan S. A. L. Nath D. Disseminated Aspergillus flavus following septic arthritis in an immunocompetent patient: a case report BMC Research Notes 2014 7, article 709 10.1186/1756-0500-7-709 2-s2.0-84930246720 \n13 Zhang R. R. Wang S. F. Lu H. W. Wang Z. H. Xu X. L. Misdiagnosis of invasive pulmonary aspergillosis: a clinical analysis of 26 immunocompetent patients International Journal of Clinical and Experimental Medicine 2014 7 12 5075 5082 2-s2.0-84921536063 25664007 \n14 Dai Z. Zhao H. Cai S. Lv Y. Tong W. Invasive pulmonary aspergillosis in non-neutropenic patients with and without underlying disease: a single-centre retrospective analysis of 52 subjects Respirology 2013 18 2 323 331 10.1111/j.1440-1843.2012.02283.x 2-s2.0-84872980477 23051143 \n15 Orzechowski Xavier M. Pasqualotto A. C. Da Penha Uchoa Sales M. Bittencourt Severo C. Peixoto Camargo J. J. Severo L. C. Invasive pulmonary aspergillosis due to a mixed infection caused by Aspergillus flavus and Aspergillus fumigatus \n Revista Iberoamericana de Micologia 2008 25 3 176 178 10.1016/s1130-1406(08)70041-x 2-s2.0-53849131728 18785789 \n16 Walsh T. J. Anaissie E. J. Denning D. W. Treatment of aspergillosis: clinical practice guidelines of the Infectious Diseases Society of America Clinical Infectious Diseases 2008 46 3 327 360 10.1086/525258 2-s2.0-39449095735 18177225 \n17 Castagnola E. Moresco L. Cappelli B. Nebulized liposomal amphotericin B and combined systemic antifungal therapy for the treatment of severe pulmonary aspergillosis after allogeneic hematopoietic stem cell transplant for a fatal mitochondrial disorder Journal of Chemotherapy 2007 19 3 339 342 10.1179/joc.2007.19.3.339 2-s2.0-34447513677 17594932 \n18 D'Silva H. Burke J. F. Jr. Cho S. Y. Disseminated aspergillosis in presumably immunocompetent host Journal of the American Medical Association 1982 248 12 1495 1497 10.1001/jama.248.12.1495 2-s2.0-0019966140 7050442\n\n",
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"mesh_terms": "D000935:Antifungal Agents; D001228:Aspergillosis; D001231:Aspergillus flavus; D001232:Aspergillus fumigatus; D001344:Autopsy; D001999:Bronchoscopy; D015199:Extracorporeal Membrane Oxygenation; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007121:Immunocompetence; D055744:Invasive Pulmonary Aspergillosis; D008875:Middle Aged; D009205:Myocarditis; D009393:Nephritis; D020953:Neuroaspergillosis; D013902:Radiography, Thoracic; D012131:Respiratory Insufficiency; D014057:Tomography, X-Ray Computed",
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"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "16440127;18177225;23051143;18785789;20463249;12689933;17525130;22420173;25301635;23533852;21881144;25928694;17594932;22605848;7050442;25664007;15229094;17578780",
"title": "Invasive Pulmonary Aspergillosis with Disseminated Infection in Immunocompetent Patient.",
"title_normalized": "invasive pulmonary aspergillosis with disseminated infection in immunocompetent patient"
} | [
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{
"abstract": "OBJECTIVE\nTo assess incidence, prevalence, risk factors, and prognosis of peripartum depression and anxiety in a prospective study of women with epilepsy.\n\n\nMETHODS\nPregnancies in women with epilepsy (n=706) were compared to pregnancies in all women without epilepsy (n=106,511) including women with specified nonepileptic chronic diseases (n=8,372) in the Norwegian Mother and Child Cohort Study. The database was linked to the Medical Birth Registry of Norway. Depression and anxiety were assessed with validated questionnaires five times from the second trimester to 36 months after delivery. Blood was drawn for analysis of antiepileptic drug (AED) concentrations.\n\n\nRESULTS\nWomen with epilepsy more often had peripartum depression (26.7%) or anxiety (22.4%) than women without epilepsy (18.9% and 14.8%, respectively, p<0.001 for both comparisons) and women with other chronic diseases (23.1% and 18.4%, respectively, p=0.03 and 0.01). Women using AEDs during pregnancy were especially at risk regardless of AED type. The risk further increased with the use of multiple AEDs and with high doses and/or plasma levels. Risk factors associated with peripartum depression and/or anxiety in the epilepsy cohort were high seizure frequency, a history of physical and/or sexual abuse, adverse socioeconomic factors, previous loss of a child, AED use, unplanned pregnancy, and prepregnancy depression and/or anxiety. The recovery rate 3 years after delivery was lower for women with epilepsy with a history of depression/anxiety or physical/sexual abuse than for women without epilepsy. Depressed women with epilepsy were less frequently treated with antidepressive drugs during pregnancy than women without epilepsy.\n\n\nCONCLUSIONS\nWomen with epilepsy frequently have depression and anxiety during and after pregnancy. Patients at risk should be identified before delivery as depressive symptoms could be undertreated in this group.",
"affiliations": "Department of Clinical Medicine, University of Bergen, Bergen, Norway; Department of Neurology, Haukeland University Hospital, Bergen, Norway.",
"authors": "Bjørk|Marte Helene|MH|;Veiby|Gyri|G|;Reiter|Simone C|SC|;Berle|Jan Øystein|JØ|;Daltveit|Anne Kjersti|AK|;Spigset|Olav|O|;Engelsen|Bernt A|BA|;Gilhus|Nils Erik|NE|",
"chemical_list": "D000927:Anticonvulsants; D000928:Antidepressive Agents",
"country": "United States",
"delete": false,
"doi": "10.1111/epi.12884",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0013-9580",
"issue": "56(1)",
"journal": "Epilepsia",
"keywords": "Antidepressive drugs; Antiepileptic drugs; MoBa; Peripartum; Postpartum; The Norwegian Mother and Child Cohort Study",
"medline_ta": "Epilepsia",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D000928:Antidepressive Agents; D001007:Anxiety; D015331:Cohort Studies; D003863:Depression; D019052:Depression, Postpartum; D003866:Depressive Disorder; D004827:Epilepsy; D005260:Female; D006801:Humans; D015994:Incidence; D009664:Norway; D011247:Pregnancy; D011248:Pregnancy Complications; D015995:Prevalence; D011379:Prognosis; D011446:Prospective Studies; D012307:Risk Factors; D011795:Surveys and Questionnaires; D055815:Young Adult",
"nlm_unique_id": "2983306R",
"other_id": null,
"pages": "28-39",
"pmc": null,
"pmid": "25524160",
"pubdate": "2015-01",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Depression and anxiety in women with epilepsy during pregnancy and after delivery: a prospective population-based cohort study on frequency, risk factors, medication, and prognosis.",
"title_normalized": "depression and anxiety in women with epilepsy during pregnancy and after delivery a prospective population based cohort study on frequency risk factors medication and prognosis"
} | [
{
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{
"reactionmeddrapt": "Anxiety",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Exposure during pregnancy",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Depression",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BJORK MH, VEIBY G, REITER SC, BERLE JO, DALTVEIT AK, SPIGSET O, ET AL. DEPRESSION AND ANXIETY IN WOMEN WITH EPILEPSY DURING PREGNANCY AND AFTER DELIVERY: A PROSPECTIVE POPULATION-BASED COHORT STUDY ON FREQUENCY, RISK FACTORS, MEDICATION, AND PROGNOSIS. EPILEPSIA 2015;56(1):28-39.",
"literaturereference_normalized": "depression and anxiety in women with epilepsy during pregnancy and after delivery a prospective population based cohort study on frequency risk factors medication and prognosis",
"qualification": "1",
"reportercountry": "NO"
},
"primarysourcecountry": "NO",
"receiptdate": "20150325",
"receivedate": "20150225",
"receiver": {
"receiverorganization": "FDA",
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},
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"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
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"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150721"
}
] |
{
"abstract": "The coronavirus disease COVID-19 is considered a pandemic disease that has developed rapidly all over the world. As of today, it is unclear whether immunosuppression confers an increased risk for pulmonary complications, or conversely, whether it can be a protective factor with respect to a cytokine storm.\nWe report the case of a 55-year-old male patient with granulomatosis with polyangiitis treated with rituximab who was infected with COVID-19 pneumonia. To the best of our knowledge, only 1 case has been reported in the literature with similar characteristics. The patient had a non-classic evolution of clinical symptoms with persistent fever and viral shedding, in addition to a negative serology.\nThis case emphasizes the management and immunity response to COVID-19 pneumonia in such patients. Data are still needed regarding patients who have prolonged B-cell depletion, which may put the patient at a higher risk for reinfection.\nDemonstration of the immunity response to COVID-19 pneumonia in an immunosuppressed patient.To highlight the management and evolution of such rare cases during this pandemic.",
"affiliations": "Department of Internal Medicine and Clinical Immunology, Hotel-Dieu de France University Hospital, Saint Joseph University, Beirut, Lebanon.;Department of Pulmonary and Critical Care Medicine, Hotel-Dieu de France University Hospital, Saint Joseph University, Beirut, Lebanon.;Department of Infectious Diseases, Hotel-Dieu de France University Hospital, Saint Joseph University, Beirut, Lebanon.;Department of Infectious Diseases, Hotel-Dieu de France University Hospital, Saint Joseph University, Beirut, Lebanon.;Department of Pulmonary and Critical Care Medicine, Hotel-Dieu de France University Hospital, Saint Joseph University, Beirut, Lebanon.;Department of Internal Medicine and Clinical Immunology, Hotel-Dieu de France University Hospital, Saint Joseph University, Beirut, Lebanon.",
"authors": "Daniel|Pascale|P|;Raad|Marc|M|;Waked|Rami|R|;Choucair|Jacques|J|;Riachy|Moussa|M|;Haddad|Fady|F|",
"chemical_list": null,
"country": "Italy",
"delete": false,
"doi": "10.12890/2020_001922",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2284-2594",
"issue": "7(10)",
"journal": "European journal of case reports in internal medicine",
"keywords": "COVID-19; SARS-CoV-2; granulomatosis with polyangiitis; rituximab",
"medline_ta": "Eur J Case Rep Intern Med",
"mesh_terms": null,
"nlm_unique_id": "101648453",
"other_id": null,
"pages": "001922",
"pmc": null,
"pmid": "33083371",
"pubdate": "2020",
"publication_types": "D016428:Journal Article",
"references": "32335169;32196933;32241793;32205856;32312768;27344959;24884562;32103284",
"title": "COVID-19 in a Patient Treated for Granulomatosis with Polyangiitis: Persistent Viral Shedding with No Cytokine Storm.",
"title_normalized": "covid 19 in a patient treated for granulomatosis with polyangiitis persistent viral shedding with no cytokine storm"
} | [
{
"companynumb": "LB-SUN PHARMACEUTICAL INDUSTRIES LTD-2020RR-274712",
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{
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},
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},
{
"actiondrug": "1",
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},
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"drugenddate": null,
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"drugindication": "COVID-19",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugrecurrence": null,
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"drugtreatmentduration": null,
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"medicinalproduct": "PITAVASTATIN."
}
],
"patientagegroup": null,
"patientonsetage": "55",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Diarrhoea",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "23.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "DANIEL P, RAAD M, WAKED R, CHOUCAIR J, RIACHY M, HADDAD F. COVID?19 IN A PATIENT TREATED FOR GRANULOMATOSIS WITH POLYANGIITIS: PERSISTENT VIRAL SHEDDING WITH NO CYTOKINE STORM. EUR J CASE REP INTERN MED. 2020?7(10):4 PAGES",
"literaturereference_normalized": "covid 19 in a patient treated for granulomatosis with polyangiitis persistent viral shedding with no cytokine storm",
"qualification": "3",
"reportercountry": "LB"
},
"primarysourcecountry": "LB",
"receiptdate": "20210111",
"receivedate": "20210111",
"receiver": {
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"receivertype": "6"
},
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"sender": {
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"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20210419"
}
] |
{
"abstract": "BACKGROUND\nSinonasal undifferentiated carcinoma (SNUC) is an uncommon neoplasm characterized by local extension and an aggressive course. Treatment often includes a combination of chemotherapy, radiation therapy, and surgery, although the optimal strategy remains unclear. Here, we present the first reported case of leptomeningeal carcinomatosis from SNUC.\n\n\nRESULTS\nA 28-year-old man with rapidly progressive headaches, congestion, and exophthalmos was found to have a nasal mass. Biopsy revealed sinonasal undifferentiated carcinoma. He had a transient response to chemotherapy followed by a sustained response to concurrent chemoradiation. At the completion of radiation, he developed subtle neurologic findings and MRI revealed diffuse, bulky leptomeningeal spread. He was able to receive only a single fraction of external beam radiation to his spinal axis before his disease rapidly progressed, leading to respiratory failure and death.\n\n\nCONCLUSIONS\nSinonasal undifferentiated carcinoma can be associated with leptomeningeal carcinomatosis, which can lead to a fulminant clinical course.",
"affiliations": "Division of Medical Oncology, Keck University of Southern California School of Medicine, USC Norris Comprehensive Cancer Center, Los Angeles, California.",
"authors": "Liu|Stephen V|SV|;Wagle|Naveed|N|;Zada|Gabriel|G|;Sun|Bonnie|B|;Go|John|J|;Rashtian|Afshin|A|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/hed.23225",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1043-3074",
"issue": "35(11)",
"journal": "Head & neck",
"keywords": "chemotherapy; leptomeningeal carcinomatosis; radiation; sinonasal undifferentiated carcinoma (SNUC)",
"medline_ta": "Head Neck",
"mesh_terms": "D000328:Adult; D001707:Biopsy, Needle; D002277:Carcinoma; D003131:Combined Modality Therapy; D018450:Disease Progression; D017809:Fatal Outcome; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D008297:Male; D008444:Maxillary Sinus Neoplasms; D055756:Meningeal Carcinomatosis; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010255:Paranasal Sinus Neoplasms; D035583:Rare Diseases; D012131:Respiratory Insufficiency",
"nlm_unique_id": "8902541",
"other_id": null,
"pages": "E343-5",
"pmc": null,
"pmid": "23471826",
"pubdate": "2013-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Leptomeningeal carcinomatosis in sinonasal undifferentiated carcinoma.",
"title_normalized": "leptomeningeal carcinomatosis in sinonasal undifferentiated carcinoma"
} | [
{
"companynumb": "US-TEVA-2021-US-1952568",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "74284",
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"drugcharacterization": "1",
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"drugdosagetext": "FOR 3 CONSECUTIVE DAYS",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "NASAL SINUS CANCER",
"drugintervaldosagedefinition": null,
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"drugrecurrence": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "ETOPOSIDE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CISPLATIN"
},
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"drugadministrationroute": "065",
"drugauthorizationnumb": "74656",
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"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "FOR 1 DAY",
"drugenddate": null,
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"drugindication": "NASAL SINUS CANCER",
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"medicinalproduct": "CISPLATIN."
}
],
"patientagegroup": "5",
"patientonsetage": "28",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Pneumocephalus",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Cerebrospinal fluid circulation disorder",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Rebound effect",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Respiratory failure",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Metastases to meninges",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Nasal sinus cancer",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Quadriparesis",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "LIU SV, WAGLE N, ZADA G, SUN B, GO J, RASHTIAN A. LEPTOMENINGEAL CARCINOMATOSIS IN SINONASAL UNDIFFERENTIATED CARCINOMA. HEAD?NECK 2013?35(11):E343?E345.",
"literaturereference_normalized": "leptomeningeal carcinomatosis in sinonasal undifferentiated carcinoma",
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},
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"receivedate": "20210916",
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},
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},
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"seriousnessother": null,
"transmissiondate": "20211014"
},
{
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"actiondrug": "6",
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"abstract": "Hereditary hemorrhagic telangiectasia (HHT) is a multisystemic inherited vascular dysplasia that leads to nosebleeds and visceral arteriovenous malformations (AVMs). Anti-angiogenic drugs thalidomide and bevacizumab have been increasingly used off-label with variable results. The HHT working group within the ERN for Rare Multisystemic Vascular Diseases (VASCERN), developed a questionnaire-based retrospective capture of adverse events (AEs) classified using the Common Terminology Criteria for Adverse Events.\n\n\n\nSixty-nine HHT patients received bevacizumab, 37 (50.6%) for high output cardiac failure/hepatic AVMs, and 32 (49.4%) for bleeding; the 69 patients received bevacizumab for a mean of 11 months for a total of 63.8 person/years treatment. 67 received thalidomide, all for epistaxis and/or gastrointestinal bleeding; they received thalidomide for a mean of 13.4 months/patient for a total of 75 person/years treatment. AEs were reported in 58 patients, 33 with bevacizumab, 37 with thalidomide. 32 grade 1-3 AEs related to bevacizumab were reported with an average incidence rate of 50 per 100 person-years. 34 grade 1-3 AEs related to thalidomide were reported with an average incidence rate of 45.3 per 100 person-years. Bevacizumab AEs were more common in females (27 AEs in 46 women) than males (6 in 23, p < 0.001). Thalidomide AEs occurred at more similar rates in males (25 AEs in 41 men, 60.9%) and females (12 in 26 (46.2%), but were more common in ENG patients (17 in 17) than in ACVRL1 (14 in 34, p < 0.0001). For bevacizumab, the most common reports were of joint pains (7/69, 10%), headache (3/69, 4.4%) and proteinuria (2/69, 3%), and for thalidomide, peripheral neuropathy (12/67, 18%); drowsiness (8/67, 12%); and dizziness (6/67, 9%). Fatal adverse events were more common in males (p = 0.009), and in patients with ENG pathogenic variants (p = 0.012). One fatal AE was possibly related to bevacizumab (average incidence rate: 1.5 per 100 person-years); 3 fatal AEs were possibly related to thalidomide (average incidence rate: 4 per 100 person-years).\n\n\n\nWith potential increase in use of Bevacizumab and Thalidomide in HHT patients, data presented support appropriate weighing of the toxicities which can arise in HHT settings and the practice recommendations for their prevention and management.",
"affiliations": "VASCERN HHT Reference Center, ASST Maggiore Hospital, Crema, Italy. elisabetta.buscarini@asst-crema.it.;Department of Cell and Molecular Medicine Centro de Investigaciones Biológicas, CSIC, U707 CIBERER, Madrid, Spain.;VASCERN HHT Reference Center, Essen University Hospital, Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany.;VASCERN HHT Reference Center, Odense Universitetshospital, Syddansk Universitet, Odense, Denmark.;VASCERN HHT Reference Center, St Antonius Ziekenhuis, Nieuwegein, Netherlands.;VASCERN HHT Reference Center, Unità Operativa Complessa di Otorinolaringoiatria, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy.;VASCERN HHT Reference Center, Centro sovraziendale Malattie rare, \"Frugoni\" Internal Medicine Unit, University of Bari \"A. Moro\", Bari, Italy.;HHT Unit, Hospital Sierrallana, Cantabria, Spain.;VASCERN HHT Reference Center, Genetic department, Hospices Civils de Lyon, Femme-Mère-Enfants Hospital, F-69677, Bron, France.;VASCERN HHT Reference Center, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, and Vascular Sciences, National Heart and Lung Institute, Imperial College London, London, UK.",
"authors": "Buscarini|Elisabetta|E|0000-0003-0863-0624;Botella|Luisa Maria|LM|;Geisthoff|Urban|U|;Kjeldsen|Anette D|AD|;Mager|Hans Jurgen|HJ|;Pagella|Fabio|F|;Suppressa|Patrizia|P|;Zarrabeitia|Roberto|R|;Dupuis-Girod|Sophie|S|;Shovlin|Claire L|CL|;|||",
"chemical_list": "D000068258:Bevacizumab; D013792:Thalidomide",
"country": "England",
"delete": false,
"doi": "10.1186/s13023-018-0982-4",
"fulltext": "\n==== Front\nOrphanet J Rare DisOrphanet J Rare DisOrphanet Journal of Rare Diseases1750-1172BioMed Central London 98210.1186/s13023-018-0982-4ResearchSafety of thalidomide and bevacizumab in patients with hereditary hemorrhagic telangiectasia http://orcid.org/0000-0003-0863-0624Buscarini Elisabetta +39 0373 280422elisabetta.buscarini@asst-crema.it 1Botella Luisa Maria cibluisa@cib.csic.es 2Geisthoff Urban urban.geisthoff@med.uni-marburg.de 3Kjeldsen Anette D. anette.kjeldsen@rsyd.dk 4Mager Hans Jurgen j.mager@antoniusziekenhuis.nl 5Pagella Fabio tpagella@libero.it 6Suppressa Patrizia patrizia.suppressa@gmail.com 7Zarrabeitia Roberto roberto.zarrabeitia@scsalud.es 8Dupuis-Girod Sophie sophie.dupuis-girod@chu-lyon.fr 9Shovlin Claire L. c.shovlin@imperial.ac.uk 10on behalf of VASCERN-HHTFederici Paolo Crocione Claudia 1 0000 0004 1759 8897grid.416292.aVASCERN HHT Reference Center, ASST Maggiore Hospital, Crema, Italy 2 0000 0001 2183 4846grid.4711.3Department of Cell and Molecular Medicine Centro de Investigaciones Biológicas, CSIC, U707 CIBERER, Madrid, Spain 3 0000 0001 2187 5445grid.5718.bVASCERN HHT Reference Center, Essen University Hospital, Department of Otorhinolaryngology, University of Duisburg-Essen, Essen, Germany 4 0000 0001 0728 0170grid.10825.3eVASCERN HHT Reference Center, Odense Universitetshospital, Syddansk Universitet, Odense, Denmark 5 0000 0004 0622 1269grid.415960.fVASCERN HHT Reference Center, St Antonius Ziekenhuis, Nieuwegein, Netherlands 6 0000 0004 1762 5736grid.8982.bVASCERN HHT Reference Center, Unità Operativa Complessa di Otorinolaringoiatria, University of Pavia, IRCCS Policlinico San Matteo Foundation, Pavia, Italy 7 0000 0001 0120 3326grid.7644.1VASCERN HHT Reference Center, Centro sovraziendale Malattie rare, “Frugoni” Internal Medicine Unit, University of Bari “A. Moro”, Bari, Italy 8 grid.413444.2HHT Unit, Hospital Sierrallana, Cantabria, Spain 9 VASCERN HHT Reference Center, Genetic department, Hospices Civils de Lyon, Femme-Mère-Enfants Hospital, F-69677 Bron, France 10 0000 0001 2113 8111grid.7445.2VASCERN HHT Reference Center, Hammersmith Hospital, Imperial College Healthcare NHS Trust, London, and Vascular Sciences, National Heart and Lung Institute, Imperial College London, London, UK 4 2 2019 4 2 2019 2019 14 283 9 2018 14 12 2018 © The Author(s). 2019Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nHereditary hemorrhagic telangiectasia (HHT) is a multisystemic inherited vascular dysplasia that leads to nosebleeds and visceral arteriovenous malformations (AVMs). Anti-angiogenic drugs thalidomide and bevacizumab have been increasingly used off-label with variable results. The HHT working group within the ERN for Rare Multisystemic Vascular Diseases (VASCERN), developed a questionnaire-based retrospective capture of adverse events (AEs) classified using the Common Terminology Criteria for Adverse Events.\n\nResults\nSixty-nine HHT patients received bevacizumab, 37 (50.6%) for high output cardiac failure/hepatic AVMs, and 32 (49.4%) for bleeding; the 69 patients received bevacizumab for a mean of 11 months for a total of 63.8 person/years treatment. 67 received thalidomide, all for epistaxis and/or gastrointestinal bleeding; they received thalidomide for a mean of 13.4 months/patient for a total of 75 person/years treatment. AEs were reported in 58 patients, 33 with bevacizumab, 37 with thalidomide. 32 grade 1–3 AEs related to bevacizumab were reported with an average incidence rate of 50 per 100 person-years. 34 grade 1–3 AEs related to thalidomide were reported with an average incidence rate of 45.3 per 100 person-years. Bevacizumab AEs were more common in females (27 AEs in 46 women) than males (6 in 23, p < 0.001). Thalidomide AEs occurred at more similar rates in males (25 AEs in 41 men, 60.9%) and females (12 in 26 (46.2%), but were more common in ENG patients (17 in 17) than in ACVRL1 (14 in 34, p < 0.0001). For bevacizumab, the most common reports were of joint pains (7/69, 10%), headache (3/69, 4.4%) and proteinuria (2/69, 3%), and for thalidomide, peripheral neuropathy (12/67, 18%); drowsiness (8/67, 12%); and dizziness (6/67, 9%). Fatal adverse events were more common in males (p = 0.009), and in patients with ENG pathogenic variants (p = 0.012). One fatal AE was possibly related to bevacizumab (average incidence rate: 1.5 per 100 person-years); 3 fatal AEs were possibly related to thalidomide (average incidence rate: 4 per 100 person-years).\n\nConclusions\nWith potential increase in use of Bevacizumab and Thalidomide in HHT patients, data presented support appropriate weighing of the toxicities which can arise in HHT settings and the practice recommendations for their prevention and management.\n\nElectronic supplementary material\nThe online version of this article (10.1186/s13023-018-0982-4) contains supplementary material, which is available to authorized users.\n\nKeywords\nHereditary hemorrhagic telangiectasiaBevacizumabThalidomideAdverse eventBleedingArteriovenous malformationEpistaxisCardiac failureNosebleedsissue-copyright-statement© The Author(s) 2019\n==== Body\nBackground\nHereditary haemorrhagic telangiectasia (HHT) is a multisystemic inherited vascular dysplasia that leads to nosebleeds, arteriovenous malformations (AVMs) in organs such as the lungs, liver and brain [1–3]. HHT is estimated to affect 85,000 European citizens [3]. Unfortunately, most health care providers have limited specific knowledge, whereas dedicated competence is critical to deal with this rare disorder [3–8].\n\nThe clinical criteria for diagnosing HHT, the Curaçao criteria, were established by a panel of experts [1]. Most HHT patients have pathogenic variants in one of two known disease-related genes, ENG (endoglin, HHT1) or ACVRL1 (activin A receptor type II-like 1, HHT2), which encode proteins involved in the transforming growth factor ß pathway [2]. Clinical presentation varies greatly depending on the number, type and location of telangiectases or AVMs with similar variation in potential morbidity and mortality. For example, one dominant clinical feature is iron deficiency anemia as a result of recurrent bleeds from either nasal or gastrointestinal telangiectases: these can lead to severe anemia requiring iron supplements and also recurrent need for blood transfusions. Other common manifestations, each present in approximately 50% of cases, are pulmonary and hepatic AVMs. Pulmonary AVMs provide direct communications between pulmonary arteries and veins (i.e. a right-to-left shunt) -the most important risks are paradoxical embolic strokes and brain abscess [6–8]. Hepatic AVMs unique to HHT involve the liver diffusely: intrahepatic shunting can lead to different clinical features, including high-output cardiac failure (HOCF), portal hypertension, encephalopathy, biliary ischemia, and mesenteric ischemia [4, 5].\n\nMultiple approaches, including surgical options, have been tried in the management of HHT- related epistaxis or gastrointestinal bleeding. While most of them have variable and temporary results, there is randomized control trial evidence in HHT to support the use of tranexamic acid [9, 10] tamoxifen [11] and even simple topical nasal treatments such as saline sprays [12]. Such treatments and/or interventional procedures can often avoid the long term use of other drugs; however interventions can be associated with local complications such as perforation of the nasal septum, and drugs with other side effects, or limited individual response. As a consequence, most patients require repeated interventions and treatments, many with only partial responses.\n\nIn recent years, angiogenesis has been implicated in the pathogenesis of HHT, where circulating concentrations of both TGF-beta and vascular endothelial growth factor (VEGF) are significantly elevated [13]. Anti-angiogenic substances have been proposed as treatments for severe HHT-related bleeding, and for complicated hepatic AVMs. Both thalidomide (TH) and bevacizumab (BZB), have been increasingly used in the latest decade in HHT patients, within and outside expert HHT-centers.\n\nBZB and TH use in oncological conditions is well established. TH is a potent immunosuppressive and antiangiogenic agent, [14–16] effective in the treatment of inflammatory diseases [17, 18], and in various cancers where VEGF plays an important role in tumor growth, invasion, and metastasis by promoting tumor angiogenesis [19–21]. Reduced bleeding has been observed in HHT patients who received TH as an antiangiogenic cancer therapy [22, 23]; TH treatment induced vessel maturation in an experimental model of HHT and reduced severe nosebleeds in six of the seven HHT patients studied [24]; and substantial improvements have been described in patients with other non HHT intestinal angiodysplasias treated with TH, when cessation of bleeding was associated with a reduction in serum VEGF levels [25, 26]. In a few small studies in HHT, TH consistently improved severity and frequency of epistaxis and improve hemoglobin concentrations while decreasing the need for transfusion [28–30]. Similarly, there is evidence for the efficacy of BZB in HHT. This humanized monoclonal antibody against VEGF, is approved in combination with chemotherapy for treating many types of advanced cancer, including colorectal cancer, non–small cell lung cancer, breast cancer, renal cell carcinoma, and glioblastoma multiforme [31, 32]. BZB improves anemia from chronic HHT-related bleeding [33, 34], and high cardiac output secondary to hepatic AVMs [35], in some cases, reversing the need for liver transplantation [36, 37].\n\nTo date, in HHT, the main indications for BZB and TH have been in two groups: (A) Patients with severe epistaxis, gastrointestinal bleeding or a combination of the two; and (B) for HOCF secondary to hepatic AVMs; either BZB or TH can be proposed for the first group of indications, whereas BZB only can be proposed for the second [22–38]. The use of BZB or TH is generally proposed when these severe HHT complications are refractory to other, often multiple, therapeutic attempts, which vary depending on type of complication; these severe HHT complications are frequently associated with substantial transfusion requirement [24, 28, 33–35]. So far, no data were systematically collected on safety profile of BZB and TH in HHT patients; it is not clear if there could be a different safety profile in HHT patients compared to oncological setting, where it has been shown that both TH and BZB expose patients to the risk of severe side effects [39–43]. On the other hand, evaluation of safety of BZB and TH in HHT settings is very important: 1) Theoretically, their antiangiogenetic actions on the perturbed vascular morphogenesis characteristic of HHT could result in either helpful vessel maturation [24] or in further bleeding and vascular complications [44–46]; 2) The use of BZB and TH in HHT is off-label and reported experience is still very limited; 3) These two drugs, which can represent the last resort for extremely sick patients and with compromised quality of life, could be used long term or even life-long.\n\nIn 2016 the European Commission launched the European Reference Networks (ERN), which are virtual networks involving healthcare providers across Europe, to tackle complex or rare diseases and conditions that require highly specialized treatment and a concentration of knowledge and resources. Presently, there are 24 ERNs involving 26 European countries, covering all major disease groups [47]. VASCERN-HHT comprises eight HHT reference centers (from UK, France, Italy [3 centers], Netherlands, Denmark, and Germany) [48].\n\nA core recommendation of the ERN auditing authority adopted by the ERN for Rare Multisystemic Vascular Diseases (VASCERN) [49], was to foster information on safety standards for rare disease patients. The VASCERN working group dedicated to HHT prioritized anti-angiogenic agents TH and BZB in HHT, as both have a potential for adverse events that warrant a great level of attention from scientific, clinical and lay HHT communities. The aim of this study was to evaluate the safety of BZB and TH use in HHT patients treated within HHT expert centers.\n\nMethods\nDrug registry- part 1\nA VASCERN-HHT Survey (Drug Registry- Part 1) was proposed first, to include all VASCERN-HHT stakeholders, including patient representatives and scientists, in addition to health care professionals (HCPs) working within, or in association with, the VASCERN HHT Centers. The HHT Centers involved in the study are tertiary care reference Centers for HHT, with similar case mixes of HHT patients, with an average HHT-specific experience of 21 years (range 15–27 years). The wide range of stakeholders consulted in Part 1 was designed to foster patient and scientific involvement with drug safety issues; cement the group’s interest by generating an early output [50] and encourage clinicians in the more demanding second stage that would be required.\n\nThe questionnaire is supplied in the Data Supplement (Additional file 1). Briefly, all respondents were asked to summarize their experience, if any, with these drugs, via an online questionnaire that included 4 questions dedicated to patients, 2 to scientists, and 13 to individual HHT Centers (the 8 in VASCERN and one cooperating Center). The questions focused on direct or indirect experience with BZB and TH, broad ranges of treated patients, and subjective agreements with a number of statements indicating perceived efficacy and safety of the two drugs in HHT. All responses were received between February 1st and 20th 2017.\n\nIn this questionnaire, responses were on a 1–7 scale where 1–3 represented disagreement (1 strongly, 2 with major reservation; 3 with minor reservation; 4 was don’t know, and 5–7 represented agreement: 5 with major reservation; 6 with minor reservation; 7 agree strongly). For graphical representation the scores were converted to − 3 to + 3 where 0 represented don’t know, 1–3 represented agreement (1 with major reservation; 2 with minor reservation; 3 agree strongly), and − 3 to − 1 represented disagreement (− 3 disagree strongly, − 2 disagree with major reservation; − 1 disagree with minor reservation).\n\nDrug registry- part 2\nAfter evaluation of Part 1 responses [50] a second survey, Drug Registry-Part 2 was proposed in May 2017 only to clinicians in the HHT Centers, to formally capture any adverse events that may have occurred while patients were being treated with BZB and TH.\n\nAll HHT Centers submitted patients treated with these agents to regular follow up according to their established center protocols for HHT treatment and surveillance, including recording of periodical checks depending on different treatment schedules, and intercurrent events, as previously reported [28, 29, 35, 51]. Data provided by HHT Centers were obtained from their HHT-specific electronic health records.\n\nOnly one respondent was allowed to respond per HHT Center, and all replies were received between May 1st and July 15th 2017. The questionnaire of Drug Registry-Part 2, (supplied as Additional file 2), included 35 questions divided into 2 sections.\n\nDescription of experience\nThe first questions were dedicated to description of the HHT Centers’ experience with either BZB or TH.\n\nFor each agent, Centers were asked for the number, age, sex, and genotype (ENG, ACVRL1, SMAD4, or unknown) of HHT patients; and specific indication for treatment. Treatment options provided were: otherwise untreatable epistaxis (nosebleeds), otherwise untreatable gastrointestinal bleeding, a combination of both nasal and gastrointestinal bleeding, or otherwise untreatable high output cardiac failure (HOCF)) for each patient. Further questions in this section were drug specific:\n\nFor TH, additional questions referred to the treatment duration expressed in months of therapy, the daily drug dosage (e.g. 50, 100, 200 mg), and the number of patients.\n\nFor BZB, additional questions referred to the treatment duration; number of patients treated with only an induction cycle (with 6 administrations every 2–3 weeks); number of patients treated with induction and maintenance; the total number of drug administrations; drug dosage (2.5 or 5 mg/kg and number of drug administrations); and details of the administration schedule (e.g. weeks’ interval for induction and for maintenance).\n\nAdverse events\nThe second section captured data on Adverse Events (AEs) using the common terminology criteria for adverse events (CTCAE, version 4.03, June 14, 2010) [52]. These define an Adverse Event (AE) as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of the medical treatment that may or may not be considered related to the medical treatment or procedure.\n\nIn the CTCAE, the severity of each AE is graded from 1 to 5 as follows: Grade 1 represents MILD, i.e. asymptomatic or mild symptoms, clinical or diagnostic observations only, where intervention not indicated. Grade 2 represents MODERATE, i.e. limiting age-appropriate instrumental activities of daily living (ADL), ie preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc., and where minimal, local or noninvasive intervention is indicated. Grade 3 represents SEVERE, i.e. medically significant but not immediately life-threatening events such as hospitalization or prolongation of hospitalization; disabling symptoms; and symptoms limiting self-care such as bathing, dressing and undressing, feeding, using the toilet, and taking medications, but not bedridden. Grade 4 represents LIFE-THREATENING consequences, where urgent intervention is indicated. Grade 5 represents DEATH related to the AE.\n\nSection 2 of the questionnaire Drug Registry-Part 2 was dedicated to the description of AE according system organ class (SOC) of CTCAE manual, identifying by anatomical or physiological system, etiology, or purpose (e.g., investigations for laboratory test results); within each system organ class, AEs were to be listed and accompanied by descriptions of severity (grade). A link to the CTCAE manual was provided within the questionnaire [52]. Every single AE that was not present before the treatment had to be described; the questionnaire allowed the description of multiple AE for the same patient.\n\nA list of more common AE occurring with either TH or BZB was provided (systemic hypertension; gastrointestinal perforation; arterial thrombosis; venous thrombosis/thromboembolic event; cardiac failure; peripheral neuropathy; joint pain; bleeding or other (to be described). If bleeding, the site was to be specified between cerebral, pulmonary, gastrointestinal and other.\n\nFor every individual AE, further information was requested on the patient demographics; genotype; drug used (either BZB or TH); AE occurring either on treatment (number of months from treatment start), or off treatment (number of months since treatment stopped); drug dosage; AE type; and AE grade from 1 to 5 (death). For Grade 5 AE, it was to be specified if death was certainly related to the drug; whether the drug may have contributed; whether the death was not related to the drug; or if causality status was unknown. Details of the AE outcome were requested (resolved completely, resolved with sequelae, unresolved/worsened, or unknown); if the treatment was interrupted or not because of the AE (and if yes, whether the AE improved after treatment interruption); eventual treatment restart or not (and if yes whether an AE that had improved recurred or not after treatment restart); any use of any other concomitant drugs possibly related to the AE. For fatal AEs, further case details were requested from the HCP.\n\nThe questionnaire-based survey was approved by the Ethics Committee of Maggiore Hospital ASST Crema, Italy.\n\nData analyses\nSTATA IC 15 (StataCorp, Texas) and GraphPad Prism 5 (Graph Pad Software Inc., San Diego) were used to calculate distributions of variables, to perform comparisons between groups, and to generate graphs. Two group comparisons were by Mann Whitney rank for continuous data or chi squared/Fisher’s exact test for categorical data.\n\nResults\nDrug registry- part 1: Estimations of efficacy and safety\nThere were 15 respondents for Drug Registry-Part 1 from European HHT Centers, and additional responses from patient representatives (N = 2) and HHT scientists (N = 3). No patient representative had experience of either BZB or TH. Two scientists reported awareness of effects of BZB or TH in HHT patients. For TH, two individual HHT Centers reported experience with 20–50 patients, one with 6–20 patients and two with fewer than 5 patients. For BZB, one individual HHT Center reported experience with 20–50 patients, one with 6–20 patients and four with fewer than 5 patients.\n\nAs noted in Fig. 1, there was agreement (with major reservations) that both TH and BZB could be helpful in treating HHT-related bleeding, and that BZB was helpful to treat hepatic AVMs. There was disagreement (with minor-major reservation) that the drugs were safe with no significant side effects for people with HHT.Fig. 1 Drug Registry-part 1: estimations of efficacy and safety are represented in panel labels:. Mean agreement with statement where 0 represented don’t know, 1–3 represented agreement (1 with major reservation; 2 with minor reservation; 3 agree strongly), and − 3 to − 1 represented disagreement (− 3 disagree strongly, − 2 disagree with major reservation; − 1 disagree with minor reservation). \n\n\n\nDrug registry-part 2: Adverse event evaluation\nTo examine further, the responses to the Drug Registry Part 2 were evaluated. Eight European HHT Centers had recommended or prescribed at least one of the drugs; six centers had prescribed BZB, four had prescribed TH. The average enrollment start for either BZB or TH was 6.5 years before the presented survey (range 3–9 years).\n\nIn total these HCPs reported 67 patients (mean age 66.4ys) treated with TH, and 69 (mean age 63.6ys) with BZB. 91 (66.9%) had pathogenic variants in ACVRL1 (HHT type 2); 27 (19.9%) in ENG, and 3 (2.2%) in SMAD4. Each drug was prescribed for a variety of indications, most commonly high output cardiac states for BZB, and epistaxis for TH. Table 1 summarises the characteristics of patients, and indications for treatment with either BZB or TH.Table 1 Demographics and indications for treatment\n\n\tThalidomide (N = 67)\tBevacizumab (N = 69)\t\nN\t%\tN\t%\t\nGender (% male)\t41\t61.2\t23\t33.3\t\nPathogenic gene\t\n ENG (HHT1)\t17\t25.4\t10\t14.5\t\n ACVRL1 (HHT2)\t34\t50.7\t57\t82.6\t\n SMAD4 (JPHT)\t2\t3.0\t1\t1.4\t\n Not known\t14\t20.9\t1\t1.4\t\nTreatment indication\t\n Epistaxis\t48\t71.6\t14\t20.3\t\n GI bleeding\t11\t16.4\t8\t11.6\t\n Epistaxis and GI bleeding\t8\t11.9\t10\t14.5\t\n High output cardiac failure\t0\t0\t37\t53.6\t\nLegend: N number of cases treated, GI gastrointestinal\n\n\n\nTreatment schedules\nThe reported treatment schedules with dosages used are provided in Table 2. These varied for both drugs. The induction regimen for BZB consisted of 6 administrations in all 69 treated patients: most BZB schedules were of an induction regime with 5 mg/kg every 2–3 weeks, followed by a maintenance dose of 5 mg/kg every 4–12 weeks.Table 2 Treatment schedules\n\nA) BZB treatment Number of patients (number of drug administrations)\tTreatment schedule\tNumber of drug administrations for different dosages\t\n Induction only\tInduction + maintenance\tInduction schedule (HCP number)\tMaintenance range \t5 mg/kg\t2.5 mg/kg\t1 mg/kg\t\n 38 (228)\t31 (481)\tEvery 3 wks (3)\nEvery 2 wks (3)\tEvery 4–12 weeks\t669\t4\t36\t\nB) TH treatment Months of treatment in 67 patients\tPts with daily dosage < 50 mg\tPts with daily dosage 50 mg\tPts with daily dosage 100 mg\tPts with daily dosage 200 mg\tPts/Mean daily dosagea\t\n 900\t31\t26\t2\t2\t5/90\n1/150\t\nLegend: ain patients treated with different dosages along the treatment\n\n\n\nTH dosages were evenly split between < 50 and > 50 mg/day, with occasional patients receiving 100 mg/day or 200 mg/day.\n\nTreatment duration\nFor BZH, 38/69 patients had an induction only regimen, with a mean induction duration of 3.1 months/patient accounting for a total treatment duration of 120.1 months across all patients. 31/69 patients had both induction and maintenance, with a mean treatment duration of 20.8 months/patient, accounting for a total treatment duration of 646.4 months across all patients. Altogether, the 69 patients were treated with BZB for a mean period of 11 months providing data on a total of 63.8 person/years treatment.\n\nThe 67 patients receiving TH were treated for a mean period of 13.4 months/patient providing data on a total of 75 person/years treatment.\n\nAdverse events\nTable 3 provides a summary of the AEs that occurred with either BZB or TH, with timing of AEs according to different AE grade. AEs Grade 1–5 were observed although no AE grade 4 was observed. No off-treatment AEs were reported.Table 3 Summary of events\n\n\tAE grade\tNumber (% of AE)\tSex, male N\tAge, mean (range)\tRatio ENG: ACVRL1: SMAD4: not known\tDose, mg/kg\tDose, mg/day, mean (range)\tNumber of patients\tMean months of treatment\nat AE\t\nBZB\t1\t5 (15)\t2\t65 (61–69)\t1:3:0:1\t5\t\t5\t44.8\t\n2\t17 (51)\t1\t60.3 (35–72)\t0:9:1:7\t5\t\t10\t45.6a\t\n3\t10 (30)\t2\t56.9 (54–73)\t0:5:0:5\t5\t\t5\t36.8b\t\n4\t0\t–\t–\t–\t–\t–\t–\t–\t\n5\t1 (3)\t1\t67\t1:0:0:0\t5\t–\t1\t36\t\nTH\t1\t8 (21)\t5\t67 (50–90)\t2:5:0:0\t–\t75 (25–100)\t7\t41.5\t\n2\t20 (54)\t15\t64.2 (53–81)\t9:6:1:0\t\t98 (50–200)\t16\t36.8\t\n3\t6 (16)\t2\t65.8 (59–69)\t4:2:0:0\t\t75 (50–100)\t6\t23.5\t\n4\t0\t–\t–\t–\t–\t–\t–\t–\t\n5\t3 (8)\t3\t66.3 (62–78)\t2:1:0:0\t–\t100 (50–200)\t3\t11.6\t\nLegend: anot available in 7; bnot available in 5\n\n\n\nSeventy AE were reported, 33 in 28 patients treated with BZB (average 1.18 events per patient), 37 in 30 patients treated with TH (average 1.23 events per patient).\n\nTable 4 provides a summary of proportion of AEs according to patient sex and genotype. Women were more likely to have reported AEs with BZB (27 AEs in 46 women [58.7%]) compared to 6 AEs in 23 men [26.1%], p < 0.001, although the only fatal event occurred in a male. For TH, slightly more men reported AEs (25 AEs in 41 men [60.9%]) compared to 12 AEs in 26 women [46.1%], but the difference was not statistically significant p = 0.32. There was no evident genotypic difference in AE reports in patients using BZB, but there was a trend for ENG patients to have more AEs reported when on TH (17 in 17 ENG patients compared to 14 in 34 ACVRL1 patients, p < 0.001).Table 4 Proportion of AEs according to patients’ sex and genotype\n\n\tTH\tBZB\t\n\tTH treatment\tTH AE\t% of pts with AE\tBZB treatment\tBZB AE\t% of pts with AE\t\nmale pts\t41\t25\t61\t23\t6\t26\t\nfemale pts\t26\t12\t46a\t46\t27\t59b\t\nENG pts\t17\t17\t100\t10\t2\t20c\t\nACVRL1 pts\t34\t14\t41\t57\t17\t30d\t\nComparing males to females : ap=0.32, b<0.01. Comparing thalidomide to bevacizumab, cp<0.001, d=0.36\n\n\n\n41/69 (59%) users of BZB and 37/67 (55%) users of TH had no AEs.\n\nThe trends for number and severity of AEs with either BZB and TH across grades 1–5 did not reach statistical significance (p value > 0.1). However, AEs tended to occur earlier with thalidomide than with BZH, with 14/34 (41.2%) versus 5/32 (16%) occurring within first 6 months of treatment (p value = 0.030).\n\nAEs grades 1–3\nTable 5 shows AE type, classified by organ system, and outcomes for AEs grade 1–3.Table 5 AE type and outcomes for AEs grade 1–3\n\n\tAE grade\tSystem Organ Class (SOC)/AE type\tAE outcome\tTreatment interruption\tImprovement after interr\tTreatment restart\tAlternative cause for AE\t\n\t\tGeneral disorders\tVascular disorders\tMusculo-Skeletal disorders\tNervous System & Psychiatric disorders\tRenal disorders\tGastroint. disorders\tReproduct system disorders\tSkin disorders\t\t\t\t\t\t\nBZB\t1\t\t1 enlarged PAVM\t1 joint pain\n1 facial pain\t\t\t\t\t2 hair loss\t1 unresolved/worsened\n4 resolved\t1 Yes\n4 No\t1 No\t1 No\tIn 2\t\n2\t1 fatigue\t2 hypertension\t6 joint pain\n1 vertebral fracture\t1 confusion\n3 headaches\t2 proteinuria\t1 diarrhea\t\t\t17 resolved\t17 No\t\t\tIn 1\t\n3\t1 fatigue\t3 hypertension\n1 arterial thrombosisa\t2 joint pain\t1 confusion\t\t1 GI bleedingb\n1 diarrhea\t\t\t1 unresolved/worsened\n9 resolved\t3 Yes\n7 No\t2 Yes\n1 No\t1 Yes\n2 No\tIn 2\t\nTH\t1\t\t\t\t5 peripheral neuropathyc\n1 somnolence\n1 drowsiness\t\t\t\t1 rash\t2 unresolved/worsened\n6 resolved\t3 Yes\n5 No\t3 Yes\t3 No\tnone\t\n2\t\t\t\t5 peripheral neuropathyd\n4 dizziness\n2 somnolence\n7 drowsiness\t\t1 constipation\t1 erectile dysfunction\t\t7 unresolved/worsened\n2 resolved with sequelae\n11 resolved\t15 Yes\n5 No\t10 Yes\n5 No\t15 No\tnone\t\n3\t1 limb edema\t1 arterial thrombosisf\t\t2 peripheral neuropathy &\n2 dizziness\t\t\t\t\t4 unresolved/worsened\n2 resolved\t4 Yes\n2 No\t2 Yes\n2 No\t1 Yes\n3 No\tIn 1\t\nLegend: aunresolved/worsened after treatment interruption\n\nbresolved completely\n\nc3 resolved completely, 2 unresolved/worsened,\n\nd1 resolved completely, 1 resolved with sequelae, 3 unresolved/worsened\n\n&2 unresolved/worsened\n\nfresolved completely\n\n\n\nThirty two grade 1–3 AEs related to BZB were reported with an average incidence rate of 50 per 100 person-years. Thirty four grade 1–3 AEs related to TH were reported with an average incidence rate of 45.3 per 100 person-years.\n\nFor BZB, the most common reports were of joint pain (9/69, 13%) and hypertension (5/69, 7.2%);\n\nFor TH, the most common reports were of peripheral neuropathy (12/67, 18%), drowsiness (8/67, 12%), and dizziness (6/67, 9%). Somnolence and drowsiness were all grade 1–2, required treatment interruption in 4 cases (in one grade 1 and three grade 2) and resolved completely after treatment interruption. Peripheral neuropathy with TH remained unresolved or worsened in two thirds of cases of present study.\n\nAEs grade 5\nDeath occurred in 4 patients (all men) while on treatment: three had ENG pathogenic variants and 1 had ACVRL1. Across the full population of treated patients, this excess in ENG deaths was statistically significant (p = 0.017).\n\nAs noted in Table 6, there was one fatal AE on BZB treatment. This was a 67-year-old male who had tolerated effective BZB treatment for 65 months (maintenance dose 5 mg/kg BZB infusion every 2 months). A mild hemoptysis at month 65 resulted in a thoracic CT scan that demonstrated pulmonary bleeding from a pulmonary AVM. The patient died from a catastrophic hemoptysis while waiting for urgent pulmonary AVM embolization. The AE was deemed possibly related to drug; pulmonary AVM spontaneous rupture was considered an alternative cause for patient death, noting such an event is highly unusual outside of pregnancy or pulmonary hypertension, which the patient did not have. The fatal AE was considered possibly related to BZB with an average incidence rate of 1.5 per 100 person-years.Table 6 AE type and outcomes for AEs grade 5 (fatal)\n\n\tAge\tSex\tGene\tIndication for treatment\tPulmonary AVMs\tTreatment response\tTreatment duration at event\tFatal event (SOC)\tDrug-related AE?\t\n\tBleeding\tSupport\tMean Hemoglobin (Hb)\t\t\nBZB\t67\tMale\t\nENG\n\tRefractory GI bleeding\tRegular blood transfusions\t< 6 g/dL\tPreviously treated, no follow up for 5 ys\tExcellent, mean Hb > 10 g/dL\t65 months\tHaemoptysis from ruptured PAVM (Vasc Disord)\tPossibly related ; theoretical alternate cause: spontaneous rupture\t\nTH\t69\tMale\t\nACVRL1\n\tRefractory epistaxis\tRegular blood transfusions\t< 7 g/dL\tno\tGood: mean Hb > 9 g/dL; fewer tx\t10 months\tCardiac failure (Card Disord)\tPossibly related; theoretical alternate cause: ischemic cardiopathy\t\n62\tMale\t\nENG\n\tRefractory GI bleeding\tRegular blood transfusions\t< 7 g/dL\tno\tPartial, mean Hb > 8 g/dL; fewer tx\t23 months\tIschemic stroke (Vasc Disord)\tpossibly related; theoretical alternate cause: atherosclerosis\t\n78\tMale\t\nENG\n\tRefractory epistaxis\tRegular blood transfusions\t< 7 g/dL\tno\tGood: mean Hb > 9 g/dL; fewer tx\t2 months\tCatastrophic epistaxis (Resp Disord)\tpossibly related; theoretical alternate cause: spontaneous nosebleed\t\nLegend: Drug dosing schedules provided in the text. SOC System Organ Classification\n\n\n\nThere were three fatal AEs during TH treatment (Table 6). All 3 cases had tolerated treatment for 1–23 months before the AE. The first, a 69-year-old male had tolerated effective treatment with TH 50 mg/day until month 10 of treatment, when he died of cardiac failure. The AE was deemed possibly related to the drug. Ischemic cardiopathy was considered an alternative cause of patient death although there was no evidence for this. The second, a 62-year-old male had tolerated treatment with TH 200 mg/day that was partially effective. On month 23 of treatment patient died of ischaemic stroke. The AE was deemed possibly related to the drug; atherosclerosis was considered an alternative cause of patient death. The third, a 78-year-old male had tolerated treatment with TH at 50 mg/day for 1 month. The dose was increased to 100 mg/day and initially tolerated and effective, but on month 2 of treatment patient died of a catastrophic nosebleed. The AE was deemed possibly related to drug; a spontaneous catastrophic nosebleed was considered an alternative cause for patient death. The three fatal AEs were considered possibly related to TH with an average incidence rate of 4 per 100 person-years.\n\nDiscussion\nThe focus of our study is on the occurrence of adverse events during BZB and TH treatment of HHT-related manifestations. Both drugs are associated with adverse events at respective event rates of 0.40 and 0.44 AEs per patient.\n\nThe strength of the present study is the evaluation of safety of BZB and TH in HHT within expert HHT centers which can offer a specific disease knowledge, an established surveillance schedule and an appropriate indication for the use of these drugs; furthermore, data provided by the present survey on safety profiles of BZB and TH in HHT patients can assist therapeutic decisions by an appropriate risk weighing, and this is particularly important in HHT complications which generally require long term treatments. Study limitations include the fact that the data were collected from Centers of reference for HHT: it has to be underscored that within European HHT Reference Centers, antiangiogenic drugs are generally reserved for patients with severe conditions (either nose or gastrointestinal bleeding, or high output cardiac decompensation) and refractory to other therapies. In such a context of critically ill patients it could be difficult to discriminate if a serious event is related to either the disease or to the drug. Retrospective collection of data may have entailed underreporting and underestimation of AEs; however within HHT Centers of reference patients are followed up periodically, particularly if on particular treatments as BZB/TH, and patients are instructed to report to the Center any problem they may encounter. This surveillance policy should have limited the possibility of missing AEs.\n\nThe size of treatment groups may seem modest but it should be remembered that the potential study cohort are a small subgroup of patients within a rare disease. In the October 2018 VASCERN Meeting, the clinical experts within VASCERN HHT estimated that the patients with HHT complications sufficiently severe to warrant BZB or TH represent fewer than 5% of HHT patients seen by them [49, 53]. Thus, based on 85,000 prevalent HHT cases in Europe, fewer than 4250 would be expected to have a severe presentation, refractory to first line treatments, possibly with substantial transfusion requirement. Similarly, within the current European population of 512 millions [54], the proportion of severe HHT cases in Europe would be in the order of 8/ million inhabitants. In support, the centers of reference of VASCERN HHT participating to this study treated with BZB/TH an average of 2.6 patients/per year/per center (the Danish Center, which has a 70% recruitment of HHT cases from the country, treated an average of 2.5 patients/year, over a Danish population of 5,770,000 (personal communication)).\n\nIt has to be emphasized, as it is usual for rare conditions, that dedicated competence is critical to evaluate and to treat HHT and two of its worst presentations of severe transfusion-dependent anemia due to chronic bleeding, and/or or high output cardiac failure due to liver AVMs. As part of the advice of an HHT center of reference, potential risks are weighed together with potential benefits in terms of survival and quality of life conferred by the addition of BZB/TH in critically ill HHT patients. Additionally, the experienced HHT centers of reference are aware of the full and emerging spectrum of HHT, [3, 5–10, 28, 35, 50, 51, 53, 55–66], and therapeutic options to offer the best care possible, including the use of other drugs and/or interventional procedures which can often avoid the use of BZB/TH. In the present study there was not a particular Center propensity for either BZB or TH, and the drug choice depended on previous experiences [28, 29, 35, 51] rather than on different patient recruitment.\n\nToxicities related to the use of BZB and TH are well recognized due to experience in oncological use. Teratogenicity is the most serious side effect of antiangiogenic drugs. TH and BZB are absolutely contraindicated in women who are, or could become, pregnant. Very common AE (> 10%) reported in relation to TH include constipation, leukopenia, anemia, thrombocytopenia, peripheral neuropathy, dizziness, impotence, thyroid dysfunction, and edema. Less common AE (1–10%) of TH include heart failure, deep vein thrombosis and pulmonary embolism [39]. Toxicities are also encountered with BZB use, in particular grade 3 medically-manageable hypertension (3–16%). In addition, other serious and sometimes fatal AEs are hemorrhage, gastrointestinal perforation related to tumor necrosis, thromboembolic events, wound healing complications, neutropenia, and nephrotic syndrome [40–43]. Table 7 illustrates the comparison of rates of main AEs reported in the present study in treating HHT patients and relevant figures reported in other settings. Whereas the rates of main AEs appear similar in these different settings, it is to be noted that bleeding complications are not reported in the use of TH outside the HHT condition; that the common presence of pulmonary AVMs in HHT renders likely paradoxical embolism of venous thromboemboli; that HHT patients can already have a high output cardiac state that enhances risks of cardiac compromise; and that in contrast to oncological conditions, HHT is not a particularly life-limiting condition [65, 66].Table 7 Main AEs’ rates (for grades 1–5) in present series compared to literature data on BZB and TH in oncology (or other) settings\n\n\tPresent study %\tLiterature [64–72] %\t\nBevacizumab\t\n Hypertension\t7.2\t5–19\t\n Bleeding\t2.8\t1.7–6.7\t\n Proteinuria\t2.8\t0.7–7.4\t\n Arterial thromboembolism\t1.4\t0.7–4.4\t\n Peripheral neuropathy\tNot described\t6.3\t\nThalidomide\t\n Somnolence/drowsiness\t16\t2–23\t\n Peripheral neuropathy\t17.9\t1–44\t\n Thromboembolic event\t2.9\t1–6\t\n Cardiac failure\t1.4\t1–8\t\n Bleeding\t1.4\tNot described\t\n\n\nThe current study has shown that AEs of lesser grade (1–2) were common, and, not surprisingly, included somnolence and drowsiness, typical of the sedative properties of TH. These minor side effects are however important for patients, as they affect quality of life of patients who need long term treatment, and as noted, can be the reason for treatment interruption. A non negligible rate of AE grade 2–3 were reported for both drugs (39%), with joint pain and peripheral neuropathy being the most frequent grade 1–3 AE for BZB and TH respectively. Peripheral neuropathy is a common, potentially severe side effect that, as suggested by the current data, may be irreversible with TH. It is a dose–dependent AE and generally occurs following chronic use over a period of months; however, reports following relatively short-term use also exist. Clinical assessment for symptoms and signs of peripheral neuropathy should be performed prior to and during TH treatment. If grade 1 or grade 2 neuropathy, the dose can be reduced by up to 50% of the last dose, whereas in the event of grade 3 or 4 neuropathy, treatment should be discontinued.\n\nArterial thrombosis complicated 1% of either BZB or TH treatments, and in the case occurring during BZB treatment, worsened even when treatment was interrupted. One of 4 fatal AEs was due to an ischemic stroke occurring during TH treatment. Thromboembolic events are well known AEs of both BZB and TH; patients with HHT receiving BZB may develop systemic or deep vein thrombosis [44, 45].\n\nBleeding events occurred in 2 patients (3%) treated with BZB, as grade 3 GI bleeding in 1 case and as catastrophic fatal pulmonary hemorrhage in 1 case; 1 case of catastrophic fatal nose bleeding occurred in 1 patient (1%) treated with TH. All three AEs were deemed possibly drug related. What is peculiar of two fatal bleedings that occurred in the present study is the catastrophic character of hemorrhage which did not leave time for any treatment. This is unusual in HHT: nosebleeds are almost never life-threatening events, even in patients anticoagulated with warfarin [61]. Furthermore, pulmonary AVMs very rarely rupture, with almost all fatal events described in the setting of pregnancy, pulmonary hypertension, excessive anticoagulation, or thrombolysis [6, 60, 62]. In the present study, a 68 year old patient treated with BZB presented enlargement of a pulmonary AVM at 24 months of treatment, which is again unusual in HHT outside of pregnancy and at this age [6, 63]. Catastrophic fatal GI bleeding, which again is not the rule for GI bleeding in HHT [64], has been reported in a patient treated with BZB for complicated liver AVMs [46]. These data could suggest a potential role of antiangiogenic drugs in destabilization and/or growth of AVMs in HHT.\n\nSome suggestions can be drawn from these data on AEs of BZB/TH in HHT, and particularly on vascular complications:i). In severe HHT-related conditions specific expertise on HHT is required to appropriately weigh benefits and risks of different available treatments [3–6];\n\nii). The present study has shown broadly similar potentials for AEs for BZB and TH. Therefore, for refractory HHT bleeding where either BZB or TH can be proposed, after a careful evaluation of risk-benefit balance on an individual basis, the two drugs can be equally considered for patients. However, the subgroup analyses suggest that ENG patients (both genders) may be more prone to AEs on TH, and that females may be more prone to AEs when on BZH. Therefore, when discussing potential risks of treatment, clinicians may include the possibility that due to a specific gender/HHT genotype combination, an individual patient may be more prone to side effects from a particular agent. Until further data on relative efficacies or AEs by gender, genotype or other patient subtype emerge, where other indications are comparable, clinicians may prefer to direct males with ENG variants to BZH rather than TH, and females with non ENG variants to TH rather than BZH. Other genotype/gender combinations have one factor in favour of each drug and no preference can be suggested at present.\n\niii). Evaluation of prothrombotic conditions should be considered before treatment with BZB and TH is started. Patients at high risk for thromboembolic events should be excluded from these treatments.\n\niv). Screening and treatment of pulmonary AVMs according to current guidelines [3, 4, 6] should be performed for every patient with HHT and particularly before considering BZB or TH treatment;\n\nv). As vascular complications can be asymptomatic [44, 73], there is a likely need for enhanced surveillance of pulmonary AVMs during BZB/TH treatment to check pulmonary AVMs size. Whether alternate strategies should be routinely employed to exclude deep vein thrombosis is not yet clear, but the possibility should be constantly considered.\n\nvi). Even minimal hemoptysis in an HHT patient on an antiangiogenic drug should prompt intensive management with thoracic CT scan, bronchoscopy, and embolization of pulmonary AVMs if needed. Discontinuation of the antiangiogenic drug is mandatory in such settings.\n\nvii). After a careful evaluation of cost-benefit balance, BZB represents an interesting option for patients with complicated liver AVMs, refractory to first-line treatment [53] and not amenable to OLT, either over the age of 65 years or poor candidates for surgery. If they respond to the drug, they should be re-evaluated for OLT with a“fast-track” to minimize the potential for AEs due to BZB use [5, 58, 59].\n\n\n\nConclusions\nThis study evaluated the safety of BZB and TH in HHT within expert HHT centers which can offer a specific disease knowledge, an established surveillance schedule, and an appropriate indication for the use of these drugs. Importantly, to weigh against potential benefits, both BZB and TH expose patients to the risk of severe side effects, with respective event rates of 0.40 and 0.44 AEs per HHT patient, including fatalities.\n\nWith potential increase in use of BZB and TH in HHT patients, these data support appropriate weighing of the toxicities which can arise from these drugs and the practice recommendations for their prevention and management. The risk profile for TH to BZB resulting from the data generated is helpful to share in pre-treatment counselling.\n\nAdditional files\n\nAdditional file 1: Questionnaire for VASCERN-HHT Survey Drug Registry- Part 1. (PDF 183 kb)\n\n \nAdditional file 2: Questionnaire for VASCERN-HHT Survey Drug Registry- Part 2. (PDF 239 kb)\n\n \n\n\nAbbreviations\nACVRL1Gene encoding the ALK-1 protein\n\nAE(s)Adverse Event/s\n\nAVM(s)Arteriovenous malformation(s)\n\nBZBBevacizumab\n\nENGGene encoding the endoglin protein\n\nERNsEuropean Reference Networks\n\nHHTHereditary haemorrhagic telangiectasia;\n\nHOCFHigh-output cardiac failure\n\nSMAD4Gene encoding the SMAD4 protein\n\nSOCSystem Organ Classification\n\nTHThalidomide\n\nVASCERNEuropean Reference Network for Rare Vascular Diseases\n\nVEGFVascular endothelial growth factor\n\nAcknowledgements\nThe authors are grateful to their colleagues in their VASCERN ERNs for fruitful discussion and suggestions (particularly Guido Manfredi, Francesca Catalano, Saverio Alicante, Freya Dröge, Marco Post, Repke Snijder, Rosangela Invernizzi, Carlo Sabbà, Anne Emmanuelle Fargeton, Jean-Cristophe Saurin); the VASCERN HHT ePAG patient group (particularly Paolo Federici, Claudia Crocione), and VASCERN (particularly Guillaume Jondeau, Marine Hurard and Natasha Barr).\n\nFunding\nNo funding to declare for present study.\n\nAvailability of data and materials\nThe datasets analysed during the current study are available from the corresponding author on reasonable request.\n\nAuthors’ contributions\nEB, SDG, and CLS developed the study concept and prepared the questionnaires; EB analysed the questionnaire responses, and drafted the manuscript; EB and CLS performed data analyses; EB, LMB, UG, ADK, HJM, FP, PS, RZ, SDG, and CLS contributed to acquisition of data, analysis and interpretation of data, were involved in drafting the manuscript and revising it critically and gave final approval of the version to be published.\n\nEthics approval and consent to participate\nThe survey was ethically approved.\n\nConsent for publication\nNot applicable\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n1. 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Boother EJ Brownlow S Tighe HC Bamford KB Jackson JE Shovlin CL Cerebral abscess associated with odontogenic bacteremias, hypoxemia, and iron loading in immunocompetent patients with right-to-left shunting through pulmonary arteriovenous malformations Clin Infect Dis 2017 65 595 603 10.1093/cid/cix373 28430880 \n9. Gaillard S Dupuis-Girod S Boutitie F Rivière S Morinière S Hatron PY ATERO study group Tranexamic acid for epistaxis in hereditary hemorrhagic telangiectasia patients: a European cross-over controlled trial in a rare disease J Thromb Haemost 2014 12 1494 1502 10.1111/jth.12654 25040799 \n10. Geisthoff UW Seyfert UT Kübler M Bieg B Plinkert PK König J Treatment of epistaxis in hereditary hemorrhagic telangiectasia with tranexamic acid - a double-blind placebo-controlled cross-over phase IIIB study Thromb Res 2014 134 565 571 10.1016/j.thromres.2014.06.012 25005464 \n11. Yaniv E Preis M Hadar T Shvero J Haddad M Antiestrogen therapy for hereditary hemorrhagic telangiectasia: a double-blind placebo-controlled clinical trial Laryngoscope 2009 119 284 288 10.1002/lary.20065 19160429 \n12. Whitehead KJ Sautter NB McWilliams JP Chakinala MM Merlo CA Johnson MH Effect of topical intranasal therapy on epistaxis frequency in patients with hereditary hemorrhagic telangiectasia: a randomized clinical trial JAMA 2016 316 943 951 10.1001/jama.2016.11724 27599329 \n13. Sadick H Riedel F Naim R Goessler U Hörmann K Hafner M Patients with hereditary hemorrhagic telangiectasia have increased plasma levels of vascular endothelial growth factor and transforming growth factor-beta1 as well as high ALK1 tissue expression Haematologica 2005 90 818 828 15951295 \n14. Barnhill RL Doll NJ Millikan LE Hastings RC Studies on the anti-inflammatory properties of thalidomide: effects on polymorphonuclear leukocytes and monocytes J Am Acad Dermatol 1984 11 814 819 10.1016/S0190-9622(84)80458-2 6512038 \n15. Moreira AL Sampaio EP Zmuidzinas A Frindt P Smith KA Kaplan G Thalidomide exerts its inhibitory action on TNF-by enhancing the mRNA degradation J Exp Med 1993 177 1675 1680 10.1084/jem.177.6.1675 8496685 \n16. D’Amato RJ Loughnan MS Flynn E Folkman J Thalidomide is an inhibitor of angiogenesis Proc Natl Acad Sci U S A 1994 91 4082 4085 10.1073/pnas.91.9.4082 7513432 \n17. Grinspan D Significant response of oral aphthosis to thalidomide treatment J Am Acad Dermatol 1985 12 85 90 10.1016/S0190-9622(85)70014-X 3980807 \n18. Hamuryudan V Mat C Saip S Ozyazgan Y Siva A Yurdakul S Thalidomide in the treatment of the mucocutaneous lesions of Behcet’s syndrome: a randomized, double-blind, placebo-controlled trial Ann Intern Med 1998 128 443 459 10.7326/0003-4819-128-6-199803150-00004 9499327 \n19. Barlogie B Desikan R Eddlemon P Spencer T Zeldis J Munshi N Extended survival in advanced and refractory multiple myeloma after single-agent thalidomide: identification of prognostic factors in a phase 2 study of 169 patients Blood 2001 98 492 494 10.1182/blood.V98.2.492 11435324 \n20. Singhal S Mehta J Desikan R Ayers D Roberson P Eddlemon P Anti-tumor activity of thalidomide in refractory multiple myeloma N Engl J Med 1999 341 1565 1571 10.1056/NEJM199911183412102 10564685 \n21. Palumbo A, Bringhen S, Caravita T, Merla E, Capparella V, Callea V, et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomised controlled trial. Lancet, 2006;367:825.\n22. Kurstin R Using thalidomide in a patient with epithelioid leiomyosarcoma and Osler-weber-Rendu disease Oncology 2002 16 21 24 11831608 \n23. Pérez-Encinas M Rabunal Martinez MJ Bello Lopez JL Is thalidomide effective for the treatment of gastrointestinal bleeding in hereditary hemorrhagic telangiectasia Haematologica 2002 87 ELT 34 \n24. Lebrin F Srun S Raymond K Martin S van den Brink S Freitas C Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia Nat Med 2010 16 420 428 10.1038/nm.2131 20364125 \n25. Kirkham SE Lindley KJ Elawad MA Blanshard C Shah N Treatment of multiple small bowel angiodysplasia causing severe life-threatening bleeding with thalidomide J Pediatr Gastroenterol Nutr 2006 42 585 587 10.1097/01.mpg.0000215308.86287.98 16707986 \n26. Bauditz J Lochs H Voderholzer W Macroscopic appearance of intestinal angiodysplasias under antiangiogenic treatment with thalidomide Endoscopy 2006 38 1036 1039 10.1055/s-2006-944829 17058171 \n27. Dabak V Kuriakose P Kamboj G Shurafa M A pilot study of thalidomide in recurrent GI bleeding due to angiodysplasias Dig Dis Sci 2008 53 632 635 10.1007/s10620-007-0067-z \n28. Hosman A Westermann CJ Snijder R Disch F Mummery CL Mager JJ Follow-up of thalidomide treatment in patients with hereditary Haemorrhagic telangiectasia Rhinology 2015 53 340 344 10.4193/Rhin14.289 26735132 \n29. Invernizzi R Quaglia F Klersy C Pagella F Ornati F Chu F Efficacy and safety of thalidomide for the treatment of severe recurrent epistaxis in hereditary haemorrhagic telangiectasia: results of a non-randomised, single-center, phase 2 study Lancet Haematol 2015 2 65 73 10.1016/S2352-3026(15)00195-7 \n30. Halderman AA, Ryan MW, Clark C, Sindwani R, Reh DD, Poetker DM, et al. Medical treatment of epistaxis in hereditary hemorrhagic telangiectasia: an evidence-based review. Int Forum Allergy Rhinol. 2018. 10.1002/alr.22094.\n31. Hurwitz H Fehrenbacher L Novotny W Cartwright T Hainsworth J Heim W Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer N Engl J Med 2004 350 2335 2342 10.1056/NEJMoa032691 15175435 \n32. Johnson DH Fehrenbacher L Novotny WF Herbst RS Nemunaitis JJ Jablons DM Randomized phase II trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small-cell lung cancer J Clin Oncol 2004 22 2184 2191 10.1200/JCO.2004.11.022 15169807 \n33. Bose P Holter JL Selby GB Bevacizumab in hereditary hemorrhagic telangiectasia N Engl J Med 2009 360 2143 2144 10.1056/NEJMc0901421 19439755 \n34. Iyer VN Apala DR Pannu BS Kotecha A Brinjikji W Leise MD Intravenous bevacizumab for refractory hereditary hemorrhagic telangiectasia-related epistaxis and gastrointestinal bleeding Mayo Clin Proc 2018 93 2 155 166 10.1016/j.mayocp.2017.11.013 29395350 \n35. Dupuis-Girod SGI Saurin JC Marion D Guillot E Decullier E Roux A Bevacizumab in patients with hereditary hemorrhagic telangiectasia and severe hepatic vascular malformations and high cardiac output JAMA 2012 307 948 955 10.1001/jama.2012.250 22396517 \n36. Vlachou PA Colak E Koculym A Kirpalani A Kim TK Hirschfield GM Improvement of ischemic cholangiopathy in three patients with hereditary hemorrhagic telangiectasia following treatment with bevacizumab J Hepatol 2013 59 186 189 10.1016/j.jhep.2013.02.006 23439260 \n37. Mitchell A, Adams LA, MacQuillan G, Tibballs J, vanden Driesen R, Delriviere L. Bevacizumab reverses need for liver transplantation in hereditary hemorrhagic telangiectasia. Liver Transpl 2008;14:210–213.\n38. Guilhem A, Fargeton AE, Simon AC, Duffau P, Harle JR, Lavigne C, et al. Intra-venous bevacizumab in hereditary hemorrhagic telangiectasia (HHT): a retrospective study of 46 patients. PLoS One. 2017;12. 10.1371/journal.pone.0188943.\n39. Palumbo A Davies F Kropff M Bladé J Delforge M Leal da Costa F Consensus guidelines for the optimal management of adverse events in newly diagnosed, transplant-ineligible patients receiving melphalan and prednisone in combination with thalidomide (MPT) for the treatment of multiple myeloma Ann Hematol 2010 89 803 811 10.1007/s00277-010-0925-1 20232066 \n40. Cohen MH Gootenberg J Keegan P Pazdur R FDA drug approval summary: bevacizumab (Avastin) plus carboplatin and paclitaxel as first-line treatment of advanced/metastatic recurrent nonsquamous non-small cell lung cancer Oncologist 2007 12 713 718 10.1634/theoncologist.12-6-713 17602060 \n41. Li J Zhou L Chen X Ba Y Addition of bevacizumab to chemotherapy in patients with ovarian cancer: a systematic review and meta-analysis of randomized trials Clin Transl Oncol 2015 17 673 683 10.1007/s12094-015-1293-z 25990506 \n42. Gressett SM Shah SR Intricacies of bevacizumab-induced toxicities and their management Ann Pharmacother 2009 43 490 501 10.1345/aph.1L426 19261963 \n43. Sandler A Gray R Perry MC Brahmer J Schiller JH Dowlati A Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer N Engl J Med 2006 355 2542 2550 10.1056/NEJMoa061884 17167137 \n44. Maestraggi Q Bouattour M Toquet S Jaussaud R Kianmanesh R Durand F Bevacizumab to Treat Cholangiopathy in Hereditary Hemorrhagic Telangiectasia: Be Cautious: A Case Report Medicine (Baltimore) 2015 94 46 10.1097/MD.0000000000001966 \n45. Stickel F Z'graggen K Bevacizumab for the treatment of Osler's disease – a note of caution Liver Int 2017 37 927 928 10.1111/liv.13361 28097789 \n46. Muller YD Oppliger R Breguet R Meyer P Rubbia-Brandt L Petignat PA Hereditary haemorrhagic telangiectasia: to transplant or not to transplant - is there a right time for liver transplantation? Liver Int 2016 36 1735 1740 10.1111/liv.13187 27864873 \n47. European Reference Networks: https://ec.europa.eu/health/ern_en Accessed 26 Oct 2018.\n48. The European Reference Network for Vascular Diseases (VASCERN) HHT WG: https://vascern.eu/expertise/rare-diseases-wgs/hht-wg/ Accessed 26 Oct2018.\n49. The European Reference Network for Rare Multisystemic Vascular Diseases : https://vascern.eu/expertise/rare-diseases-wgs/hht-wg/ Accessed 26 Oct2018.\n50. Buscarini E, Botella LM, Geisthoff UW, Kjeldsen A, Mager HJ, Pagella F, et al. Vascern HHT survey 2: drug registry-part 1. Angiogenesis. 2017. 10.1007/s10456-017-9584-3.\n51. Buscarini E Manfredi G Gazzaniga P Reduzzi L Danesino C Olivieri C Thalidomide for treatment of chronic severe bleeding in hereditary hemorrhagic telangiectasia Hematol Meet Rep 2009 3 20 21 \n52. CTCAE, 4.03 https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03/. Accessed 15 Apr 2017.\n53. Buscarini E Leandro G Conte D Danesino C Daina E Manfredi G Natural history and outcome of hepatic vascular malformations in a large cohort of patients with hereditary hemorrhagic teleangiectasia Dig Dis Sci 2011 56 2166 2178 10.1007/s10620-011-1585-2 21290179 \n54. EU European population, https://ec.europa.eu/eurostat/documents/2995521/9063738/3-10072018-BP-EN.pdf/ccdfc838-d909-4fd8-b3f9-db0d65ea457f. Accessed 28 Oct 2018.\n55. Shovlin CL, Bamford KB, Sabbà C, Mager HJ, Kjeldsen AD, Droege F, et al. Prevention of serious infections in hereditary haemorrhagic telangiectasia: roles for prophylactic antibiotics, the pulmonary capillaries- but not vaccination. Haematologica. 2018; in press.\n56. Livesey JA Manning RA Meek JH Jackson JE Kulinskaya E Laffan MA Low serum iron levels are associated with elevated plasma levels of coagulation factor VIII and pulmonary emboli/deep venous thromboses in replicate cohorts of patients with hereditary haemorrhagic telangiectasia Thorax 2012 67 328 333 10.1136/thoraxjnl-2011-201076 22169361 \n57. Thielemans L, Layton DM, Shovlin CL. Low serum haptoglobin and blood films suggest intravascular haemolysis contributes to severe anaemia in hereditary haemorrhagic telangiectasia. Haematologica. 2018. 10.3324/haematol.2018.205682 [Epub ahead of print].\n58. Dupuis-Girod S Buscarini E Hereditary hemorrhagic telangiectasia: to transplant or not to transplant? Liver Int 2016 36 1741 1744 10.1111/liv.13210 27864870 \n59. Dupuis-Girod S Buscarini E Response to bevacizumab for the treatment of Rendu-Osler disease-a note of caution Liver Int 2017 37 928 10.1111/liv.13385 28544692 \n60. Shovlin CL Buscarini E Hughes JMB Allison DJ Jackson JE Long-term outcomes of patients with pulmonary arteriovenous malformations considered for lung transplantation, compared with similarly hypoxaemic cohorts BMJ Open Respir Res 2017 4 e000198 10.1136/bmjresp-2017-000198 \n61. Devlin HL Hosman AE Shovlin CL Antiplatelet and anticoagulant agents in hereditary hemorrhagic telangiectasia N Engl J Med 2013 28 368 876 878 10.1056/NEJMc1213554 \n62. Shovlin CL Sodhi V McCarthy A Lasjaunias P Jackson JE Sheppard MN Estimates of maternal risks of pregnancy for women with hereditary haemorrhagic telangiectasia (Osler-weber-Rendu syndrome): suggested approach for obstetric services BJOG 2008 115 1108 1115 10.1111/j.1471-0528.2008.01786.x 18518871 \n63. Rizvi A Macedo P Babawale L Tighe HC Hughes JMB Jackson JE Hemoglobin is a vital determinant of arterial oxygen content in hypoxemic patients with pulmonary arteriovenous malformations Ann Am Thorac Soc 2017 14 903 911 10.1513/AnnalsATS.201611-872OC 28267932 \n64. Kjeldsen AD Kjeldsen J Gastrointestinal bleeding in patients with hereditary hemorrhagic telangiectasia Am J Gastroenterol 2000 95 415 418 10.1111/j.1572-0241.2000.01792.x 10685743 \n65. Kjeldsen AD Vase P Green A Hereditary haemorrhagic telangiectasia: a population-based study of prevalence and mortality in Danish patients J Intern Med 1999 245 31 39 10.1046/j.1365-2796.1999.00398.x 10095814 \n66. Kjeldsen A Aagaard KS Tørring PM Möller S Green A 20-year follow-up study of Danish HHT patients-survival and causes of death Orphanet J Rare Dis 2016 11 157 10.1186/s13023-016-0533-9 27876060 \n67. Brufsky AM Hurvitz S Perez E Swamy R Valero V O'Neill V RIBBON-2: a randomized, double-blind, placebo-controlled, phase III trial evaluating the efficacy and safety of bevacizumab in combination with chemotherapy for second-line treatment of human epidermal growth factor receptor 2-negative metastatic breast cancer J Clin Oncol 2011 29 4286 4293 10.1200/JCO.2010.34.1255 21990397 \n68. Hurwitz HI Tebbutt NC Kabbinavar F Giantonio BJ Guan ZZ Mitchell L Efficacy and safety of bevacizumab in metastatic colorectal cancer: pooled analysis from seven randomized controlled trials Oncologist 2013 18 1004 1012 10.1634/theoncologist.2013-0107 23881988 \n69. Chen X Chen Y Cai X Zhang D Fan L Qiu H Efficacy and safety of bevacizumab in elderly patients with advanced colorectal cancer: a meta-analysis J Cancer Res Ther 2017 13 869 877 10.4103/jcrt.JCRT_405_17 29237919 \n70. Misawa S Sato Y Katayama K Nagashima K Aoyagi R Sekiguchi Y Safety and efficacy of thalidomide in patients with POEMS syndrome: a multicentre, randomised, double-blind, placebo-controlled trial Lancet Neurol 2016 15 1129 1137 10.1016/S1474-4422(16)30157-0 27496680 \n71. Palumbo A Waage A Hulin C Beksac M Zweegman S Gay F Safety of thalidomide in newly diagnosed elderly myeloma patients: a meta-analysis of data from individual patients in six randomized trials Haematologica 2013 98 87 94 10.3324/haematol.2012.067058 22875621 \n72. Palmaro A Rougé-Bugat ME Gauthier M Despas F Moulis G Lapeyre-Mestre M Real-life practices for preventing venous thromboembolism in multiple myeloma patients: a cohort study from the French health insurance database Pharmacoepidemiol Drug Saf 2017 26 578 586 10.1002/pds.4180 28198064 \n73. Brinjikji W Nasr DM Wood CP Iyer VN Pulmonary arteriovenous malformations are associated with silent brain infarcts in hereditary hemorrhagic telangiectasia patients Cerebrovasc Dis 2017 44 179 185 10.1159/000478734 28746925\n\n",
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"issn_linking": "1750-1172",
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"keywords": "Adverse event; Arteriovenous malformation; Bevacizumab; Bleeding; Cardiac failure; Epistaxis; Hereditary hemorrhagic telangiectasia; Nosebleeds; Thalidomide",
"medline_ta": "Orphanet J Rare Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000068258:Bevacizumab; D004844:Epistaxis; D005260:Female; D006470:Hemorrhage; D006801:Humans; D008297:Male; D012189:Retrospective Studies; D011795:Surveys and Questionnaires; D013683:Telangiectasia, Hereditary Hemorrhagic; D013792:Thalidomide; D055815:Young Adult",
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{
"abstract": "Implementation of ABO-incompatible (ABOi) pediatric heart transplantation has contributed to significant reduction in the mortality of infants on the waiting list, without increasing the risk of rejection. This has been attributed to the immature and therefore not fully competent immune system in this population group, which results in lower production of isohemagglutinins compared to older children and adults. Serial evaluations of isohemagglutinin titers in infants revealed cases with absence of donor specific anti-blood group antibodies. However, it is currently unknown whether continuous exposure to donor antigens is necessary to prevent formation of donor specific isohemagglutinins (DSI) in recipients. We are reporting a case of an infant who underwent ABOi heart transplantation, with no evidence of DSI even 4 years after ABO-compatible retransplantation. Hence, temporary exposure to donor antigens in infants may contribute to permanent absence of donor specific anti-blood group antibodies, suggesting the possibility of induced permanent B cell tolerance.",
"affiliations": "Department of Pediatric Cardiology and Intensive Care Medicine, Ludwig-Maximilians-University Munich, Munich, Germany.",
"authors": "Kohler|S|S|;Engmann|R|R|;Birnbaum|J|J|;Fuchs|A|A|;Kaczmarek|I|I|;Netz|H|H|;Kozlik-Feldmann|R|R|",
"chemical_list": "D000017:ABO Blood-Group System; D006388:Hemagglutinins",
"country": "United States",
"delete": false,
"doi": "10.1111/ajt.12973",
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"issn_linking": "1600-6135",
"issue": "14(12)",
"journal": "American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons",
"keywords": "ABO incompatibility; clinical research/practice; donor-specific hyporesponsiveness; heart transplantation/cardiology; tolerance",
"medline_ta": "Am J Transplant",
"mesh_terms": "D000017:ABO Blood-Group System; D001787:Blood Group Incompatibility; D005260:Female; D006084:Graft Rejection; D006331:Heart Diseases; D016027:Heart Transplantation; D006388:Hemagglutinins; D006801:Humans; D007108:Immune Tolerance; D007223:Infant; D011183:Postoperative Complications; D011379:Prognosis; D012086:Reoperation; D014019:Tissue Donors",
"nlm_unique_id": "100968638",
"other_id": null,
"pages": "2903-5",
"pmc": null,
"pmid": "25293954",
"pubdate": "2014-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "ABO-compatible retransplantation after ABO-incompatible infant heart transplantation: absence of donor specific isohemagglutinins.",
"title_normalized": "abo compatible retransplantation after abo incompatible infant heart transplantation absence of donor specific isohemagglutinins"
} | [
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"medicinalproduct": "AZATHIOPRINE."
}
],
"patientagegroup": "3",
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"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Left ventricle outflow tract obstruction",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "3"
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "18.1",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2007"
}
},
"primarysource": {
"literaturereference": "KOHLER S, ENGMANN R, BIRNBAUM J, FUCHS A, KACZMAREK I, NETZ H, ET AL.. ABO-COMPATIBLE RETRANSPLANTATION AFTER ABO INCOMPATIBLE INFANT HEART TRANSPLANTATION:ABSENCE OF DONOR SPECIFIC ISOHEMAGGLUTININS. AMERICAN JOURNAL OF TRANSPLANTATION. 2014?14 (12):2903-5",
"literaturereference_normalized": "abo compatible retransplantation after abo incompatible infant heart transplantation absence of donor specific isohemagglutinins",
"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20151012",
"receivedate": "20150114",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportid": 10709941,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160304"
},
{
"companynumb": "DE-APOTEX-2015AP009576",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CYCLOSPORINE"
},
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},
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"drugdosagetext": "TARGET LEVEL 11-13 NG/ML",
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"drugindication": "IMMUNOSUPPRESSION",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TACROLIMUS."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
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"drugadministrationroute": "065",
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"drugdosagetext": "UNK",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "IMMUNOSUPPRESSION",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
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"drugtreatmentdurationunit": null,
"medicinalproduct": "AZATHIOPRINE."
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "TACROLIMUS"
},
"drugadditional": null,
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "TARGET LEVEL 7-8 NG/ML",
"drugenddate": null,
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"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
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"drugstartdate": null,
"drugstartdateformat": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "TACROLIMUS."
}
],
"patientagegroup": "3",
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Gastrointestinal disorder",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Left ventricle outflow tract obstruction",
"reactionmeddraversionpt": "19.0",
"reactionoutcome": "3"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KOHLER, S; ENGMANN, R; BIRNBAUM, J; FUCHS, A; KACZMAREK, I; NETZ, H ET AL.. ABO-COMPATIBLE RETRANSPLANTATION AFTER ABO-INCOMPATIBLE INFANT HEART TRANSPLANTATION: ABSENCE OF DONOR SPECIFIC ISOHEMAGGLUTININS.. AM-J-TRANSPLANT 2014. 2014;14(12):2903-2905",
"literaturereference_normalized": "abo compatible retransplantation after abo incompatible infant heart transplantation absence of donor specific isohemagglutinins",
"qualification": "3",
"reportercountry": "DE"
},
"primarysourcecountry": "DE",
"receiptdate": "20160509",
"receivedate": "20160509",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 12347053,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20160815"
}
] |
{
"abstract": "The presentation of drug-induced lupus erythematosus (DILE) is typically mild, with a significantly lower incidence of life-threatening end-organ dysfunction relative to idiopathic systemic lupus erythematosus. DILE is an uncommon cause of cardiac tamponade but has been reported in patients treated with procainamide, isoniazid, hydralazine, sulfasalazine, and carbamazepine. We present a case of DILE presenting with cardiac tamponade associated with infliximab use that resolved with discontinuation of the medication and administration of high-dose steroids. In conclusion, DILE should be considered in the differential diagnosis in cases of pericarditis with cardiac tamponade without a clear cause.",
"affiliations": "Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada. Electronic address: dharnett@toh.on.ca.;St Clare's Mercy Hospital, Memorial University of Newfoundland, St John's, Newfoundland, Canada.;St Clare's Mercy Hospital, Memorial University of Newfoundland, St John's, Newfoundland, Canada.",
"authors": "Harnett|David T|DT|;Chandra-Sekhar|Harnahalli B|HB|;Hamilton|Sean F|SF|",
"chemical_list": "D000911:Antibodies, Monoclonal; D005765:Gastrointestinal Agents; D014409:Tumor Necrosis Factor-alpha; D000069285:Infliximab",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0828-282X",
"issue": "30(2)",
"journal": "The Canadian journal of cardiology",
"keywords": null,
"medline_ta": "Can J Cardiol",
"mesh_terms": "D000328:Adult; D000911:Antibodies, Monoclonal; D002305:Cardiac Tamponade; D003093:Colitis, Ulcerative; D004452:Echocardiography; D005765:Gastrointestinal Agents; D006801:Humans; D000069285:Infliximab; D008180:Lupus Erythematosus, Systemic; D008297:Male; D020519:Pericardiocentesis; D014409:Tumor Necrosis Factor-alpha",
"nlm_unique_id": "8510280",
"other_id": null,
"pages": "247.e11-2",
"pmc": null,
"pmid": "24373757",
"pubdate": "2014-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Drug-induced lupus erythematosus presenting with cardiac tamponade: a case report and literature review.",
"title_normalized": "drug induced lupus erythematosus presenting with cardiac tamponade a case report and literature review"
} | [
{
"companynumb": "CA-HIKMA PHARMACEUTICALS CO. LTD-2017CA002988",
"fulfillexpeditecriteria": "1",
"occurcountry": "CA",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "1",
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "POWDER FOR INJECTION",
"drugdosagetext": "UNK (EVERY 8 WEEKS)",
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"drugindication": "COLITIS ULCERATIVE",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "INFLIXIMAB HOSPIRA"
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "MESALAMINE"
},
"drugadditional": null,
"drugadministrationroute": null,
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"medicinalproduct": "MESALAZINE"
},
{
"actiondrug": null,
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"activesubstancename": "AZATHIOPRINE"
},
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"drugintervaldosageunitnumb": "1",
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"medicinalproduct": "AZATHIOPRINE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": null,
"drugadministrationroute": null,
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"drugbatchnumb": null,
"drugcharacterization": "2",
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"medicinalproduct": "PREDNISONE."
},
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "COLCHICINE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "2",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "COLCHICINE."
}
],
"patientagegroup": null,
"patientonsetage": null,
"patientonsetageunit": null,
"patientsex": null,
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Cardiac tamponade",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pericarditis",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Lupus-like syndrome",
"reactionmeddraversionpt": "19.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "HARNETT, D.. DRUG-INDUCED LUPUS ERYTHEMATOSUS PRESENTING WITH CARDIAC TAMPONADE: A CASE REPORT AND LITERATURE REVIEW. CANADIAN JOURNAL OF CARDIOLOGY. 2014;30 (2):247.E11-247.E12",
"literaturereference_normalized": "drug induced lupus erythematosus presenting with cardiac tamponade a case report and literature review",
"qualification": "3",
"reportercountry": "CA"
},
"primarysourcecountry": "CA",
"receiptdate": "20170314",
"receivedate": "20170314",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13335499,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20170428"
}
] |
{
"abstract": "BACKGROUND\nExperimental experience and the technological evolution of minimally invasive surgical devices have allowed initial reports describing the clinical applicability of natural orifice translumenal endoscopic surgery (NOTES). Colorectal resections are an interesting target for the NOTES platform. Theoretically, the transrectal approach could overcome the proposed limitations of transvaginal access, increasing NOTES clinical applicability. Hybrid procedures such as minilaparoscopy-assisted natural orifice surgery (MA-NOS) are the safe progression to pure NOTES. This report describes the first clinical case of a transrectal MA-NOS total colectomy.\n\n\nMETHODS\nThe patient was a 36-year-old man with severe ulcerative colitis (UC) who experienced failure of immunosuppressive therapy. The standard steps of laparoscopic total colectomy were respected, with basic triangulation maintained throughout the case. A transrectal endoscopic device was used for optic assistance, colon dissection, ileum section, and specimen retrieval. Transrectal MA-NOS total colectomy was assisted by three laparoscopic ports: a 12-mm port used as the terminal ileostomy site, a 2-mm needle epigastric port, and a 5-mm umbilical port used as a drain site at the final intervention. No intraoperative complications occurred.\n\n\nRESULTS\nThe total operative time was 240 min. Oral intake was initiated on postoperative day 2. Because of UC rectal activity, a course with azathioprine was completed, and the patient was discharged receiving 1 g of rectal mesalazine for maintenance. The final pathology demonstrated pancolonic inflammatory bowel disease in the form of UC with severe activity.\n\n\nCONCLUSIONS\nTransrectal MA-NOS total colectomy was feasible and safe in the reported case. Improvement in NOTES instrumentation and selective clinical applications are mandatory before clinical trials.",
"affiliations": "Department of Gastrointestinal Surgery, Institute of Digestive and Metabolic Diseases, Hospital Clínic, University of Barcelona, Villarroel 170, 08036 Barcelona, Spain. alacy@clinic.ub.es",
"authors": "Lacy|Antonio M|AM|;Saavedra-Perez|David|D|;Bravo|Raquel|R|;Adelsdorfer|Cedric|C|;Aceituno|Montserrat|M|;Balust|Jaume|J|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00464-011-2117-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0930-2794",
"issue": "26(7)",
"journal": "Surgical endoscopy",
"keywords": null,
"medline_ta": "Surg Endosc",
"mesh_terms": "D003082:Colectomy; D003093:Colitis, Ulcerative; D005240:Feasibility Studies; D006801:Humans; D007081:Ileostomy; D010535:Laparoscopy; D008297:Male; D057605:Natural Orifice Endoscopic Surgery; D012007:Rectum; D013048:Specimen Handling; D055815:Young Adult",
"nlm_unique_id": "8806653",
"other_id": null,
"pages": "2080-5",
"pmc": null,
"pmid": "22258297",
"pubdate": "2012-07",
"publication_types": "D002363:Case Reports; D023362:Evaluation Study; D016428:Journal Article",
"references": "20010345;18461385;20204417;15233681;20186432;17173916;21442425;18362621;19343435;19242758",
"title": "Minilaparoscopy-assisted natural orifice total colectomy: technical report of a minilaparoscopy-assisted transrectal resection.",
"title_normalized": "minilaparoscopy assisted natural orifice total colectomy technical report of a minilaparoscopy assisted transrectal resection"
} | [
{
"companynumb": "ES-MYLANLABS-2018M1087904",
"fulfillexpeditecriteria": "1",
"occurcountry": "ES",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "AZATHIOPRINE"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": "075568",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "150 MILLIGRAM, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "COLITIS ULCERATIVE",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "150",
"drugstructuredosageunit": "003",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "AZATHIOPRINE."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "3",
"drugadministrationroute": "065",
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": null,
"drugdosagetext": "MAINTENANCE DOSE",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "COLITIS ULCERATIVE",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
"drugstartdate": null,
"drugstartdateformat": null,
"drugstructuredosagenumb": "5",
"drugstructuredosageunit": "007",
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "INFLIXIMAB"
}
],
"patientagegroup": null,
"patientonsetage": "36",
"patientonsetageunit": "801",
"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Treatment failure",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Pulmonary tuberculosis",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "6"
}
],
"summary": {
"narrativeincludeclinical": "CASE EVENT DATE: 2010"
}
},
"primarysource": {
"literaturereference": "LACY AM, SAAVEDRA-PEREZ D, BRAVO R, ADELSDORFER C, ACEITUNO M, BALUST J. MINILAPAROSCOPY-ASSISTED NATURAL ORIFICE TOTAL COLECTOMY: TECHNICAL REPORT OF A MINILAPAROSCOPY-ASSISTED TRANSRECTAL RESECTION. SURG-ENDOSC 2012?26(7):2080-2085.",
"literaturereference_normalized": "minilaparoscopy assisted natural orifice total colectomy technical report of a minilaparoscopy assisted transrectal resection",
"qualification": "3",
"reportercountry": "ES"
},
"primarysourcecountry": "ES",
"receiptdate": "20181210",
"receivedate": "20181210",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 15706859,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190205"
}
] |
{
"abstract": "Cytomegalovirus (CMV) is a common opportunistic infection in solid organ transplant (SOT) recipients in the first 6 months after transplant. Late onset CMV infection or disease outside the classical risk period is uncommon and can present with atypical signs and symptoms. Here, we report a case of late onset CMV presenting as a colonic stricture more than 10 years after liver transplantation in the absence of traditional CMV risk factors. We also briefly review CMV colitis presenting as a mass or stricture in SOT recipients.",
"affiliations": "Division of Gastroenterology and Hepatology, Carolinas Medical Center, Atrium Health, Charlotte, NC, USA.;Carolinas Pathology Group, Charlotte, NC, USA.;Transplant Center, Carolinas Medical Center, Atrium Health, Charlotte, NC, USA.;Center for Liver Diseases and Liver transplantation, Carolinas Medical Center, Atrium Health, Charlotte, NC, USA.;Center for Liver Diseases and Liver transplantation, Carolinas Medical Center, Atrium Health, Charlotte, NC, USA.;Division of Infectious Diseases, Carolinas Medical Center, Atrium Health, Charlotte, NC, USA.",
"authors": "Zeidan|Joseph H|JH|;Kamionek|Michal|M|;Noell|Bennett C|BC|;Schmeltzer|Paul A|PA|;deLemos|Andrew S|AS|;Gajurel|Kiran|K|https://orcid.org/0000-0001-7141-8322",
"chemical_list": "D000998:Antiviral Agents",
"country": "Denmark",
"delete": false,
"doi": "10.1111/tid.13259",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1398-2273",
"issue": "22(2)",
"journal": "Transplant infectious disease : an official journal of the Transplantation Society",
"keywords": "CMV; colonic stricture; cytomegalovirus; liver; transplant",
"medline_ta": "Transpl Infect Dis",
"mesh_terms": "D000368:Aged; D000998:Antiviral Agents; D003092:Colitis; D003106:Colon; D003251:Constriction, Pathologic; D003587:Cytomegalovirus; D003586:Cytomegalovirus Infections; D005260:Female; D006801:Humans; D016031:Liver Transplantation; D008297:Male; D012307:Risk Factors; D012812:Sigmoidoscopy",
"nlm_unique_id": "100883688",
"other_id": null,
"pages": "e13259",
"pmc": null,
"pmid": "32034980",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Late onset CMV disease presenting as a colonic stricture in a liver transplant recipient.",
"title_normalized": "late onset cmv disease presenting as a colonic stricture in a liver transplant recipient"
} | [
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"abstract": "Spotted fevers are diseases caused by bacterial agents belonging to the spotted-fever (SF) group of the genus Rickettsia. The first documented case of SF in Pernambuco State, Northeast Brazil, was reported here. Also, it is the first case described of fatal SF in Northeast region of Brazil. The patient was a resident of Arcoverde municipality and the probable site of infection lies in Sertania municipality, both in Pernambuco State, a semi-arid region of Brazil. The patient had not visited other areas where SF is endemic. The patient showed clinical manifestations and epidemiological exposure compatible with SF, and the infection was confirmed by molecular biology techniques.",
"affiliations": "Secretaria de Vigilância em Saúde, Ministério da Saúde, Brasília, Distrito Federal, Brazil.;Secretaria de Saúde do Estado de Pernambuco, Recife, Pernambuco, Brazil.;Secretaria de Saúde do Estado de Pernambuco, Recife, Pernambuco, Brazil.;Secretaria de Vigilância em Saúde, Ministério da Saúde, Brasília, Distrito Federal, Brazil.;Laboratório de Referência Nacional para Vetores das Riquetsioses, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.;Departamento de Medicina Veterinária, Universidade Federal Rural de Pernambuco, Recife, Pernambuco, Brazil.;Departamento de Medicina Veterinária, Universidade Federal Rural de Pernambuco, Recife, Pernambuco, Brazil.;Laboratório de Referência Nacional para Vetores das Riquetsioses, Fundação Oswaldo Cruz, Rio de Janeiro, Rio de Janeiro, Brazil.",
"authors": "Oliveira|Stefan Vilges de|SV|;Costa|Raylene Medeiros Ferreira|RMF|;Ferreira|Geane|G|;Pereira|Simone Valéria Costa|SVC|;Amorim|Marinete|M|;Monteiro|Maria Fernanda Melo|MFM|;Alves|Leucio Câmara|LC|;Gazeta|Gilberto Salles|GS|",
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"country": "Brazil",
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"doi": "10.1590/s1678-9946201860021",
"fulltext": "\n==== Front\nRev Inst Med Trop Sao PauloRev. Inst. Med. Trop. Sao PaulorimtspRevista do Instituto de Medicina Tropical de São Paulo0036-46651678-9946Instituto de Medicina Tropical 298464720060410.1590/S1678-9946201860021Brief CommunicationFatal case of spotted fever in a patient from Northeastern\nBrazil de Oliveira Stefan Vilges \n1\n\n2\nCosta Raylene Medeiros Ferreira \n3\nFerreira Geane \n3\nPereira Simone Valéria Costa \n1\nAmorim Marinete \n2\nMonteiro Maria Fernanda Melo \n4\nAlves Leucio Câmara \n4\nGazeta Gilberto Salles \n2\n\n1 Ministério da Saúde, Secretaria de Vigilância em Saúde, Brasília,\nDistrito Federal, Brazil\n2 Fundação Oswaldo Cruz, Laboratório de Referência Nacional para\nVetores das Riquetsioses, Rio de Janeiro, Rio de Janeiro, Brazil\n3 Secretaria de Saúde do Estado de Pernambuco, Recife, Pernambuco,\nBrazil\n4 Universidade Federal Rural de Pernambuco, Departamento de Medicina\nVeterinária, Recife, Pernambuco, BrazilCorrespondence to: Stefan Vilges de Oliveira. Ministério da Saúde,\nSecretaria de Vigilância em Saúde, SRTV 702, Via W 5 Norte, CEP 70723-040,\nBrasília, Distrito Federal, Brazil. E-mail:\nstefanbio@yahoo.com.brCONFLICT OF INTERESTS\n\nThe authors declare that they have no competing interests.\n\nAUTHORS’ CONTRIBUTIONS\n\nSVO and GSG participated in the study planning; MFM and LCA were responsible\nfor the molecular diagnosis. RMFC, GF, SVCP and MA were involved in\ndiscussion of results and the drafting/ reviewing of the manuscript. All\nauthors have read and approved the final manuscript.\n\n28 5 2018 2018 60 e2124 11 2017 1 3 2018 This is an Open Access article distributed under the terms of the\nCreative Commons Attribution Non-Commercial License, which permits\nunrestricted non-commercial use, distribution, and reproduction in any\nmedium, provided the original work is properly cited. ABSTRACT\nSpotted fevers are diseases caused by bacterial agents belonging to the\nspotted-fever (SF) group of the genus Rickettsia. The first\ndocumented case of SF in Pernambuco State, Northeast Brazil, was reported here.\nAlso, it is the first case described of fatal SF in Northeast region of Brazil.\nThe patient was a resident of Arcoverde municipality and the probable site of\ninfection lies in Sertania municipality, both in Pernambuco State, a semi-arid\nregion of Brazil. The patient had not visited other areas where SF is endemic.\nThe patient showed clinical manifestations and epidemiological exposure\ncompatible with SF, and the infection was confirmed by molecular biology\ntechniques.\n\nRickettsiaDifferential diagnosisTick-borne diseasesBrazilian semi-arid, Caatinga biome\n==== Body\nINTRODUCTION\nSpotted fever (SF) is an infectious, acute, febrile disease of varying severity,\nmainly transmitted by ticks\n1\n\n,\n\n2\n. It has a non-specific symptomatology, during which early\nclinical-epidemiological diagnosis is a great challenge\n3\n. The rash, considered the only clinical marker, is not always present, which\ndelays diagnosis and hinders appropriate medical action\n4\n.\n\nIn Brazil, the occurrence of other diseases of epidemic nature and more incidents\n(with similar symptomatology) add to the diagnostic difficulty, since it is\nnecessary to consider the occurrence of other acute febrile diseases during\nassessment of cases\n5\n.\n\nSF is widespread, with the highest incidence rate in the South and Southeast\n6\n. Classically, severe cases were associated with Rickettsia\nrickettsii, which have been recorded in anthropized areas of the\nCerrado and Atlantic Rainforest biomes. The lethality rate of R.\nrickettsii infection in Brazil exceeds 50%, and may even reach\n100%\n7\n\n-\n\n10\n.\n\nIn the Atlantic Rainforest, SF is also caused by Rickettsia sp.\nAtlantic Rainforest strain, a species genetically close to Rickettsia\nparkeri, Rickettsia sibirica and Rickettsia\nafricae. In these area, both milder clinical forms were observed,\nhaving as common characteristics the presence of inoculation eschars (lesion at the\ntick attachment site) and lymphadenopathy\n2\n\n,\n\n11\n\n-\n\n17\n. In the Northeast of Brazil, Rickettsia sp. Atlantic\nRainforest strain has been recorded from fragments of Atlantic Rainforest in the\nStates of Bahia and Ceara, though there were no reports of associated deaths\n6\n\n,\n\n15\n\n-\n\n17\n. Here we described the first fatal case of spotted fever in the Northeast\nBrazil.\n\nCase presentation\nA 78-year-old male patient with Alzheimer’s disease, resident of Arcoverde\nmunicipality, State of Pernambuco, was admitted to hospital on November 14,\n2015, with fever, oliguria and palmar and plantar rash. Symptom onset was\nreported to have begun approximately seven days before, accompanied by a\nprogressive decline in general conditions. After admission, there was worsening\nof the clinical state, with tachypnea and decline in renal function. The patient\nwas hospitalized, and management for pulmonary sepsis and renal dysfunction were\ninitiated.\n\nAfter 24 hours, a seizures occurred (there was no history of epilepsy). The\npatient was sedated (dormonid [midazolam] + fentanyl), intubated and transferred\nto the State referral hospital in Recife, Pernambuco (PE), where he was admitted\nto the intensive care unit. There, the following were observed: bilateral\npleural effusion, leukocytosis with left upper shift; distended abdomen; Miotic\npupils, GOT/AST - 188 U/L; GPT/ALT - 76 U/L; Total Bilirubin - 2.10 mg/dL,\nDirect - 2.00 mg/dL, Indirect - 0.10 mg/dL; CK MB - 12 U/L; CK Total - 438 U/L.\nThe diagnostic hypotheses were severe viral meningoencephalitis; metabolic\nencephalopathy; acute respiratory failure or metabolic ileus. Treatment with\nintramuscular ceftriaxone and acyclovir was initiated.\n\nOn November 21st, 2015, the patient’s condition got worsened,\nsecretions were accumulating in the respiratory tract in moderate quantity.\nTeicoplanin was included in the treatment.\n\nOn November 24th, suspicion of rickettsiosis was raised as a result of\nthe family information about the patient’s routine visit to a rural property,\nlocated in Sertania municipality, State of Pernambuco, where he had direct and\nindirect contact with animals (dogs, horses, goats, armadillos, cows).\nDoxycycline treatment administered twice a day was initiated. The patient did\nnot improve during treatment and died on January 16th, 2016.\n\nA blood sample collected on November 24th, 2015 and kept at -20ºC, was\nsent for analysis of Rickettsia sp. using the Polymerase Chain\nReaction (PCR). We used gene-specific primers CS-78 (forward\n[5’-GCAAGTATCGGTGAGGATGTAAT-3’]), CS-323 (reverse\n[5’-GCTTCCTTAAAATTCAATAAATCAGGAT’-3’]) - which amplify a 401-bp fragment of the\nCitrate Synthase gene (gltA). Ultrapure milli-Q water was used, free of DNA, as\nthe negative control, and Rickettsia parkeri genomic DNA as the\npositive control. PCR temperature conditions included an initial cycle at 95 °C\nfor 3 min; 40 cycles of 15 s at 95 °C, 30 s at 48 °C and 30 s at 72 °C and one\nfinal cycle at 72 °C for 7 min\n18\n\n,\n\n19\n.\n\nThe blood sample tested positive. However, the obtained sequence did not allow\nthe construction of a phylodendrogram to determine the identity of the detected\nrickettsia.\n\nDISCUSSION\nAlthough the indirect immunofluorescence test is considered the gold standard for SF\ndiagnosis, there was initially no clinical suspicion. Thus, the sampling procedure\ndid not follow the protocol established by the Brazilian Ministry of Health\n19\n and, thus, it was not possible to evaluate the serological conversion by\nusing paired samples collected with a minimum interval of 14 days. However, case\nconfirmation can be made by other laboratory criteria, including molecular\nmethods\n19\n. The performed molecular assays detected a genomic-specific gene fragment,\nconfirming the patient’s infection by Rickettsia sp.\n\nThe absence of initial clinical and epidemiological indicators, coupled with the\nrapid evolution of SF, has resulted in rickettsial deaths in several Brazilian\nStates\n3\n\n,\n\n5\n\n,\n\n6\n. Rickettsia rickettsii shows the strongest pathological\nalterations associated with the most severe and lethal clinical conditions. The\neffects of this pathogenic mechanism result in localized inflammation and\nprocoagulant processes, causing increased vascular permeability, edema, hypovolemia\nand hypotension with vascular insufficiency associated with the subsequent leukocyte\nmononuclear response of the host\n20\n. However, even if the patient’s clinical evolution is compatible with\nR. rickettsii infections\n19\n, existing data are insufficient to infer which rickettsia species was\nresponsible for the infection. Also, it is not possible to evaluate whether the\ninfection got worsened due to comorbidity/patient’s advanced age, or whether the use\nof different antimicrobials during treatment could have interfered in the disease\nprogression, which had a morbidity period distinct from that known for R.\nrickettsii\n\n8\n.\n\nDuring the epidemiological investigation of the case, it was considered that the\npatient had no history of travel to any area where SF is known to be endemic, and\nthat the probable site of infection (PSI) (in Sertania municipality, PE) was the\nonly environment frequented by the patient possessing favorable conditions for\ndevelopment of the rickettsial enzootic and epidemic cycle. The rural property,\nabout 60 km from the patient’s home, was frequently visited, primarily serving as a\nrecreation area, as well as for the rearing of a few wild animals (armadillos), kept\nin captivity as a food source, and a variety of domestic animals (cows, goats etc.).\nAn environmental investigation in the PSI, conducted during the patient’s\nhospitalization period, did not detect any of the ticks known in Brazil for\ntransmitting rickettsia\n2\n.\n\nThis result indicates the possibility of a still unknown transmission scenario in the\ncountry. The SF foci closer to the Caatinga biome have been detected only in the\nState of Ceara so far. However, these areas were located in Atlantic forest\nfragments and, like other foci in Brazilian Atlantic forests, involved dogs,\nAmblyomma ovale ticks and Rickettsia sp.\nstrain Atlantic Rainforest, and mild to moderate disease associated with inoculation\nswelling and lymphadenopathy\n15\n\n,\n\n17\n. In contrast, both Sertania municipality and Arcoverde municipality (where\nthe patient resided) lie within the Caatinga biome, in a typical area of the\nBrazilian semi-arid region\n21\n. This area lacks any previous known epidemiological context for SF\nestablishment. R. rickettsii was recently detected in\nRhipicephalus sanguineus in areas of spotted fever transmission\nin Northeastern Brazil\n22\n, indicating the presence of this tick in areas where the ecoepidemiological\nprofile is still unknown. However, this tick has a wide geographic distribution and\nis responsible for SF transmission in other parts of the world\n1\n. This potential vector was found during the PSI investigation, but a PCR for\nRickettsia was negative for the analyzed samples\n23\n.\n\nConsidering that this is the first SF case in this region, to confirm identification\nof the transmission site and increase the robustness of the existing laboratory\nresults, blood collection of contact people, area residents and animals (dogs and\nhorses), as well as a seasonal monitoring of vector fauna, could reinforce the\nidentity of the probable site of infection and support characterization of this new\ntransmission scenario.\n\nCONCLUSIONS\nThe first SF case is reported from Pernambuco State, in the Brazilian semiarid area,\nCaatinga biome, as the first death in the Northeast of Brazil associated with\nRickettsia sp.\n\nACKNOWLEDGMENTS\nWe would like to thank the team from the Zoonosis Surveillance Technical Unit, the\ntechnical group for rodent-related diseases from the Brazilian Ministry of Health,\nand the team for epidemiological and environmental surveillance of Pernambuco. We\nalso thank Adrian Paul Ashton Barnett for the English review and comments to\nmanuscript.\n==== Refs\nREFERENCES\n1 Parola P Paddock CD Socolovschi C Labruna MB Mediannikov O Kernif T et al Update on tick-borne rickettsioses around the world: a geographic\napproach Clin Microbiol Rev 2013 26 657 702 24092850 \n2 Szabó MP Pinter A Labruna MB Ecology, biology and distribution of spotted-fever tick vectors\nin Brazil Front Cell Infect Microbiol 2013 3 27 \n3 Oliveira SV Caldas EP Colombo S Gazeta GS Labruna MB Santos FC et al A fatal case of Brazilian spotted fever in a non-endemic area in\nBrazil: the importance of having health professionals who understand the\ndisease and its areas of transmission Rev Soc Bras Med Trop 2016 49 653 5 27812666 \n4 Biggs HM Behravesh CB Bradley KK Dahlgren FS Drexler NA Dumler JS et al Diagnosis and management of tickborne rickettsial diseases: Rocky\nMountain spotted fever and other spotted fever group rickettsioses,\nehrlichioses, and anaplasmosis - United States MMWR Recomm Rep 2016 65 1 44 \n5 Lopez DM de Mello FL Giordano Dias CM Almeida P Araújo M Magalhães MA et al Evaluating the surveillance system for spotted fever in Brazil\nusing machine-learning techniques Front Public Health 2017 5 323 \n6 Oliveira SV Guimarães JN Reckziegel GC Neves BM Araújo-Vilges KM Fonseca LX et al An update on the epidemiological situation of spotted fever in\nBrazil J Venom Anim Toxins Incl Trop Dis 2016 22 22 \n7 Lemos E Rozental T Villela CL Brazilian spotted fever: description of a fatal clinical case in\nthe State of Rio de Janeiro Rev Soc Bras Med Trop 2002 35 523 5 12621675 \n8 Angerami RN Câmara M Pacola MR Rezende RC Duarte RM Nascimento EM et al Features of Brazilian spotted fever in two different endemic\nareas in Brazil Ticks Tick Borne Dis 2012 3 346 348 23168052 \n9 Labruna MB Mattar V S Nava S Bermudez S Venzal JM Dolz G et al Rickettsioses in Latin America, Caribbean, Spain and\nPortugal Rev MVZ Córdoba 2011 16 2435 2457 \n10 Faccini-Martínez AA Muñoz-Leal S Acosta IC Oliveira SV Duré AI Cerutti C Jr et al Confirming Rickettsia rickettsii as the etiological agent of\nspotted fever group rickettsiosis in human lethal cases from Espírito Santo\nstate, Brazil Ticks Tick Borne Dis 2018 9 496 499 29371125 \n11 Silva N Eremeeva ME Rozental T Ribeiro GS Paddock CD Ramos EA et al Eschar-associated spotted fever rickettsiosis, Bahia,\nBrazil Emerg Infect Dis 2011 17 275 278 21291605 \n12 Vizzoni VF Silva AB Cardoso KM Santos FB Stenzel B Amorim M et al Genetic identification of Rickettsia sp. strain Atlantic\nrainforest in an endemic area of a mild spotted fever in Rio Grande do Sul\nstate, Southern Brazil Acta Trop 2016 162 142 145 27338183 \n13 Krawczak FS Munõz-Leal S Guztzazky AC Oliveira SV Santos FC Angerami RN et al Rickettsia sp. strain Atlantic rainforest infection in a patient\nfrom a spotted fever-endemic area in southern Brazil Am J Trop Med Hyg 2016 95 551 3 27325804 \n14 Oliveira SV Regarding the ecoepidemiology of a tick-borne spotted fever\nSouthernmost state of Brazil Ann Clin Cytol Pathol 2017 3 1048 \n15 Oliveira SV Tick-borne spotted fever in the northeast of Brazil: the series\nof cases a new endemic area Rev Med UFC 2016 56 8 9 \n16 Spolidorio MG Labruna MB Mantovani E Brandão PE Richtzenhain LJ Yoshinari NH Novel spotted fever group rickettsiosis, Brazil Emerg Infect Dis 2010 16 521 523 20202436 \n17 Moerbeck L Vizzoni VF Machado-Ferreira E Cavalcante RC Oliveira SV Soares CA et al Rickettsia (Rickettsiales: Rickettsiaceae) vector biodiversity in\nhigh altitude Atlantic Forest fragments within a semiarid climate: a new\nendemic area of spotted-fever in Brazil J Med Entomol 2016 53 1458 1466 27480099 \n18 Labruna MB Whitworth T Horta MC Bouyer DH McBride JW Pinter A et al Rickettsia species infecting Amblyomma cooperi ticks from an area\nin the state of São Paulo, Brazil, where Brazilian spotted fever is\nendemic J Clin Microbiol 2004 42 90 98 14715737 \n19 Brasil Ministério da Saúde Secretaria de Vigilância em Saúde Coordenação-Geral de Desenvolvimento da Epidemiologia em\nServiços Guia de vigilância em saúde: volume único 2ª Brasília Ministério da Saúde 2017 cited 2018 Feb 5 http://portalarquivos.saude.gov.br/images/pdf/2017/outubro/06/Volume-Unico-2017.pdf \n20 Walker DH Raoult D Rickettsia ricketsii and other spotted fever group rickettsiae\n(Rocky Mountain spotted fever and other spotted fever) Mandell GL Bennett JE Dolin R. editors Mandell, Douglas, and Bennett’s Principles and practices of infectious\ndiseases 6th New York Elsevier/Churchill Livingstone 2005 2287 2295 \n21 Borsato R coordenação Ecorregiões do Brasil: prioridades terrestres e marinhas Curitiba Instituto Life 2015 \n22 Silva AB Duarte MM Cavalcante RC Oliveira SV Vizzoni VF Duré AI et al Rickettsia rickettsii infecting Rhipicephalus sanguineus sensu\nlato (Latreille 1806), in high altitude atlantic forest fragments, Ceará\nstate, Brazil Acta Trop 2017 173 30 33 28535905 \n23 Silva AB Cardoso KM Oliveira SV Costa RM Oliveira G Amorim M et al Rickettsia amblyommatis infecting Amblyomma pseudoconcolor in\narea of new focus of spotted fever in northeast Brazil Acta Trop 2018 182 305 308 29545159\n\n",
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{
"abstract": "BACKGROUND\nMental illness is a leading cause of non-fatal disease burden worldwide. Natural health products (NHPs) are sought by patients with mental health conditions as a safer and more 'natural' option than conventional pharmacotherapy; however, the possible adverse events (AE) and interactions between NHPs and prescription medicines are not fully known.\n\n\nOBJECTIVE\nThe aim of this study was to determine (i) the prevalence of adult patients with mental health conditions taking prescription medications only, NHPs only, NHPs and prescription medications concurrently, or neither, (ii) which prescription medications and NHPs are most commonly used, (iii) AEs (serious and non-serious) experienced in the last 30 days for each product use group.\n\n\nMETHODS\nMental health clinics in Alberta and Ontario, Canada, were included in an active surveillance study investigating NHP-drug interactions. On their first clinic visit, adult mental health patients were provided with a form inquiring about prescription drug use, NHP use, and any undesirable health events experienced in the last month. Healthcare professionals were also asked to report AEs.\n\n\nRESULTS\nA total of 3079 patients were screened at 11 mental health clinics in Alberta and Ontario. In total, 620 AEs were reported in 447 patients (14.9%). The majority of adverse events were seen in patients using both NHPs and prescription medicines (58.8%), followed by patients taking only prescription medicines (37.1%), NHPs only (3.4%) and neither (0.67%). Combining NHPs and prescription medications increases the likelihood of experiencing AEs (OR 2.1; p < 0.001; 95% CI 1.7-2.6).\n\n\nCONCLUSIONS\nAdult patients with mental health conditions who are taking both prescription medications and NHPs are more likely to report an adverse event than patients taking prescription drugs or NHPs alone. Polypharmacy increases the likelihood of an adverse event. Active surveillance is feasible and could contribute to enhanced pharmacovigilance.",
"affiliations": "Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, 4-584 Edmonton Clinic Health Academy (ECHA), 11405-87 Ave NW, Edmonton, AB, T6G 1C9, Canada.;Naturopathic Medicine, Bastyr University California-San Diego Campus, San Diego, USA.;Temerty Faculty of Medicine, University of Toronto, Toronto, Canada.;Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Canada.;Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.;S.T.A.R.T. Clinic (Stress, Trauma, Anxiety, Rehabilitation and Treatment) for Mood and Anxiety Disorders, Northern School of Medicine (NOSM), Thunder Bay, Canada.;Department of Psychiatry, Temerty Faculty of Medicine, University of Toronto, Toronto, Canada.;Department of Psychiatry, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Canada.;School of Pharmacy, University of Auckland, Auckland, New Zealand.;Department of Pediatrics, Faculty of Medicine and Dentistry, University of Alberta, 4-584 Edmonton Clinic Health Academy (ECHA), 11405-87 Ave NW, Edmonton, AB, T6G 1C9, Canada. svohra@ualberta.ca.",
"authors": "Zorzela|Liliane|L|;Khamba|Baljit|B|;Sparks|Emma|E|;Necyk|Candace|C|;Urichuk|Liana|L|;Katzman|Martin A|MA|;Koczerginski|David|D|;Chue|Pierre|P|;Barnes|Joanne|J|;Vohra|Sunita|S|http://orcid.org/0000-0002-6210-7933",
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"country": "New Zealand",
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"doi": "10.1007/s40264-021-01092-w",
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"issue": "44(9)",
"journal": "Drug safety",
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"other_id": null,
"pages": "999-1006",
"pmc": null,
"pmid": "34322863",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": "23902484;7249508",
"title": "Study of Natural Products Adverse Reactions (SONAR) in Adults with Mental Health Conditions: A Cross-Sectional Study.",
"title_normalized": "study of natural products adverse reactions sonar in adults with mental health conditions a cross sectional study"
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"literaturereference": "Zorzela L, Khamba B, Khamba E, Necyk C, Urichuk L, Katzman MA et al. Study of Natural Products Adverse Reactions (SONAR) in Adults with Mental Health Conditions: A Cross-Sectional Study. Drug Safety. 2021",
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{
"abstract": "BACKGROUND\nDiabetic papillopathy is a rare diagnosis of exclusion characterized by unilateral or bilateral optic disc edema with variable degrees of visual loss. Although the visual prognosis has been generally reported as favorable, the presence of severe disc edema associated with macular edema prompts the need for treatment. We present a specific and unreported therapeutic approach consisting of intravitreal aflibercept and subtenon triamcinolone acetonide injections in two patients with evidence of diabetic papillopathy and macular edema.\n\n\nMETHODS\nIn the first case, a 60-year-old Caucasian woman affected by type II diabetes mellitus presented with fundoscopic evidence of sequential bilateral optic disc edema associated with acute severe visual loss in both eyes. The second patient, a diabetic 57-year-old Caucasian male, presented with sudden painless visual loss in his left eye. Multimodal imaging and systemic findings correlated towards an infrequent diagnosis of diabetic papillopathy. In a period of 5-7 weeks after treatment, both patients experienced almost full visual and anatomical recovery. A steady situation was observed at 12 months of follow-up.\n\n\nCONCLUSIONS\nBoth our cases displayed a severe grade of optic disc edema, which was optimally reversed with intravitreal aflibercept and subtenon triamcinolone acetonide leading to a relatively rapid and safe improvement in visual acuity.",
"affiliations": "The Eye Clinic, Experimental Sciences, Polytechnic University of Marche, Via Conca, 71, Torrette, AN, 60126, Italy. arapi_ilir@hotmail.com.;Eye Insitute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates.;The Eye Clinic, Experimental Sciences, Polytechnic University of Marche, Via Conca, 71, Torrette, AN, 60126, Italy.;The Eye Clinic, Mother Theresa University Hospital, Tirana, Albania.",
"authors": "Arapi|Ilir|I|;Neri|Piergiorgio|P|;Giovannini|Alfonso|A|;Grezda|Arjeta|A|",
"chemical_list": "D005938:Glucocorticoids; D011993:Recombinant Fusion Proteins; C533178:aflibercept; D040262:Receptors, Vascular Endothelial Growth Factor",
"country": "England",
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"fulltext": "\n==== Front\nJ Med Case Rep\nJ Med Case Rep\nJournal of Medical Case Reports\n1752-1947\nBioMed Central London\n\n3129\n10.1186/s13256-021-03129-1\nCase Report\nCombined therapy with intravitreal aflibercept and subtenon corticosteroids in eyes with severe diabetic papillopathy: two case reports\nArapi Ilir arapi_ilir@hotmail.com\n\n13\nNeri Piergiorgio nerip@clevelandclinicabudhabi.ae\n\n2\nGiovannini Alfonso a.giovannini@univpm.it\n\n1\nGrezda Arjeta arjeta_demi@yahoo.com\n\n3\n1 grid.7010.6 0000 0001 1017 3210 The Eye Clinic, Experimental Sciences, Polytechnic University of Marche, Via Conca, 71, Torrette, AN 60126 Italy\n2 Eye Insitute, Cleveland Clinic Abu Dhabi, Abu Dhabi, United Arab Emirates\n3 The Eye Clinic, Mother Theresa University Hospital, Tirana, Albania\n22 10 2021\n22 10 2021\n2021\n15 51818 1 2021\n22 9 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\nDiabetic papillopathy is a rare diagnosis of exclusion characterized by unilateral or bilateral optic disc edema with variable degrees of visual loss. Although the visual prognosis has been generally reported as favorable, the presence of severe disc edema associated with macular edema prompts the need for treatment. We present a specific and unreported therapeutic approach consisting of intravitreal aflibercept and subtenon triamcinolone acetonide injections in two patients with evidence of diabetic papillopathy and macular edema.\n\nCase presentation\n\nIn the first case, a 60-year-old Caucasian woman affected by type II diabetes mellitus presented with fundoscopic evidence of sequential bilateral optic disc edema associated with acute severe visual loss in both eyes. The second patient, a diabetic 57-year-old Caucasian male, presented with sudden painless visual loss in his left eye. Multimodal imaging and systemic findings correlated towards an infrequent diagnosis of diabetic papillopathy. In a period of 5–7 weeks after treatment, both patients experienced almost full visual and anatomical recovery. A steady situation was observed at 12 months of follow-up.\n\nConclusions\n\nBoth our cases displayed a severe grade of optic disc edema, which was optimally reversed with intravitreal aflibercept and subtenon triamcinolone acetonide leading to a relatively rapid and safe improvement in visual acuity.\n\nKeywords\n\nDiabetic papillopathy\nAflibercept\nSubtenon triamcinolone acetonide\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nDiabetic patients are susceptible to an uncommon form of optic neuropathy that is characterized by an acute optic disc edema with a relative absence of significant optic nerve dysfunction [1]. Diabetic papillopathy (DP) seems not to be associated with the severity of diabetic retinopathy (DR), while it affects one or both eyes and has been described in either type I or type II diabetes [2, 3]. Although the pathophysiology of DP remains to be fully elucidated, a combination of factors focused on the optic disc such as diabetic microangiopathy and a small disc have been reported as possible mechanisms [1, 4, 5]. Owing to the lack of a specific treatment protocol, different approaches were described, employing corticosteroids and anti-vascular endothelial growth factor (VEGF) injections, in order to reduce the disc swelling.\n\nTo the best of our knowledge, herein we report on the first successful employment of a combination therapy including subtenon triamcinolone acetonide injection (STTAI) and intravitreal aflibercept injection (IAI) in two patients who were affected by DP.\n\nCase reports\n\nCase 1\n\nA 60-year-old Caucasian lady with poorly controlled type 2 diabetes mellitus (DM) presented herself 3 days after an acute drop in visual acuity in the right eye (OD), with a vision of 6/360. The patient was on oral hypoglycemic agents, and the last measured glycated hemoglobin (HbA1c) was 10.9%. Intraocular pressure (IOP) was 15 mmHg in both eyes (OU). The patient was phakic and had a normal anterior examination bilaterally, without signs of afferent pupillary defect (APD). Fundus examination and fundus autofluorescence (FAF) showed, respectively, a swollen optic disc and diffuse peripapillary hypoautofluorescence in OD (Fig. 1A, B) and a moderate nonproliferative diabetic retinopathy (NPDR) in OU. Fundus fluorescein angiography (FFA) highlighted dye leakage from the optic disc, while spectral domain optical coherent tomography (SD-OCT) imaging in OD revealed an abnormal increase in the retinal nerve fiber layer (RNFL) thickness and macular edema (ME) (Fig. 1B, C). Magnetic resonance imaging (MRI) scan of the brain and the laboratory work-up including inflammatory/infective etiologies and sedimentation rate (ESR) produced normal results. The patient was diagnosed with severe DP, and after informed consent she received an IAI (2 mg/0.05 mL) (Eylea Bayer Pharma AG) associated with a STTAI (40 mg/mL) (Kenacort Bristol-Myers Squibb Australia Pty Ltd). Seven weeks following the injections, the best corrected visual acuity (BCVA) in OD was 20/30 with an almost complete resolution of the optic disc edema (Fig. 1E–H). Within 30 days from the first presentation, the patient’s left eye (OS) exhibited more or less the same clinical picture as OD (Fig. 2A–C), with a BCVA of 6/60. The patient underwent the same therapy associated with a remarkable anatomic improvement (Fig. 1D–G) and a BCVA of 20/25 within 5 weeks. IOP values remained in the normal range at 6 months.Fig. 1 A Infrared image showing severe swelling of the nerve (left eye), splinter hemorrhages, and superficial dilated vessels associated with nonproliferative diabetic retinopathy. B Fundus autofluorescence showing diffuse peripapillary hypoautofluorescence and foveal hyperautofluorescence spots consistent with macular edema. C Fundus fluorescein angiography highlighting hyperfluorescence due to telangiectatic capillaries during the late venous phase. D Spectral domain optical coherent tomography revealing a significant increase in retinal nerve fiber layer thickness, serous retinal detachment (SRD), and macular edema. E After treatment, fundus fluorescein angiography showing a hypofluorescent disc and a remarkable reduction of macular leakage. F Notice the reduction of retinal nerve fiber layer thickness and macular edema\n\nFig. 2 A Infrared imaging and B Fundus autofluorescence showing evidence of moderate-to-severe optic disc edema, peripapillary hypoautofluorescence, and foveal cysts in left eye. C Spectral domain optical coherent tomography showing marked edema of the optic disc and macular edema. Five weeks post-treatment D autofluorescence, E fundus fluorescein angiography, and F spectral domain optical coherent tomography showing marked regression of disc swelling with mild signs of macular edema, respectively\n\nCase 2\n\nA 57-year-old Caucasian male with a 10-year history of type 2 DM presented with sudden visual loss in OD. The patient was on insulin therapy (HbA1c 11.2%). The patient was phakic, BCVA was 6/120, IOP was 17 mmHg, and there were no signs of APD. Fundoscopy revealed a swelling of the optic disc with telangiectatic vessels, along with mild NPDR (Fig. 3A, B). Moderate disc leakage and serous macular detachment were noted on FFA and OCT (Fig. 3C, D). A neurologic consultation with cranial MRI and lab findings showed no abnormality. Five weeks after receiving IAI and STTAI, the patient’s BCVA returned to 20/30, with regression of the disc edema (Fig. 3E–G). The patient developed moderate steroid-induced hypertension after 3 weeks and was treated with topical antiglaucomatous drugs. Written consent to publish case details was obtained from both patients.Fig. 3 A Infrared imaging showing severe diabetic papillopathy with B diffuse hypoautofluorescence; C late venous phase associated with hyperfluorescent telangiectatic vessels associated with moderate leakage and mild nonproliferative diabetic retinopathy; D Spectral domain-optical coherent tomography revealing diffuse retinal nerve fiber layer thickening and serous macular detachment in left eye. Five weeks post injections there is strong evidence of improvement in multimodal imaging (E, F)\n\nDiscussion\n\nAbove we present the clinical findings of three eyes (two patients) consistent with DP, undergoing combined therapy with locoregional corticosteroids and anti-VEGFs. Although the differential diagnosis of DP includes a variety of entities such as infectious/inflammatory optic neuropathies, central retinal vein occlusion, idiopathic intracranial hypertension, and hypertensive retinopathy, its main differential remains non-arteritic anterior ischemic optic neuropathy (NA-AION). Our cases were associated with low BCVA due to the severity of DP and the concomitant ME, while the timing and level of visual recovery clearly distinguish DP from an eventual NA-AION diagnosis [2, 6, 7]. Moreover, our cases were associated with angiographic features not showing delays of filling in the prelaminar portion of the optic disc. In addition, no dysfunction of this structure was observed during follow-up. Recent studies report that DP patients have a shorter disease duration and are relatively younger compared with AION patients [8].\n\nEven though the exact pathogenesis of DP remains a subject of controversy, different theories have been proposed to explain its occurrence. The dysmetabolic events seem to be leading to epi-/peripapillary microangiopathy with consequent leakage into and around the optic nerve head (ONH), while others believe that these ischemic and toxic optic nerve head changes might be related to a circulatory compromise in the deeper laminar vascular structures and axoplasmic flow disruption [9, 10]. The interplay between inflammatory cytokines and VEGF might serve as a rationale for the successful employment of corticosteroids and anti-VEGF agents in DP-related edema [11].\n\nThe anti-inflammatory effects, inhibitory effects on VEGF synthesis, and role in reducing vascular permeability of corticosteroids associated with the synergistic rapid decrease of VEGF provided by anti-VEGF agents achieved good efficacy in our study. Given the speculative and dichotomous mechanism of disc swelling in DP and owing to the severe drop in vision of our cases, we opted for a dual therapy. Our choice of the subtenon route for the triamcinolone acetonide (TA) injection was mainly influenced by the lesser extent of complications compared with the intravitreal route, and by the lens status. Intravitreal TA (IVTA) has limitations, including elevated IOP, cataract progression, pseudo-endophthalmitis, and infectious endophthalmitis [12–14], while STTAI is not free of potential complications such as accidental injection directly into the choroidal or retinal circulation, perforation of the ocular bulb, occlusion of the central retinal artery, and cataract [15]. Another reason was that, through this approach, the intravitreal therapy would be eventually focused on the superficial resolution of venous engorgement and stabilization of the hematoretinal barrier, while STTAI performed superonasally would target the deep nerve vasculature and the consequent decongestion. Indeed, there are reports supporting the employment of peri-/retrobulbar injections to attain sufficient corticosteroid concentrations around the optic nerve [16, 17].\n\nNumerous papers regarding eventual therapies in DP include periocular/intravitreal corticosteroids, intravitreal anti-VEGFs, and laser photocoagulation. Mansour et al. reported on the beneficial effects of subtenon betamethasone injection in six eyes with DP and ME, highlighting the anti-edema and angiostatic effects of corticosteroids, as well as the good safety profile with only one eye requiring antiglaucomatous therapy. The authors underlined the importance of superonasal/temporal injections to reach the optic nerve and macular area, respectively [18]. IVTA injection alone was associated with rapid improvement in vision from a baseline BCVA of counting fingers at 1 m in a DP case [19]. The main suggestion was to reserve such a treatment for bilateral cases with severe drop in vision.\n\nThe actual literature provides numerous papers reporting on the efficacy of anti-VEGF agents while accentuating the role of VEGF in the vascular permeability of telangiectatic disc vessels and macular capillaries, given that ME is a common finding in more than half of DP patients [20–23]. The common denominator of these cases is represented by the mild-to-moderate grade of severity of DP, the baseline BCVA > 0.1, and the lack of macular edema. In the absence of precise markers of disease severity, the aforementioned criteria might eventually guide the therapeutic choice.\n\nWe were able to find only one paper dealing with a combined approach in the case of a patient affected by DP, where the authors administered intravenous bevacizumab and IVTA injection [24]. In this case, compared with ours, visual recovery was noticed relatively early, presumably owing to the mild clinical severity of DP. There are many reports of off-label use of intravitreal triamcinolone in cases of persistent and refractory diabetic macular edema. In the comparison between IVTA and STTAI, Choi et al. reported that both routes had similar effects on diabetic macular edema (DME), but that IVTA increased IOP after 3 months [25]. Ozdek et al. found a threefold increase in the number of eyes showing a significant increase in IOP (> 21 mmHg) that had been undergoing IVTA compared with STTAI [26]. Regarding the risk of cataract progression, patients treated with STTAI showed an evident safety profile [27, 28]. Kurt et al. recently reported similar anatomic and functional improvements after both IVTA and STTAI administrations in diabetic eyes [29]. Moreover, in this study, both routes of injection led to a significant constriction of retinal arteries and veins and, as a result, to the decline of vascular permeability and leakage [30]. The choice of TA delivery in the ocular compartment is subject to various opinions, and we agree that further research including larger samples is warranted to confirm our findings.\n\nIn conclusion, we affirm that DP is a challenging and rare diagnosis. As shown in our study, a specific treatment combining sequential IAI and STTAI for severe cases associated with macular edema would be beneficial in terms of a relatively fast and safe recovery.\n\nAbbreviations\n\nDP Diabetic papillopathy\n\nDR Diabetic retinopathy\n\nSTTAI Subtenon triamcinolone acetonide injection\n\nIAI Intravitreal aflibercept injection\n\nDM Diabetes mellitus\n\nHbA1c Glycated hemoglobin\n\nIOP Intraocular pressure\n\nOD Right eye\n\nOU Both eyes\n\nAPD Afferent pupillary defect\n\nFAF Fundus autofluorescence\n\nNPDR Nonproliferative diabetic retinopathy\n\nFFA Fundus fluorescein angiography\n\nSD-OCT Spectral domain optical coherence tomography\n\nRNFL Retinal nerve fiber layer\n\nMRI Magnetic resonance imaging\n\nME Macular edema\n\nESR Sedimentation rate\n\nBCVA Best corrected visual acuity\n\nOS Left eye\n\nNA-AION Non-arteritic anterior ischemic optic neuropathy\n\nOCTA Optical coherence tomography angiography\n\nIVTA Intravitreal triamcinolone acetonide\n\nAcknowledgements\n\nWe thank the patients for agreeing to publish this report.\n\nAuthors’ contributions\n\nIA carried out planning and data acquisition and interpretation, and was responsible for drafting and revising the manuscript. PN was involved with planning, data interpretation, and drafting and revising the manuscript. AG was involved with data analysis and manuscript drafting and revision. AD carried out data acquisition and interpretation. All authors read and approved the final manuscript.\n\nFunding\n\nThe authors have not received grant support or research funding related to the current study, and neither have they any proprietary interests in the materials described in the article.\n\nAvailability of data and materials\n\nAll data generated or analyzed during this study are included in this manuscript.\n\nDeclarations\n\nEthics approval and consent to participate\n\nAll procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. This is a case report, retrospectively describing the course of the diagnostics and therapy, and thus does not require approval of the local bioethical committee.\n\nConsent for publication\n\nWritten informed consent was obtained from the patients for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.\n\nCompeting interests\n\nThe authors declare no competing financial interests\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Appen RE Chandra SR Klein R Myers FL Diabetic papillopathy Am J Ophthalmol 1980 90 203 209 10.1016/S0002-9394(14)74854-8 7425031\n2. Regillo CD Brown GC Savino PJ Byrnes GA Benson WE Tasman WS Diabetic papillopathy. Patient characteristics and fundus findings Arch Ophthalmol 1995 113 7 889 895 10.1001/archopht.1995.01100070063026 7605280\n3. Bayraktar Z Alacali N Bayraktar S Diabetic papillopathy in type II diabetic patients Retina 2002 22 752 758 10.1097/00006982-200212000-00011 12476102\n4. Inoue M Tsukahara Y Vascular optic neuropathy in diabetes mellitus Jpn J Ophthalmol 1997 41 328 331 10.1016/S0021-5155(97)00068-3 9363563\n5. Beri M Klugman MR Kohler JA Hayreh SS Anterior ischemic optic neuropathy VII. Incidence of bilaterality and various influencing factors Ophthalmology 1987 94 1020 1028 10.1016/S0161-6420(87)33350-0 3658362\n6. Hayreh SS Anterior ischemic optic neuropathy Arch Neurol 1981 38 675 678 10.1001/archneur.1981.00510110035002 7305693\n7. Dickersin K Everett D Feldon S Hooper F Kaufman D Kelman S Ischemic Optic Neuropathy Decompression Trial Research Group Ischemic optic neuropathy decompression trial, twenty-four-month update Arch Ophthalmol 2000 118 793 798 10.1001/archopht.118.6.793 10865316\n8. Hua R Qu L Ma B Yang P Sun H Liu L Diabetic optic neuropathy and its risk factors in Chinese patients with diabetic retinopathy Invest Ophthalmol Vis Sci 2019 60 10 3514 3519 10.1167/iovs.19-26825 31412110\n9. Feldman-Billard S, Dupas B. Eye disorders other than diabetic retinopathy in patients with diabetes. Diabetes Metab. 2021:101279.\n10. Slagle WS Musick AN Eckermann DR Diabetic papillopathy and its relation to optic nerve ischemia Optom Vis Sci 2009 86 e395 e403 10.1097/OPX.0b013e318198927c 19225435\n11. Giuliari GP Sadaka A Chang PY Cortez RT Diabetic papillopathy: current and new treatment options Curr Diabetes Rev 2011 7 3 171 175 10.2174/157339911795843122 21418004\n12. Diabetic Retinopathy Clinical Research Network A randomized trial comparing intravitreal triamcinolone acetonide and focal/grid photocoagulation for diabetic macular edema Ophthalmology 2008 115 1447 1459 10.1016/j.ophtha.2008.06.015 18662829\n13. Fong AH Chan CK Presumed sterile endophthalmitis after intravitreal triamcinolone (Kenalog)—more common and less benign than we thought? Asia Pac J Ophthalmol (Phila). 2017 6 1 45 49 10.1097/APO.0000000000000194 28161929\n14. Moshfeghi DM Kaiser PK Scott IU Acute endophthalmitis following intravitreal triamcinolone acetonide injection Am J Ophthalmol 2003 136 791 796 10.1016/S0002-9394(03)00483-5 14597028\n15. Mueller AJ Jian G Banker AS The effect of deep posterior subtenon injection of corticosteroids on intraocular pressure Am J Ophthalmol 1998 125 158 163 10.1016/S0002-9394(99)80085-3 9467440\n16. Hyndiuk RA Reagan MG Radioactive depot-corticosteroid penetration into monkey ocular tissue Arch Ophthalmol 1968 80 499 503 10.1001/archopht.1968.00980050501019 4970748\n17. Weijtens O van der Sluijs FA Schoemaker RC Lentjes EG Cohen AF Romijn FP Peribulbar corticosteroid injection: vitreal and serum concentrations after dexamethasone disodium phosphate injection Am J Ophthalmol 1997 123 3 358 363 10.1016/S0002-9394(14)70131-X 9063245\n18. Mansour AM El-Dairi MA Shehab MA Shahin HK Shaaban JA Antonios SR Periocular corticosteroids in diabetic papillopathy Eye (Lond) 2005 19 1 45 51 10.1038/sj.eye.6701418 15094720\n19. Al-Haddad CE Jurdi FA Bashshur ZF Intravitreal triamcinolone acetonide for the management of diabetic papillopathy Am J Ophthalmol 2004 137 6 1151 1153 10.1016/j.ajo.2004.01.032 15183815\n20. Yildirim M Kilic D Dursun ME Dursun B Diabetic papillopathy treated with intravitreal ranibizumab Int Med Case Rep J. 2017 22 10 99 103 10.2147/IMCRJ.S132479\n21. Kim M Lee JH Lee SJ Diabetic papillopathy with macular edema treated with intravitreal ranibizumab Clin Ophthalmol 2013 7 2257 2260 10.2147/OPTH.S55076 24348012\n22. Ornek K Oğurel T Intravitreal bevacizumab for diabetic papillopathy J Ocul Pharmacol Ther 2010 26 2 217 218 10.1089/jop.2009.0125 20334555\n23. Cho IH Ma DJ Swept-source optical coherence tomography angiography findings of diabetic papillopathy after intravitreal bevacizumab Am J Ophthalmol Case Rep. 2020 19 100748 10.1016/j.ajoc.2020.100748 32490284\n24. Feng J Qu JF Jiang YR Resolution of diabetic papillopathy with a single intravitreal injection of bevacizumab combined with triamcinolone acetonide Graefes Arch Clin Exp Ophthalmol 2013 251 11 2651 2652 10.1007/s00417-013-2403-7 23801191\n25. Choi YJ Oh IK Oh JR Huh K Intravitreal versus posterior subtenon injection of triamcinolone acetonide for diabetic macular edema Korean J Ophthalmol 2006 20 205 209 10.3341/kjo.2006.20.4.205 17302204\n26. Ozdek S Bahceci UA Gurelik G Hasanreisoglu B Posterior subtenon and intravitreal triamcinolone acetonide for diabetic macular edema J Diabetes Complications 2006 20 246 251 10.1016/j.jdiacomp.2005.06.015 16798476\n27. Bakri SJ Kaiser PK Posterior subtenon triamcinolone acetonide for refractory diabetic macular edema Am J Ophthalmol 2005 139 290 294 10.1016/j.ajo.2004.09.038 15733990\n28. Cellini M Pazzaglia A Zamparini E Leonetti P Campos EC Intravitreal vs. subtenon triamcinolone acetonide for the treatment of diabetic cystoid macular edema BMC Ophthalmol 2008 8 5 10.1186/1471-2415-8-5 18366650\n29. Kurt MM Çekiç O Akpolat Ç Aslankurt M Elçioğlu M Vessel diameter study: intravitreal vs posterior subtenon triamcinolone acetonide injection for diabetic macular edema Eye (Lond) 2017 31 8 1155 1162 10.1038/eye.2017.46 28338665\n30. Nagel E Vilser W Autoregulative behavior of retinal arteries and veins during changes of perfusion pressure: a clinical study Graefes Arch Clin Exp Ophthalmol 2004 242 13 17 10.1007/s00417-003-0663-3 14648137\n\n",
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{
"abstract": "Fluoroquinolone use has been known to be associated with tendinopathy and tendon rupture for over 30 years. Hand and wrist involvement has been reported rarely, yet without early recognition and withdrawal of the fluoroquinolone, there is potential for significant morbidity.\n\n\n\nWe searched Medline using a comprehensive search strategy for fluoroquinolones and tendinopathy of the hand and wrist, and provide a case report of a possible levofloxacin-related tendon rupture in a patient with a previous mutilating hand injury.\n\n\n\nWe located 10 previously reported cases of fluoroquinolone-associated tendinopathy in the hand or wrist ranging from 1983 to 2015. Unlike Achilles tendinopathy, women were no more likely than men to have tendon rupture affecting the hands or wrists. Our patient was a 59-year-old man with prior tendon repair but otherwise noncontributory medical history who experienced spontaneous tendon rupture on an extended course of levofloxacin and required extensive pulley and boutonnière repair.\n\n\n\nGiven the extensive damage that may be caused to weakened tissue, clinicians should maintain a high index of suspicion of tendinopathy in patients taking fluoroquinolones who have had previous tendon repairs, particularly in the setting of unexplained changes in recovery trajectory.",
"affiliations": "1 The Buncke Clinic, San Francisco, CA, USA.;1 The Buncke Clinic, San Francisco, CA, USA.;1 The Buncke Clinic, San Francisco, CA, USA.",
"authors": "Berger|Israel|I|;Goodwin|Isak|I|;Buncke|Gregory M|GM|",
"chemical_list": "D000900:Anti-Bacterial Agents; D064704:Levofloxacin",
"country": "United States",
"delete": false,
"doi": "10.1177/1558944717701237",
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"issue": "12(5)",
"journal": "Hand (New York, N.Y.)",
"keywords": "adverse events; fluoroquinolone; pulley reconstruction; tendinopathy; tendon repair; tendon rupture; tenolysis",
"medline_ta": "Hand (N Y)",
"mesh_terms": "D000900:Anti-Bacterial Agents; D006225:Hand; D006801:Humans; D064704:Levofloxacin; D008297:Male; D008875:Middle Aged; D052256:Tendinopathy; D014955:Wrist Joint",
"nlm_unique_id": "101264149",
"other_id": null,
"pages": "NP121-NP126",
"pmc": null,
"pmid": "28366020",
"pubdate": "2017-09",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D000078182:Systematic Review",
"references": "10526383;1496284;17235408;17532707;20215992;20567731;20725547;21840134;22035890;23026288;23888427;24701103;24916809;26205818;29252438;6223241;7633807;7761724;9289004",
"title": "Fluoroquinolone-Associated Tendinopathy of the Hand and Wrist: A Systematic Review and Case Report.",
"title_normalized": "fluoroquinolone associated tendinopathy of the hand and wrist a systematic review and case report"
} | [
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{
"abstract": "Doxorubicin is one of the most active drugs for sarcoma. Pegylated liposomal doxorubicin (PLD) is a unique formulation of doxorubicin, which carries a more favorable toxicity profile in comparison with free doxorubicin. The main toxicity of PLD is hand-foot syndrome. Unlike free doxorubicin, PLD is unlikely to cause alopecia, nausea, myelosuppression, or cardiotoxicity. Additionally, no premedications are required. We describe the case of a 50-year-old man with advanced retroperitoneal liposarcoma who developed irreversible PLD-associated progressive renal failure requiring chronic hemodialysis due to a thrombotic microangiopathy. No cardiotoxicity was noted 84 months after he initiated PLD. This case describes a lesser known toxicity of PLD and may be a toxicity of long-term treatment with other liposomal drugs.",
"affiliations": "Division of Hematology and Oncology, Department of Medicine, University of Arizona Cancer Center, 1515 N. Campbell Ave, Tucson, AZ, USA.;Department of Medicine, The University of Minnesota Medical Center, Office Mayo Mail Code 480, 420 Delaware St. SE, Minneapolis, MN, 55455, USA.;Laboratory Medicine and Pathology, The University of Minnesota Medical Center, Minneapolis, MN, USA.;Laboratory Medicine and Pathology, The University of Minnesota Medical Center, Minneapolis, MN, USA.;Department of Medicine, The University of Minnesota Medical Center, Office Mayo Mail Code 480, 420 Delaware St. SE, Minneapolis, MN, 55455, USA. skubi001@umn.edu.",
"authors": "Savani|Malvi|M|;Woerner|Katti|K|;Bu|Lihong|L|;Birkenbach|Mark|M|;Skubitz|Keith M|KM|http://orcid.org/0000-0002-0690-9595",
"chemical_list": "D000903:Antibiotics, Antineoplastic; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00280-020-04203-z",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0344-5704",
"issue": "87(2)",
"journal": "Cancer chemotherapy and pharmacology",
"keywords": "Doxorubicin; Renal toxicity; Sarcoma",
"medline_ta": "Cancer Chemother Pharmacol",
"mesh_terms": "D000903:Antibiotics, Antineoplastic; D018450:Disease Progression; D004317:Doxorubicin; D006801:Humans; D008080:Liposarcoma; D008297:Male; D008875:Middle Aged; D011092:Polyethylene Glycols; D006435:Renal Dialysis; D051437:Renal Insufficiency; D012186:Retroperitoneal Neoplasms; D057049:Thrombotic Microangiopathies",
"nlm_unique_id": "7806519",
"other_id": null,
"pages": "289-294",
"pmc": null,
"pmid": "33388949",
"pubdate": "2021-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "8313389;3461207",
"title": "Pegylated liposomal doxorubicin-induced renal toxicity in retroperitoneal liposarcoma: a case report and literature review.",
"title_normalized": "pegylated liposomal doxorubicin induced renal toxicity in retroperitoneal liposarcoma a case report and literature review"
} | [
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},
"primarysource": {
"literaturereference": "SAVANI M, WOERNER K, BU L, BIRKENBACH M, SKUBITZ K. PEGYLATED LIPOSOMAL DOXORUBICIN?INDUCED RENAL TOXICITY IN RETROPERITONEAL LIPOSARCOMA: A CASE REPORT AND LITERATURE REVIEW. CANCER CHEMOTHERAPY AND PHARMACOLOGY. 2021?.",
"literaturereference_normalized": "pegylated liposomal doxorubicin induced renal toxicity in retroperitoneal liposarcoma a case report and literature review",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20210205",
"receivedate": "20210122",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 18777941,
"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": "Background There is very little evidence relating to the association of herbal medicine with diarrhea and the development of acute kidney injury (AKI). This study reports a case of diarrhea-induced AKI, possibly related to an individual ingesting copious amounts of homemade mixed fruit and herb puree. Case presentation A 45-year-old Thai man with diabetes had diarrhea for 2 days, as a result of taking high amounts of a puree made up of eight mixed fruits and herbs over a 3-day period. He developed dehydration and stage 2 AKI, with a doubling of his serum creatinine. He had been receiving enalapril, as a prescribed medication, over one year. After he stopped taking both the puree and enalapril, and received fluid replacement therapy, within a week his serum creatinine had gradually decreased. The combination of puree, enalapril and AKI may also have induced hyperkalemia in this patient. Furthermore, the patient developed hyperphosphatemia due to his worsening kidney function, exacerbated by regularly taking some dietary supplements containing high levels of phosphate. His serum levels of potassium and phosphate returned to normal within a week, once the patient stopped both the puree and all dietary supplements, and had begun receiving treatment for hyperkalemia. Results The mixed fruit and herb puree taken by this man may have led to his diarrhea due to its effect; particularly if the patient was taking a high concentration of such a drink. Both the puree and enalapril are likely to attenuate the progression of kidney function. The causal relationship between the puree and AKI was probable (5 scores) assessed by the modified Naranjo algorithm. This is the first case report, as far as the authors are aware, relating the drinking of a mixed fruit and herbal puree to diarrhea and AKI in a patient with diabetes. Conclusions This case can alert health care providers to the possibility that herbal medicine could induce diarrhea and develop acute kidney injury.",
"affiliations": null,
"authors": "Wanitsriphinyo|Suphamat|S|;Tangkiatkumjai|Mayuree|M|",
"chemical_list": "D028321:Plant Preparations; D004656:Enalapril",
"country": "Germany",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1553-3840",
"issue": "14(1)",
"journal": "Journal of complementary & integrative medicine",
"keywords": null,
"medline_ta": "J Complement Integr Med",
"mesh_terms": "D058186:Acute Kidney Injury; D003920:Diabetes Mellitus; D003928:Diabetic Nephropathies; D003967:Diarrhea; D019587:Dietary Supplements; D004656:Enalapril; D005638:Fruit; D006801:Humans; D008297:Male; D008875:Middle Aged; D008517:Phytotherapy; D028321:Plant Preparations",
"nlm_unique_id": "101313855",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "28282296",
"pubdate": "2017-03-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Herbal and dietary supplements related to diarrhea and acute kidney injury: a case report.",
"title_normalized": "herbal and dietary supplements related to diarrhea and acute kidney injury a case report"
} | [
{
"companynumb": "TH-BAUSCH-BL-2017-008256",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ENALAPRIL"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "018998",
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"drugcharacterization": "1",
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"medicinalproduct": "ENALAPRIL"
},
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ENALAPRIL"
},
"drugadditional": "1",
"drugadministrationroute": "065",
"drugauthorizationnumb": "018998",
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"drugcharacterization": "1",
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"drugdosagetext": "DOSE: (20) ?X2",
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"medicinalproduct": "ENALAPRIL"
}
],
"patientagegroup": null,
"patientonsetage": "45",
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"patientsex": "1",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Drug interaction",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Food interaction",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
},
{
"reactionmeddrapt": "Hyperkalaemia",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Acute kidney injury",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "2"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WANITSRIPHINYO S. HERBAL AND DIETARY SUPPLEMENTS RELATED TO DIARRHEA AND ACUTE KIDNEY INJURY: A CASE REPORT. JOURNAL OF COMPLEMENTARY AND INTEGRATIVE MEDICINE. 2017;14 (1):0061.",
"literaturereference_normalized": "herbal and dietary supplements related to diarrhea and acute kidney injury a case report",
"qualification": "2",
"reportercountry": "TH"
},
"primarysourcecountry": "TH",
"receiptdate": "20170411",
"receivedate": "20170407",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 13416722,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170830"
}
] |
{
"abstract": "BACKGROUND\nDonor-specific HLA antibody (DSA) is associated with the risk of allograft loss due to antibody-mediated rejection (ABMR). The majority of de novo DSA after kidney transplantation is directed toward donor HLA-DQ antigens. A HLA-DQ antigen is a heterodimer consisting of an alpha and beta chain. Traditionally, HLA-DQA1 typing has not been part of the pretransplant evaluation. Therefore, DQ alpha proteins are not usually taken into account in the interpretation of HLA-DQ antibody reactions.\n\n\nMETHODS\nWe hereby present a case of a kidney transplant recipient with 0% pretransplant panel reactive antibody. She received kidney allograft from her husband. Two years after transplantation, she experienced abdominal swelling, and enlargement of transplanted kidney was identified. A biopsy of the allograft kidney demonstrated chronic active ABMR. DSAs were investigated using immunoglobulin G (IgG) and C1q single antigen bead (SAB) assay. HLAMatchmaker analysis was performed to identify eplets that explain the antibody reactivity patterns.\n\n\nRESULTS\nThe IgG SAB analysis of a patient's serum at the time of rejection showed positive reactions with all DQ2-carrying beads with mean fluorescence intensity (MFI) > 10000. However, the C1q assay demonstrated strong reaction to only HLA-DQA1∗05:01-DQB1∗02:01-carrying bead with MFI = 22462, whereas weak or no reactions against other HLA-DQ2-carrying beads were found. High-resolution HLA typing revealed that HLA-DQA1∗05:01 and DQB1∗02:01 were mismatched donor antigens. HLAMatchmaker analysis showed that the antibodies were reactive toward 40GR3 eplet on DQA1 and 45GE3 eplet on DQB1.\n\n\nCONCLUSIONS\nThis case highlights the clinical significance of antibodies specific to both DQ alpha and DQ beta chains after kidney transplantation.",
"affiliations": "Histocompatibility and Immunogenetics Laboratory, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand. Electronic address: duangtawan.tha@mahidol.ac.th.;Histocompatibility and Immunogenetics Laboratory, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Immunopathology Laboratory, Department of Pathology, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.;Division of Nephrology, Department of Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University, Bangkok, Thailand.",
"authors": "Thammanichanond|Duangtawan|D|;Tammakorn|Chutima|C|;Worawichawong|Suchin|S|;Kantachuvesiri|Surasak|S|",
"chemical_list": "D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D007518:Isoantibodies",
"country": "United States",
"delete": false,
"doi": "10.1016/j.transproceed.2020.02.127",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0041-1345",
"issue": "52(6)",
"journal": "Transplantation proceedings",
"keywords": null,
"medline_ta": "Transplant Proc",
"mesh_terms": "D000328:Adult; D005260:Female; D006084:Graft Rejection; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006801:Humans; D007518:Isoantibodies; D016030:Kidney Transplantation; D014019:Tissue Donors; D014184:Transplantation, Homologous",
"nlm_unique_id": "0243532",
"other_id": null,
"pages": "1931-1936",
"pmc": null,
"pmid": "32444122",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Antibody-Mediated Rejection Due to Donor-Specific HLA-DQB1 and DQA1 Antibodies After Kidney Transplantation: A Case Report.",
"title_normalized": "antibody mediated rejection due to donor specific hla dqb1 and dqa1 antibodies after kidney transplantation a case report"
} | [
{
"companynumb": "NVSC2020TH144291",
"fulfillexpeditecriteria": "1",
"occurcountry": "TH",
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{
"actiondrug": "5",
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"activesubstancename": "TACROLIMUS"
},
"drugadditional": "3",
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"drugindication": "RENAL TRANSPLANT",
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"medicinalproduct": "TACROLIMUS."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISOLONE"
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},
{
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},
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
},
{
"actiondrug": "5",
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"activesubstancename": "TACROLIMUS"
},
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"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY",
"drugintervaldosagedefinition": null,
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"drugrecurreadministration": "3",
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"medicinalproduct": "TACROLIMUS."
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "MYCOPHENOLATE MOFETIL"
},
"drugadditional": "3",
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"drugauthorizationnumb": "65379",
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"drugindication": "IMMUNOSUPPRESSANT DRUG THERAPY",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": null,
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"drugstructuredosageunit": null,
"drugtreatmentduration": null,
"drugtreatmentdurationunit": null,
"medicinalproduct": "MYCOPHENOLATE MOFETIL."
}
],
"patientagegroup": null,
"patientonsetage": "31",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Transplant rejection",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Product use in unapproved indication",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "THAMMANICHANOND D, TAMMAKORN C, WORAWICHAWONG S, KANTACHUVESIRI. ANTIBODY-MEDIATED REJECTION DUE TO DONOR-SPECIFIC HLA-DQB1 AND DQA1 ANTIBODIES AFTER KIDNEY TRANSPLANTATION: A CASE REPORT. TRANSPLANTATION PROCEEDINGS. 2020?1-6",
"literaturereference_normalized": "antibody mediated rejection due to donor specific hla dqb1 and dqa1 antibodies after kidney transplantation a case report",
"qualification": "3",
"reportercountry": "TH"
},
"primarysourcecountry": "TH",
"receiptdate": "20200527",
"receivedate": "20200527",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 17830387,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20200714"
}
] |
{
"abstract": "Recent surveillance from US hospitals shows that more than 99.5% of vancomycin-resistant enterococci (VRE) isolates remain susceptible to daptomycin. This report describes emergence of daptomycin-resistant VRE at a major cancer center. The percentage of patients with daptomycin-resistant VRE bacteremia increased from 3.4% in 2007 to 15.2% in 2009 ([Formula: see text]). Without susceptibility data, empiric daptomycin therapy for VRE infections should be used with caution.",
"affiliations": "Infectious Disease Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA. kambojm@mskcc.org",
"authors": "Kamboj|Mini|M|;Cohen|Nina|N|;Gilhuley|Kathleen|K|;Babady|N Esther|NE|;Seo|Susan K|SK|;Sepkowitz|Kent A|KA|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017576:Daptomycin",
"country": "United States",
"delete": false,
"doi": "10.1086/659152",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0899-823X",
"issue": "32(4)",
"journal": "Infection control and hospital epidemiology",
"keywords": null,
"medline_ta": "Infect Control Hosp Epidemiol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000900:Anti-Bacterial Agents; D016470:Bacteremia; D002648:Child; D017576:Daptomycin; D024901:Drug Resistance, Multiple, Bacterial; D016984:Enterococcus faecium; D005260:Female; D016908:Gram-Positive Bacterial Infections; D006801:Humans; D008297:Male; D008826:Microbial Sensitivity Tests; D008875:Middle Aged; D009369:Neoplasms; D020713:Vancomycin Resistance",
"nlm_unique_id": "8804099",
"other_id": null,
"pages": "391-4",
"pmc": null,
"pmid": "21460492",
"pubdate": "2011-04",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": "11353628;15793168;16007529;7494007;19748426;15573054;17316896;16178502;18180351;16455945",
"title": "Emergence of daptomycin-resistant VRE: experience of a single institution.",
"title_normalized": "emergence of daptomycin resistant vre experience of a single institution"
} | [
{
"companynumb": "US-CUBIST PHARMACEUTICALS, INC.-2011S1000134",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "DAPTOMYCIN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": "021572",
"drugbatchnumb": null,
"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "INJECTION",
"drugdosagetext": null,
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"drugindication": "OFF LABEL USE",
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"medicinalproduct": "CUBICIN"
},
{
"actiondrug": null,
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"activesubstancename": "GENTAMICIN"
},
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"drugcharacterization": "2",
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"drugdosageform": null,
"drugdosagetext": "UNK UNK, UNK",
"drugenddate": null,
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"drugindication": "ENTEROCOCCAL INFECTION",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "GENTAMICIN"
},
{
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},
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"drugdosageform": "INJECTION",
"drugdosagetext": "UNK UNK, UNK",
"drugenddate": null,
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"drugindication": "ENTEROCOCCAL INFECTION",
"drugintervaldosagedefinition": null,
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"medicinalproduct": "CUBICIN"
}
],
"patientagegroup": null,
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"patientonsetageunit": null,
"patientsex": null,
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"reaction": [
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Drug resistance",
"reactionmeddraversionpt": "17.1",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KAMBOJ M, COHEN N, GILHULEY K, BABADY NE, SEO SK, SEPKOWITZ KA. EMERGENCE OF DAPTOMYCIN-RESISTANT VRE: EXPERIENCE OF A SINGLE INSTITUTION. INFECTION CONTROL AND HOSPITAL EPIDEMIOLOGY. 2011;32 (4):391-394",
"literaturereference_normalized": "emergence of daptomycin resistant vre experience of a single institution",
"qualification": "1",
"reportercountry": "US"
},
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"receivedate": "20140930",
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},
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}
] |
{
"abstract": "BACKGROUND\nBleeding from esophageal varices is a serious medical problem because of the risk of recurrent bleeding and high mortality rate (17-54%). Gastroesophageal varices develop in 50% of cirrhotic patients with portal hypertension, but can also develop in other pre- or post-hepatic causes of portal hypertension.\n\n\nMETHODS\nWe reported a 48-year-old female patient with portal hy- pertension caused by mesenterial vein thrombosis due to congenital thrombophilia. The patient was hospitalized several times be- cause of recurrent gastroesophageal bleeding. Thrombosis of portal, lienal and mesenteric veins was diagnosed using multislice computed tomography (MSCT) angiography. Sclerotherapy and/or variceal ligation could not be used due to variceal size and distribution. Beta blockers were ineffective. Balloon tamponade and octreotide were used in each massive bleeding episode. Carvedilol therapy was introduced but rebleeding occured. Surgical treatment was considered a high risk procedure due to massive thrombosis of mesenterial veins, patient's general condition and high risk of postoperative thrombotic events. Thus, long-acting somatostatin analogue--Sandostatin LAR was initiated at a dose of 30 mg im/month. The patient responded to the therapy well and variceal bleeding did not occur for the following 3 months. After 3 months another episode of gastric variceal hemorrhage occurred and surgical treatment was reconsidered. Total gastrectomy was performed in order to prevent repeated bleeding from large gastric varices and the patient recovered successfully, and after 1 year is symptom-free. Conclusion. Long-lasting somatostatin analogue was used for the first time in treatment of gastroesophageal variceal hemorrhage in the patient with prehepatic portal hypertension. It was effective as temporary therapeutic option allowing the improvement of the patients general condition and adequate planning of elective surgical procedure. Futher reports are needed in order to compare efficacy in treatment of patients with variceal bleeding, where poor outcome is expected.",
"affiliations": null,
"authors": "Alempijević|Tamara|T|;Balović|Ana|A|;Pavlović-Marković|Aleksandra|A|;Tarabar|Dino|D|;Krstić|Miodrag|M|;Miljić|Predrag|P|;Bjelović|Miloš|M|",
"chemical_list": "D005765:Gastrointestinal Agents; D015282:Octreotide",
"country": "Serbia",
"delete": false,
"doi": "10.2298/vsp1503283a",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0042-8450",
"issue": "72(3)",
"journal": "Vojnosanitetski pregled",
"keywords": null,
"medline_ta": "Vojnosanit Pregl",
"mesh_terms": "D004932:Esophageal and Gastric Varices; D005260:Female; D005765:Gastrointestinal Agents; D006471:Gastrointestinal Hemorrhage; D006801:Humans; D008875:Middle Aged; D015282:Octreotide; D011169:Portal Vein; D012008:Recurrence; D020246:Venous Thrombosis",
"nlm_unique_id": "21530700R",
"other_id": null,
"pages": "283-6",
"pmc": null,
"pmid": "25958482",
"pubdate": "2015-03",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Efficacy of long-acting somatostatin analogs in recurrent variceal bleeding in a patient with pre-hepatic portal vein thrombosis.",
"title_normalized": "efficacy of long acting somatostatin analogs in recurrent variceal bleeding in a patient with pre hepatic portal vein thrombosis"
} | [
{
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"reaction": [
{
"reactionmeddrapt": "Gastric varices haemorrhage",
"reactionmeddraversionpt": "18.0",
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{
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}
],
"summary": null
},
"primarysource": {
"literaturereference": "ALEMPIJEVIC.T, BALOVIC.A, PAVLOVIC-MARKOVIC.A, TARABAR.D, KRSTIC.M, MILJIC.P, BJELOVIC.M.. EFFICACY OF LONG-ACTING SOMATOSTATIN ANALOGS IN RECURRENT VARICEAL BLEEDING IN A PATIENT WITH PRE-HEPATIC PORTAL VEIN THROMBOSIS. VOJNOSANIT PREGL. 2015;72:283-286",
"literaturereference_normalized": "efficacy of long acting somatostatin analogs in recurrent variceal bleeding in a patient with pre hepatic portal vein thrombosis",
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},
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}
] |
{
"abstract": "Our prior phase I study of the combination of vascular endothelial growth factor (VEGF) antibody, bevacizumab, and VEGF receptor (VEGFR) inhibitor, sunitinib, in advanced solid tumors identified an encouraging response evaluation. An expansion phase of this study was thus undertaken to obtain further safety data, response assessment and characterization of pharmacodynamic biomarkers in melanoma, renal, and adrenal carcinoma patients. Patients with metastatic solid tumors received sunitinib (37.5 mg/d, 4 wk on/2 wk off) and bevacizumab (5 mg/kg intravenously every 2 wk). Responses were assessed every 2 cycles. Serum levels of angiogenic molecules were measured using ELISA assays. Twenty-two patients were enrolled, including 11 melanoma, 5 renal cell carcinoma (RCC), 5 adrenal cancer, and 1 angiosarcoma. Grade 3 or higher adverse events were observed in 15 patients, including hypertension (41%), thrombocytopenia (23%), and fatigue (14%). Three RCC patients, and 1 melanoma patient developed thrombotic microangiopathy (TMA). Partial response (PR) occurred in 21% patients, including melanoma (2), adrenal (1), and renal (1) carcinomas. Overall, 6 patients demonstrated some reduction in their tumor burden. Serum VEGF and several other proangiogenic proteins declined over the first 4 wk of treatment whereas the putative VEGF-resistant protein, prokineticin-2, increased over 10-fold. Occurrence of TMA related to dual VEGF/VEGFR inhibition can result from systemic or nephron specific injury even in non-renal malignancies. While the combination of sunitinib and bevacizumab was clinically efficacious in renal cell carcinoma and melanoma, the observance of microangiopathy, even in non-RCC patients, is a significant toxicity that precludes further clinical development.",
"affiliations": "Cleveland Clinic Taussig Cancer Institute; Cleveland, OH USA.;Case Western University; Cleveland, OH USA.;Cleveland Clinic Taussig Cancer Institute; Cleveland, OH USA.;Cleveland Clinic Taussig Cancer Institute; Cleveland, OH USA.;Case Western University; Cleveland, OH USA.;National Cancer Institute; Rockville, MD USA.;Cleveland Clinic Taussig Cancer Institute; Cleveland, OH USA.;Cleveland Clinic Taussig Cancer Institute; Cleveland, OH USA.",
"authors": "Mittal|Kriti|K|;Koon|Henry|H|;Elson|Paul|P|;Triozzi|Pierre|P|;Dowlati|Afshin|A|;Chen|Helen|H|;Borden|Ernest C|EC|;Rini|Brian I|BI|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D054316:Biomarkers, Pharmacological; D005768:Gastrointestinal Hormones; D007211:Indoles; D009479:Neuropeptides; C423608:PROK2 protein, human; D011758:Pyrroles; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib",
"country": "United States",
"delete": false,
"doi": "10.4161/cbt.29187",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1538-4047",
"issue": "15(8)",
"journal": "Cancer biology & therapy",
"keywords": "VEGF; VEGFR; angiogenesis; bevacizumab; sunitinib",
"medline_ta": "Cancer Biol Ther",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D000068258:Bevacizumab; D054316:Biomarkers, Pharmacological; D005260:Female; D005768:Gastrointestinal Hormones; D006801:Humans; D007211:Indoles; D008297:Male; D008875:Middle Aged; D009369:Neoplasms; D009479:Neuropeptides; D011758:Pyrroles; D040262:Receptors, Vascular Endothelial Growth Factor; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A",
"nlm_unique_id": "101137842",
"other_id": null,
"pages": "975-81",
"pmc": null,
"pmid": "24842548",
"pubdate": "2014-08",
"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": "5077799;12170181;7531947;6823562;15736481;12115882;19389518;2479986;11891198;23217102;20439632;22184396;8548760;18215115;20952514;19224847;22184370;15327840;11417749;11208853;4332371;22547772;17927489;18337603;19346489;22573349;11919240;12890841;22410864;10338335;16314737;14679134;19228739;18064003;20633984;16033831;12409337;18632597;19895243;12516032;16460450;16409133;16912153;17786538;19773375;21194438;18268320;2479987;17438101;12893434;19965686;22718841;15618473;22196268;18363112;16760911;15963249",
"title": "Dual VEGF/VEGFR inhibition in advanced solid malignancies: clinical effects and pharmacodynamic biomarkers.",
"title_normalized": "dual vegf vegfr inhibition in advanced solid malignancies clinical effects and pharmacodynamic biomarkers"
} | [
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"reaction": [
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"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Thrombocytopenia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Death",
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"reactionoutcome": "5"
},
{
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"reactionoutcome": "6"
},
{
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}
],
"summary": {
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}
},
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"abstract": "This report describes a case of pericardial effusion and tamponade that appeared several weeks after WATCHMAN device (Boston Scientific, Natick, Massachusetts) placement for left atrial appendage occlusion. The report also discusses the likely etiology and clinical management of this uncommon condition. (Level of Difficulty: Intermediate.).",
"affiliations": "Division of Cardiology, Loma Linda University Medical Center, Loma Linda, California.;Division of Cardiology, Loma Linda University Medical Center, Loma Linda, California.;Division of Cardiology, Loma Linda University Medical Center, Loma Linda, California.",
"authors": "Nandkeolyar|Shuktika|S|;Parwani|Purvi|P|;Contractor|Tahmeed|T|",
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"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(19)30021-X\n10.1016/j.jaccas.2019.04.003\nCase Report\nClinical Case\nA Case of Delayed Hemorrhagic Effusive-Constrictive Pericarditis After Left Atrial Appendage Occlusion Device Placement\nNandkeolyar Shuktika MD\nParwani Purvi MBBS\nContractor Tahmeed MD tcontractor@llu.edu\n@TahmeedC\n∗\nDivision of Cardiology, Loma Linda University Medical Center, Loma Linda, California\n∗ Address for correspondence: Dr. Tahmeed Contractor, Loma Linda University Medical Center, 11234 Anderson Street, Loma Linda, California 92354. tcontractor@llu.edu@TahmeedC\n19 6 2019\n6 2019\n19 6 2019\n1 1 2731\n25 3 2019\n26 4 2019\n26 4 2019\n© 2019 The Authors\n2019\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nThis report describes a case of pericardial effusion and tamponade that appeared several weeks after WATCHMAN device…\n\nThis report describes a case of pericardial effusion and tamponade that appeared several weeks after WATCHMAN device (Boston Scientific, Natick, Massachusetts) placement for left atrial appendage occlusion. The report also discusses the likely etiology and clinical management of this uncommon condition. (Level of Difficulty: Intermediate.)\n\nGraphical abstract\n\nKey Words\n\natrial fibrillation\ncardiac tamponade\neffusive-constrictive pericarditis\nleft atrial appendage closure device\npericardial effusion\n==== Body\nThe WATCHMAN device (Boston Scientific, Natick, Massachusetts) is an increasingly popular, Food and Drug Administration–approved device for left atrial appendage (LAA) occlusion in patients with nonvalvular atrial fibrillation who seek an alternative to oral anticoagulation (1). Its safety and efficacy have been demonstrated in 2 major randomized control trials: PREVAIL (Prospective Randomized Evaluation of the WATCHMAN Left Atrial Appendage Closure Device in Patients with Atrial Fibrillation Versus long-term Warfarin Therapy) and PROTECT AF (Percutaneous Closure of the Left Atrial Appendage versus Warfarin Therapy for Prevention of Stroke in Patients with Atrial Fibrillation) 2, 3. The rate of pericardial effusion post-WATCHMAN implantation in these trials was approximately 2% to 5% 2, 3. Most of these were acute hemorrhagic pericardial effusions that manifested within 7 days of implant as a result of macroperforation. The etiology, prevalence, and clinical consequences of delayed pericardial effusions after WATCHMAN placement are not well described. In this report, we describe a case of pericardial effusion and tamponade that appeared several weeks after WATCHMAN placement. We also depict the likely etiology and clinical management of this uncommon condition.Learning Objectives\n\n• Delayed pericardial effusion several weeks after implantation is a rare complication that implanting physicians should be aware of. Follow-up TEE should include evaluation of the pericardial space so that this complication is not missed.\n\n• Late pericardial effusion is likely caused by microperforation during implantation that results in a subclinical hemopericardium. This sets off a vicious cycle of inflammation and increased bleeding in the setting of anticoagulation, which ultimately results in cardiac tamponade.\n\n• Delayed, hemorrhagic effusive-constrictive pericarditis can be managed with pericardiocentesis and anti-inflammatory agents, without the need for cardiac surgery.\n\nHistory of Presentation\n\nAn 87-year-old female patient with a history of atrial fibrillation and a CHA2DS2-VASc (congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, prior stroke of transient ischemic attack or thromboembolism, vascular disease, age 65 to 74 years, and sex category [female]) score of 4 was referred for placement of an LAA occlusion device. On examination, she was normotensive, with an irregularly irregular pulse of 87 beats/min, without any jugular venous distention or peripheral edema.\n\nPast Medical History\n\nShe had a history of esophageal ulcers and frequent falls, which resulted in an intracranial hemorrhage, so she was deemed high risk for significant bleeding with long-term oral anticoagulation.\n\nInitial Management: Placement of WATCHMAN Device\n\nThe LAA was measured as an average diameter of 26 mm on transesophageal echocardiogram (TEE). Therefore, a #30 WATCHMAN device was placed. After deployment, the “PASS” criteria were met: the position of the device at the LAA os was confirmed, and the tug test revealed that the device was anchored with 20% compression without any peridevice leaks. The device was released, and the patient recovered well without any immediate complications (Figures 1A to 1C).Figure 1 Initial WATCHMAN Positioning in the LAA\n\n(A) A 3-dimensional transesophageal echocardiography image of WATCHMAN device (Boston Scientific, Natick, Massachusetts) in place in the left atrial appendage (LAA) was obtained intraoperatively. No peridevice leak was seen by (B) Doppler on transesophageal echocardiography or (C) angiography. (D) Bright pericardium on post-operative day 1.\n\nThe following day, the patient’s exam remained unchanged except she reported substernal chest pain that was worse when lying down and improved with sitting up. A transthoracic echocardiogram (TTE) revealed a bright pericardium but did not demonstrate pericardial effusion (Figure 1D). She was discharged on 0.6 mg colchicine twice a day for suspected post-procedural pericarditis and continued warfarin. The chest pain persisted 1 week later, and TTE again revealed a bright pericardium without pericardial effusion. She was continued on colchicine. On 4-week follow-up, she reported a gradual resolution of chest pain. No TTE was performed given her clinical improvement, and colchicine was discontinued.\n\nFollow-up\n\nHer routine 6-week TEE revealed a moderate pericardial effusion without evidence of tamponade (Figure 2A). Three days later, she presented with significant dyspnea and tachycardia. A TTE revealed a large pericardial effusion with findings suggestive of cardiac tamponade (Figure 2B). During urgent pericardiocentesis, 500 ml sanguineous fluid was drained, and a pericardial drain was left in place. Pericardial fluid analysis revealed 1,201,000/mm3 red blood cells, 6,452/mm3 nucleated cells, pH 7.6, and negative Gram stain, suggestive of a concomitant inflammatory and hemorrhagic process. Serum sedimentation rate and C-reactive protein were found to be elevated at 49 mm/h and 2.7 mg/dl, respectively. Computed tomographic angiography showed no obvious macroperforation of the device. The post-pericardiocentesis TTE revealed constrictive physiology (Figures 2C to 2E).Figure 2 Echocardiographic Evidence of Delayed Effusive-Constrictive Pericarditis\n\n(A) A 6-week follow-up transesophageal echocardiography with a short-axis view demonstrating a moderate pericardial effusion surrounding a WATCHMAN device (Boston Scientific, Natick, Massachusetts) in the left atrial appendage. (B) Transthoracic echocardiography on post-operative day 55 demonstrating a large pericardial effusion with right ventricular collapse in diastole. (D) After pericardial effusion drainage, a persistent large, noncollapsing inferior vena cava and 45% mitral inflow velocity variation with respiration remained. (E) Post-drainage, computed tomography angiography illustrated the WATCHMAN device within the lumen of the left atrial appendage. (F to I) Late gadolinium enhancement (arrowheads) seen in the pericardium on cardiac magnetic resonance.\n\nDifferential Diagnosis\n\nThe suspected cause of the delayed effusion was microperforation leading to inflammatory effusive-constrictive pericarditis with delayed secondary bleeding. She was not started on nonsteroidal anti-inflammatory drugs because of the hemorrhagic effusion and her history of esophageal ulcer.\n\nManagement\n\nShe was given a 1-week taper of methylprednisolone in addition to continuing colchicine for a total of 3 months. On follow-up, TTE 1 week later revealed elevated right atrial pressure, septal bounce, and thickened pericardium suggestive of constriction, although no effusion. One month later, repeat TTE showed normalized filling pressures, mild septal bounce, and a bright pericardium without pericardial effusion. A cardiac magnetic resonance image obtained after a full 3 months of colchicine therapy revealed pericardial thickness of 4 mm with patchy late gadolinium enhancement in the pericardium (Figures 2F to 2I).\n\nDiscussion\n\nWe report delayed pericardial effusion and subsequent effusive constrictive pericarditis after WATCHMAN device placement. To the best of our knowledge, this is the first such reported case.\n\nAcute pericardial effusion and tamponade secondary to macroperforation during WATCHMAN device expansion or tugging when testing for appropriate anchoring are known complications of this procedure. Although an oversized device can cause perforation, the #30 WATCHMAN (15% larger than the 26-mm LAA os) device used in this patient is within the sizing recommendations for fixation and stable positioning (4). The incidence of pericardial effusion in both the prospective EWOLUTION registry and the Boston Scientific manufacturer-compiled registry is close to 1%, significantly lower than the rates demonstrated in the original randomized controlled trials 5, 6. Physicians who implant these devices should be aware of the very rare complication of delayed pericardial effusion several weeks after implantation. Follow-up 6-week TEE should include evaluation of the pericardial space so that this rare complication is not missed.\n\nThe pathophysiology of late pericardial effusion and subsequent constrictive-effusive pericarditis after WATCHMAN device placement is unclear. We hypothesize that the following sequence of events resulted in this clinical presentation (Figure 3): 1) given the delay in development of the pericardial effusion, a microperforation at the time of the implantation led to a subclinical hemopericardium; 2) blood in the pericardial space, which is a known trigger for pericardial inflammation (7), resulted in inflammatory pericarditis; 3) worsening inflammation in the setting of systemic anticoagulation caused pericardial effusion and tamponade; 4) persistent inflammation post-pericardiocentesis resulted in constrictive physiology; and 5) patchy fibrosis persisted after resolution of the inflammation, thus explaining the cardiac magnetic resonance findings of pericardial delayed enhancement.Figure 3 Inflammatory Cascade\n\nThe series of events leading to delayed effusive-constrictive pericarditis post-WATCHMAN device (Boston Scientific, Natick, Massachusetts) placement. CMRI = cardiac magnetic resonance imaging; LGE = late gadolinium enhancement; TTE = transthoracic echocardiogram.\n\nManagement of microperforation-related inflammatory pericarditis with ongoing systemic anticoagulation is challenging. In this case, a 3-month course of colchicine alone was insufficient to control the inflammation; instead, we postulate that initial dual or triple anti-inflammatory therapy (with addition of nonsteroidal anti-inflammatory drugs and/or a taper of steroids) would have prevented subsequent pericardial effusion and constriction. The patient’s history of esophageal ulcer dissuaded us from adding additional agents initially. The use of corticosteroids in post-procedural pericarditis remains controversial because of the fear of recurrent pericarditis and pericardial effusion 8, 9. In this case, a short course of corticosteroids in addition to colchicine resulted in resolution of inflammation without the development of the dreaded steroid-related recurrent effusion. This case demonstrates that pericardiocentesis with aggressive management of inflammation is sufficient to reverse effusive-constrictive pericarditis without the need for cardiac surgery (10).\n\nConclusions\n\nWe report microperforation-related delayed hemorrhagic effusive-constrictive pericarditis after WATCHMAN device placement. Further evaluation is necessary to characterize the clinical presentation and management strategy of this rare complication.\n\nDr. Parwani is the Social Media Consultant for JACC Journals. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n==== Refs\nReferences\n\n1 January C.T. Wann L.S. Calkins H. AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society J Am Coll Cardiol 2019 Jan 21 [E-pub ahead of print]\n2 Holmes D.R. Kar S. Price M.J. Prospective randomized evaluation of the Watchman left atrial appendage closure device in patients with atrial fibrillation versus long-term warfarin therapy: the PREVAIL trial J Am Coll Cardiol 64 2014 1 12 24998121\n3 Reddy V.Y. Sievert H. Halperin J. Percutaneous left atrial appendage closure vs warfarin for atrial fibrillation: a randomized clinical trial JAMA 312 2014 1988 1998 25399274\n4 Kavinsky C.J. Kusumoto F.M. Bavry A.A. SCAI/ACC/HRS institutional and operator requirements for left atrial appendage occlusion J Am Coll Cardiol 67 2016 2295 2305 26686261\n5 Schmidt B. Betts T.R. Sievert H. Incidence of pericardial effusion after left atrial appendage closure: the impact of underlying heart rhythm—data from the EWOLUTION study J Cardiovasc Electrophysiol 29 2018 973 978 29722469\n6 Reddy V.Y. Gibson D.N. Kar S. Post-FDA approval, initial U.S. clinical experience with Watchman left atrial appendage closure for stroke prevention in atrial fibrillation J Am Coll Cardiol 69 2017 253 261 27816552\n7 Adler Y. Charron P. Imazio M. 2015 ESC guidelines for the diagnosis and management of pericardial diseases: the Task Force for the Diagnosis and Management of Pericardial Diseases of the European Society of Cardiology (ESC) endorsed by: the European Association for Cardio-Thoracic Surgery (EACTS) Eur Heart J 36 2015 2921 2964 26320112\n8 Imazio M. Brucato A. Cumetti D. Corticosteroids for recurrent pericarditis: high versus low doses: a nonrandomized observation Circulation 118 2008 667 671 18645054\n9 Imazio M. Brucato A. Cemin R. A randomized trial of colchicine for acute pericarditis N Engl J Med 369 2013 1522 1528 23992557\n10 Feng D. Glockner J. Kim K. Cardiac magnetic resonance imaging pericardial late gadolinium enhancement and elevated inflammatory markers can predict the reversibility of constrictive pericarditis after antiinflammatory medical therapy: a pilot study Circulation 124 2011 1830 1837 21969014\n\n",
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"abstract": "Febrile infection-related epilepsy syndrome (FIRES) is a devastating epilepsy affecting normal children after a febrile illness. FIRES presents with an acute phase with super-refractory status epilepticus and all patients progress to a chronic phase with persistent refractory epilepsy. The typical outcome is severe encephalopathy or death. The authors present 7 children from 5 centers with FIRES who had not responded to antiepileptic drugs or other therapies who were given cannabadiol (Epidiolex, GW Pharma) on emergency or expanded investigational protocols in either the acute or chronic phase of illness. After starting cannabidiol, 6 of 7 patients' seizures improved in frequency and duration. One patient died due to multiorgan failure secondary to isoflourane. An average of 4 antiepileptic drugs were weaned. Currently 5 subjects are ambulatory, 1 walks with assistance, and 4 are verbal. While this is an open-label case series, the authors add cannabidiol as a possible treatment for FIRES.",
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{
"abstract": "Objective: To explore the occurrence, clinical characteristics, diagnosis and treatment of glomerulitis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods: Analysis were carried out based on the clinical data of 6 patients with de novo glomerulitis following allo-HSCT hospitalized in Henan Tumor Hospital from January 2008 to December 2016, and the clinical manifestation, pathology, diagnosis, treatment and outcome were investigated. Results: The occurrence of glomerulitis was 1.26% (6/478). The median time was 447(272-1 495) d after allo-HSCT. Proteinuria and varying degrees of edema were present in all patients. Of the 6 patients, 4 patients with impaired renal function, 3 cases of hypertension, 5 cases of urine occult blood positive, 2 cases of hyperlipidemia. 5 patients underwent acute graft-versus-host disease (GVHD), 4 patients accompanied with chronic GVHD at diagnosis. Kidney pathology showed typical features of minimal change diseases in 1 patient, membranous nephropathy in 4 patients and mesangial proliferative glomerulonephritis in 1 case. Immunohistochemistry of glomerular lesions revealed that the immune complex deposition included IgG in 4 patients, C3 in 3 patients, IgM and C1q in 1 patient. Serum ANA was positive in 2 patients and serum IgG and IgM were in high level in 1 patient, respectively. Only 1 case was effective on glucocorticoid. 5 cases treated by low dose cyclophosphamide combined with mycophenolate mofetil (MMF), 2 cases achieved complete remission, and 3 cases were partial remission. Up to now, 2 cases died with lung infection, and 4 patients survived. Conclusion: The predominant pathological type of glomerulitis was membranous nephropathy. Low-dose cyclophosphamide combined with MMF was an effective treatment.",
"affiliations": "Department of Hematology, Affiliated Cancer Hospital Zhengzhou University, Henan Tumor Hospital, Institute of Hematology, Zhengzhou 450003, China.",
"authors": "Zhou|J|J|;Zu|Y L|YL|;Gui|R R|RR|;Zhang|Yanli|Y|;Fu|Y W|YW|;Yu|F K|FK|;Zhao|H F|HF|;Li|Z|Z|;Lin|Q D|QD|;Wang|J|J|;Zuo|W L|WL|;Song|Y P|YP|",
"chemical_list": "D009173:Mycophenolic Acid",
"country": "China",
"delete": false,
"doi": "10.3760/cma.j.issn.0253-2727.2018.09.011",
"fulltext": "\n==== Front\nZhonghua Xue Ye Xue Za Zhi\nZhonghua Xue Ye Xue Za Zhi\nCJH\nChinese Journal of Hematology\n0253-2727 2707-9740 Editorial office of Chinese Journal of Hematology No. 288, Nanjing road, Heping district, Tianjin \n\n30369188\ncjh-39-09-757\n10.3760/cma.j.issn.0253-2727.2018.09.011\n论著\n异基因造血干细胞移植后肾小球肾炎六例临床分析\nClinical analysis of six cases with the de novo glomerulitis after allogeneic hematopoietic stem cell transplantation 周 健 Zhou Jian 祖 璎玲 Zu Yingling 桂 瑞瑞 Gui Ruirui 张 龑莉 Zhang Yanli 符 粤文 Fu Yuewen 喻 凤宽 Yu Fengkuan 赵 慧芳 Zhao Huifang 李 珍 Li Zhen 林 全德 Lin Quande 王 娟 Wang Juan 左 文丽 Zuo Wenli 宋 永平 Song Yongping 450003 郑州大学附属肿瘤医院、河南省肿瘤医院血液科，河南省血液病研究所Department of Hematology, Affiliated Cancer Hospital Zhengzhou University, Henan Tumor Hospital, Institute of Hematology, Zhengzhou 450003, China\n徐 茂强 通信作者：宋永平(Song Yongping)，Email：songyongping001@126.com\n9 2018 \n39 9 757 760\n13 3 2018 2018年版权归中华医学会所有Copyright © 2018 by Chinese Medical Association2018This work is licensed under a Creative Commons Attribution 3.0 License (CC-BY-NC). The Copyright own by Publisher. Without authorization, shall not reprint, except this publication article, shall not use this publication format design. Unless otherwise stated, all articles published in this journal do not represent the views of the Chinese Medical Association or the editorial board of this journal.目的\n探讨异基因造血干细胞移植（allo-HSCT）后肾小球肾炎的发病、诊断及治疗情况。\n\n方法\n回顾性分析2008年1月至2016年12月河南省肿瘤医院allo-HSCT后肾小球肾炎患者的临床资料。\n\n结果\n478例allo-HSCT患者中6例（1.26%）发生肾小球肾炎，男3例，女3例，中位年龄22（12~36）岁；重型再生障碍性贫血（SAA）2例，急性髓系白血病（AML）4例，移植前均无明确的肾脏病病史，中位发生时间为移植后447（272~1 495）d。4例患者肾功能异常，5例尿潜血阳性，3例高血压，2例高血脂。5例患者曾发生急性GVHD，4例发病时伴有慢性GVHD。肾脏病理：微小病变型肾病1例，膜性肾病4例，系膜增生性肾小球肾炎伴缺血性损伤1例。肾脏免疫组化：IgG阳性4例，IgM阳性1例，C3阳性3例，C1q阳性1例。2例血清抗核抗体阳性，IgG和IgM升高各1例。仅1例患者糖皮质激素治疗有效。5例患者采用低剂量环磷酰胺联合霉酚酸酯治疗，2例完全有效，3例部分有效。4例患者生存良好，2例患者死于肺感染。\n\n结论\nallo-HSCT后肾小球肾炎的病理类型以膜性肾病为主，低剂量环磷酰胺联合霉酚酸酯可获得较好疗效。\n\nObjective\nTo explore the occurrence, clinical characteristics, diagnosis and treatment of glomerulitis after allogeneic hematopoietic stem cell transplantation (allo-HSCT).\n\nMethods\nAnalysis were carried out based on the clinical data of 6 patients with de novo glomerulitis following allo-HSCT hospitalized in Henan Tumor Hospital from January 2008 to December 2016, and the clinical manifestation, pathology, diagnosis, treatment and outcome were investigated.\n\nResults\nThe occurrence of glomerulitis was 1.26% (6/478). The median time was 447(272–1 495) d after allo-HSCT. Proteinuria and varying degrees of edema were present in all patients. Of the 6 patients, 4 patients with impaired renal function, 3 cases of hypertension, 5 cases of urine occult blood positive, 2 cases of hyperlipidemia. 5 patients underwent acute graft-versus-host disease (GVHD), 4 patients accompanied with chronic GVHD at diagnosis. Kidney pathology showed typical features of minimal change diseases in 1 patient, membranous nephropathy in 4 patients and mesangial proliferative glomerulonephritis in 1 case. Immunohistochemistry of glomerular lesions revealed that the immune complex deposition included IgG in 4 patients, C3 in 3 patients, IgM and C1q in 1 patient. Serum ANA was positive in 2 patients and serum IgG and IgM were in high level in 1 patient, respectively. Only 1 case was effective on glucocorticoid. 5 cases treated by low dose cyclophosphamide combined with mycophenolate mofetil (MMF), 2 cases achieved complete remission, and 3 cases were partial remission. Up to now, 2 cases died with lung infection, and 4 patients survived.\n\nConclusion\nThe predominant pathological type of glomerulitis was membranous nephropathy. Low-dose cyclophosphamide combined with MMF was an effective treatment.\n\n造血干细胞移植肾小球肾炎移植物抗宿主病Hematopoietic stem cell transplantationGlomerulonephritisGraft vs host disease\n==== Body\n异基因造血干细胞移植（allo-HSCT）已广泛应用于多种血液系统疾病的治疗。随着移植技术的逐渐进步，移植后存活率提高且生存时间明显延长，造血干细胞移植相关肾病也逐渐引起重视。本研究对近年来河南省肿瘤医院血液科治疗的6例allo-HSCT后新发肾小球肾炎患者的临床资料进行回顾性分析，以加深对移植后肾小球肾炎的了解。\n\n病例与方法\n1．病例：2008年1月至2016年12月，在河南省肿瘤医院血液科接受allo-HSCT且移植后存活>100 d的血液病患者共478例（男287例，女191例），其中6例（1.26%）患者诊断为移植后肾小球肾炎。诊断符合以下标准：移植6个月后发病、伴蛋白尿，肾脏病理诊断为肾小球病变[1]。\n\n2．预处理方案和GVHD的预防及诊断标准：重型再生障碍性贫血（SAA）患者预处理方案采用环磷酰胺+兔抗胸腺细胞球蛋白（ATG）+氟达拉滨（Flu）±全身放疗（TBI），急性髓系白血病（AML）患者采用Bu/Cy（白消安+环磷酰胺）为基础的预处理方案。同胞相合移植采用环孢素A（CsA）联合短疗程甲氨蝶呤（MTX）预防移植物抗宿主病（GVHD），无关供者移植加用吗替麦考酚酯（MMF）。急性GVHD和慢性GVHD的诊断采用西雅图标准。\n\n3．移植后肾小球肾炎的治疗：首选糖皮质激素治疗，对移植后免疫抑制剂已停用或减量患者给予甲泼尼龙1~2 mg·kg−1·d−1治疗；糖皮质激素无效患者改用低剂量环磷酰胺（200 mg每周1次）联合MMF治疗。疗效标准[2]：完全缓解（CR）：24 h尿蛋白≤0.3 g；部分缓解（PR）：24 h尿蛋白>0.3~3.4 g；无效（NR）：24 h尿蛋白>3.4 g。\n\n4．随访：所有病例通过门诊和电话随访，随访截止时间为2018年2月28日，中位随访时间为31（5~34）个月。\n\n结果\n1．一般资料：478例allo-HSCT后生存期长于3个月的患者中，6例（1.26%）确诊为新发的肾小球肾炎，男3例，女3例，中位年龄22（12~36）岁；SAA 2例，AML 4例。同胞全相合移植3例，无关供者移植3例；干细胞来源均为外周血干细胞。回输单个核细胞（MNC）中位数10.26（4.79~17.42）×108/kg，CD34+细胞中位数4.83（2.14~14.98）×106/kg。6例患者移植前均无乙型肝炎、丙型肝炎和糖尿病病史。6例患者基本资料见表1。\n\n表1 6例异基因造血干细胞移植后肾小球肾炎患者的一般资料\n例号\t性别\t年龄（岁）\t诊断\t干细胞来源\tHLA配型\t预处理方案\tGVHD预防方案\t急性GVHD\t慢性GVHD\t随访时间（月）\t\n1\t男\t33\tSAA\t外周血\t无关供者8/10\tCy+Flu+ATG+TBI\tCsA+MTX+MMF\t有\t有\t34\t\n2\t男\t12\tSAA\t外周血\t无关供者10/10\tCy+Flu+ATG\tCsA+MTX+MMF\t无\t有\t33\t\n3\t女\t22\tAML\t外周血\t无关供者10/10\tBU/Cy+Vp16+ATG\tCsA+MTX+MMF\t有\t无\t24\t\n4\t女\t36\tAML\t外周血\t同胞低分6/6\tBU/Cy\tCsA+MTX\t有\t有\t13\t\n5\t女\t22\tAML\t外周血\t同胞低分6/6\t改良BU/Cy\tCsA+MTX\t有\t无\t19\t\n6\t男\t42\tAML\t外周血\t同胞低分6/6\t改良BU/Cy\tCsA+MTX\t有\t有\t5\t\n注：HLA：人类白细胞抗原；SAA：重型再生障碍性贫血；AML：急性髓系白血病；Cy：环磷酰胺；Flu：氟达拉滨；ATG：抗胸腺细胞球蛋白；TBI：全身放疗；Vp16：依托泊苷；Bu：白消安；CsA：环孢素A；MTX：甲氨蝶呤；MMF：霉酚酸酯\n\n2．临床表现：6例患者发病时间均在移植6个月后，中位发病时间为移植后447（272~1 495）d。下肢水肿5例，眼睑水肿2例，大量腹水1例，1例患者无明显水肿症状，高血压3例。2例患者已停用免疫抑制剂；2例处于慢性GVHD治疗期间，2例处于免疫抑制剂减量过程中。5例曾发生急性GVHD，4例患者诊断时合并慢性GVHD，其中局限型3例、广泛型1例（表2）。\n\n表2 6例异基因造血干细胞移植后肾小球肾炎患者的临床资料\n例号\t发病时间（d）\t临床表现\t诊断时cGVHD\t诊断时免疫抑制剂\t24 h尿蛋白定量（g）\t肾脏病理诊断\t尿潜血\t肌酐\t抗核抗体\t病理抗体\t血清Ig\t治疗与转归\t\n1\t+272\t下肢及眼睑水肿\t广泛性\t减量\t3.79\tMPG\t阳性\t升高\t+\tIgM\tIgM\t糖皮质激素（NR）\t\n\t\t\t\t\t\t\t\t\t\t\t\tMMF+Cy（PR）\t\n2\t+367\t下肢水肿\t局限性\t使用\t3.92\tMGN\t阳性\t正常\t−\tIgG、C3\t正常\t糖皮质激素（NR）\t\n\t\t\t\t\t\t\t\t\t\t\t\tMMF+Cy（PR）\t\n3\t+546\t无\t无\t停用\t0.62\tMGN\t阴性\t升高\t−\tIgG\t正常\tMMF+Cy（CR）\t\n4\t+527\t下肢及眼睑水肿、腹水\t局限性\t使用\t14.4\tMGN\t阳性\t正常\t−\tIgG、C3\tIgG\t糖皮质激素（NR）\t\n\t\t\t\t\t\t\t\t\t\t\t\tMMF +Cy（PR）\t\n\t\t\t\t\t\t\t\t\t\t\t\t死于肺感染\t\n5\t+1 495\t下肢水肿\t无\t停用\t0.81\tMGN\t阳性\t升高\t+\tIgG、C3\t正常\t糖皮质激素（NR）\t\n\t\t\t\t\t\t\t\t\t\t\t\tMMF+Cy（CR）\t\n6\t+298\t下肢水肿\t局限性\t减量\t1.85\tMCD\t阳性\t升高\t−\t阴性\t正常\t糖皮质激素（CR）\t\n\t\t\t\t\t\t\t\t\t\t\t\t死于肺感染\t\n注：cGVHD：慢性移植物抗宿主病；MCD：微小病变血型肾病；MGN：膜性肾病；MPG：系膜增生性肾小球肾炎。MMF：吗替麦考酚酯；Cy：环磷酰胺。CR：完全缓解；PR：部分有效；NR：无反应\n\n3．病理学检测：微小病变型肾病（MCD）1例，膜性肾病（MGN）4例，系膜增生性肾小球肾炎（MPG）伴缺血性损伤1例。6例患者肾脏病理抗体中，IgG（+）4例，IgM（+）1例，C3（+）3例，C1q（+）1例，1例IgA（±）（表2）。\n\n4．相关实验室检查：全部患者随机尿常规检查尿蛋白阳性；4例患者有血肌酐升高，肾功能Ⅰ/Ⅱ度异常，5例患者血尿素氮升高，4例患者血尿酸升高。5例患者尿潜血阳性，2例患者血脂升高。3例患者白蛋白<30 g/L，24 h尿蛋白定量>3.5 g，达到肾病综合征的诊断标准。2例患者ANA阳性，1例血清IgG升高，1例血清IgM升高。\n\n5．疗效与转归：全部患者治疗时间均>6个月。5例患者在原有免疫抑制剂基础上给予甲泼尼龙1~2 mg·kg−1·d−1治疗，仅1例患者达到CR，糖皮质激素减量后出现复发；4例患者糖皮质激素治疗4周后无好转，换用低剂量环磷酰胺联合MMF治疗，同时快速减量甲泼尼龙；1例患者直接采用环磷酰胺联合MMF治疗。治疗1个月后评估，CR 1例，PR 1例，NR 4例；治疗6个月后评估，CR 1例，PR 5例。2例患者因肺部真菌感染分别在治疗6个月和9个月时死亡。治疗1年后评估，CR 2例，PR 2例。至随访截止，2例患者死亡，4例存活患者均为无病生存，仍在维持治疗中。\n\n讨论\nallo-HSCT后迟发性肾病主要指移植6个月后发生的肾小球肾炎，常发生在allo-HSCT后6~48个月[3]。本组6例患者的中位发病时间为447（272~1 495）d。1988年Hiesse等[4]首先报道1例慢性髓性白血病患者骨髓移植后发生肾病综合征。allo-HSCT肾小球肾炎发病率较低，Cho等[2]报道，韩国2 800例骨髓移植患者中15例（0.54%）发生肾小球肾炎。成人移植后肾病综合征的发生率为0.37%~1.00%[1],[5]–[6]。本中心移植后肾小球肾炎的发生率为1.26%（6/478），稍高于文献报道。这可能与我中心多采用外周血干细胞移植有关。allo-HSCT后肾小球肾炎的主要临床表现为蛋白尿和肾病综合征。蛋白尿是早期表现，可伴有不同程度下肢水肿，镜下血尿不明显，肾功能大多正常，病情进展到严重的程度，即表现为肾病综合征[1]。本资料中6例患者均有蛋白尿，4例血肌酐升高，5例血尿素氮升高，4例血尿酸升高，4例尿潜血阳性；3例患者合并高血压，2例血脂升高。本研究6例患者中MGN 4例，MCD 1例，MPG伴缺血性损伤1例，和其他文献报道一致。\n\n移植后肾小球肾炎（包括肾病综合征）蛋白尿的病因和发病机制仍不清楚，目前多数学者认为是慢性GVHD的一种少见的表现形式[7]，原因如下：①均发生于移植3个月后，多发生于免疫抑制剂减量或停药后数月，且往往同时出现[8]。本组6例患者发病均在移植6个月后，3例发病时合并慢性GVHD，2例患者已停用免疫抑制剂，2例处于慢性GVHD治疗期间，2例处在免疫抑制剂减量过程中。②大部分病例肾脏病理活检可见大量上皮下沉积物，与GVHD小鼠模型肾脏病理相似，考虑为GVHD导致的抗原抗体复合物[9]。③约70%的患者体内出现高水平自身抗体[10]，循环中自身抗体的出现与病情并不一致[11]。④CD20单抗用于治疗难治性移植后肾病同样有效[5],[12]。因此，慢性GVHD相关MGN病的发病可能与移植物T淋巴细胞识别宿主抗原而致敏、增殖、分化，使B淋巴细胞活化，产生自身抗体，并使免疫复合物在肾小球上皮下沉积或上皮下产生原位免疫复合物，及免疫细胞释放细胞因子损伤肾基底膜有关[13]。也有人认为活化T细胞分泌的干扰素γ和肿瘤坏死因子与肾病综合征的发生有关[14]。此外，一些研究认为移植后肾病与年龄、巨细胞病毒感染、放射性肾病、干细胞来源、预防GVHD药物引起的肾毒性作用及溶血尿毒综合征等有关[15]。本组6例患者中5例曾发生急性GVHD，其中4例诊断时有慢性GVHD表现。本研究未发现移植后肾小球肾炎的危险因素，因其发病率低，危险因素尚不清楚，有学者认为可能和干细胞来源、慢性GVHD和HLA匹配程度有关，确切的危险因素需要将来分析多中心的临床资料获取。\n\n移植后肾小球肾炎的治疗多采用联合使用免疫抑制剂。如病理类型为MCD，治疗多以糖皮质激素治疗为主，若为MGN则在糖皮质激素治疗的基础上联合使用CsA、他克莫司、MMF或硫唑嘌呤等免疫抑制剂。与原发性MGN相比，GVHD相关MGN对免疫抑制剂的反应较好[6]。多数患者预后较好，但症状消退缓慢，疗程需2~12个月，大剂量糖皮质激素冲击及联合用药均不能缩短病程[13]。本研究中5例患者采用糖皮质激素联合CsA或他克莫司治疗，仅1例有效，换用低剂量环磷酰胺联合MMF后均有效。体内B淋巴细胞异常在慢性GVHD发生与发展中起一定作用，用抗CD20单克隆抗体治疗难治性移植后肾病可取得满意疗效[5],[12]。有报道间充质干细胞在治疗中也有一定的疗效[16]。此外，对少数顽固性病例，肿瘤坏死因子阻断剂可能有效[17]。\n\n总之，移植后的肾病重在早期发现早期治疗，蛋白尿是移植后肾病的早期信号，要重视尿常规的监测。不同的病理类型在免疫抑制剂的治疗强度有所不同，一旦明确诊断移植后肾病，建议停用CsA和他克莫司等肾毒性强的药物，换用MMF或西罗莫司等肾毒性弱的药物，从而减少肾毒性强的药物的使用可以延缓肾功能的恶化。我们建议对疗效不佳的患者加用环磷酰胺或MMF。\n\n郑州大学第一附属医院肾脏病理科权松霞老师协助进行肾脏病理检查\n==== Refs\nReferences\n1 Imai H Oyama Y Miura AB Hematopoietic cell transplantation-related nephropathy in Japan[J] Am J Kidney Dis 2000 36 3 474 480 10.1053/ajkd.2000.9787 10977778 \n2 Cho YH Kang SH Kim Y De novo glomerulitis associated with graft-versus-host disease after allogeneic hematopoietic stem cell transplantation: a single-center experience[J] Kidney Res Clin Pract 2013 32 3 121 126 10.1016/j.krcp.2013.07.004 26877927 \n3 韩 晶晶 仇 惠英 卢 国元 异基因造血干细胞移植相关性膜性肾病2例[J] 中国实用内科杂志 2008 28 3 230 231 10.3969/j.issn.1005-2194.2008.03.025 \n4 Hiesse C Goldschmidt E Santelli G Membranous nephropathy in a bone marrow transplant recipient[J] Am J Kidney Dis 1988 11 2 188 191 3277409 \n5 Reddy P Johnson K Uberti JP Nephrotic syndrome associated with chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation[J] Bone Marrow Transplant 2006 38 5 351 357 10.1038/sj.bmt.1705446 16862167 \n6 陈 瑶 黄 晓军 张 晓辉 异基因造血干细胞移植后并发肾病综合征的单中心临床分析[J] 中华内科杂志 2011 50 7 572 575 10.3760/cma.j.issn.0578-1426.2011.07.010 22041267 \n7 于 建平 崔 若兰 童 书鹏 异基因外周血造血干细胞移植后膜性肾病临床和病理表现[J] 中华血液学杂志 2001 22 8 415 417 10.3760/j:issn:0253-2727.2001.08.006 \n8 Brukamp K Doyle AM Bloom RD Nephrotic syndrome after hematopoietic cell transplantation: do glomerular lesions represent renal graft-versus-host disease?[J] Clin J Am Soc Nephrol 2006 1 4 685 694 10.2215/CJN.00380705 17699273 \n9 van Leer EH Bruijn JA Prins FA Redistribution of glomerular dipeptidyl peptidase type IV in experimental lupus nephritis. Demonstration of decreased enzyme activity at the ultrastructural level[J] Lab Invest 1993 68 5 550 556 8098785 \n10 Svegliati S Olivieri A Campelli N Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-versus-host disease[J] Blood 2007 110 1 237 241 10.1182/blood-2007-01-071043 17363728 \n11 Haseyama K Watanabe J Oda T, et a1 Nephrotic syndrome related to chronic graft versus host disease after allogeneic bone marrow transplantation in a patient with malignant lymphoma[J] Rinsho Ketsueki 1996 37 12 1383 1388 8997126 \n12 Vischini G Cudillo L Ferrannini M Rituximab in post allogeneic hematopoietic stem cell transplantation membranous nephropathy: a case report[J] J Nephrol 2009 22 1 160 163 19229832 \n13 Hingorani S Chronic kidney disease in long-term survivors of hematopoietic cell transplantation: epidemiology, pathogenesis, and treatment[J] J Am Soc Nephrol 2006 17 7 1995 2005 10.1681/ASN.2006020118 16723390 \n14 Seconi J Watt V Ritchie DS Nephrotic syndrome following allogeneic stem cell transplantation associated with increased production of TNF-alpha and interferon-gamma by donor T cells[J] Bone Marrow Transplant 2003 32 4 447 450 10.1038/sj.bmt.1704151 12900785 \n15 罗 晓丹 刘 启发 宁 涓 异基因造血干细胞移植后迟发性肾病综合征临床分析[J] 中华医学杂志 2007 87 46 3280 3283 10.3760/j.issn:0376-2491.2007.46.011 18396625 \n16 Zhang X Peng Y Fan Z Mesenchymal stem cells may ameliorate nephrotic syndrome post-allogeneic hematopoietic stem cell transplantation-case report[J] Front Immunol 2017 8 962 10.3389/fimmu.2017.00962 28855905 \n17 Ducloux D Bresson-Vautrin C Chalopin J Use of pentoxifylline in membranous nephropathy[J] Lancet 2001 357 9269 1672 1673 11425374\n\n",
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"keywords": "Glomerulonephritis; Graft vs host disease; Hematopoietic stem cell transplantation",
"medline_ta": "Zhonghua Xue Ye Xue Za Zhi",
"mesh_terms": "D005921:Glomerulonephritis; D006086:Graft vs Host Disease; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D009173:Mycophenolic Acid; D012189:Retrospective Studies",
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"title": "Clinical analysis of six cases with the de novo glomerulitis after allogeneic hematopoietic stem cell transplantation.",
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"abstract": "BK virus nephropathy (BKN) is uncommonly reported in native kidneys; mostly reported in bone marrow transplant patients. This case report represents an interesting clinical scenario of biopsy-proven BKN in native kidneys, in the presence of more than one million copies/mL of BK virus in serum.",
"affiliations": "Penn State Health Milton S. Hershey Medical Center Hershey Pennsylvania.;Penn State Health Milton S. Hershey Medical Center Hershey Pennsylvania.;Penn State Health Milton S. Hershey Medical Center Hershey Pennsylvania.;Penn State Health Milton S. Hershey Medical Center Hershey Pennsylvania.",
"authors": "Al Zein|Said|S|;Price|Hayley|H|;Chen|Guoli|G|;Kaur|Gurwant|G|",
"chemical_list": null,
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"fulltext": "\n==== Front\nClin Case RepClin Case Rep10.1002/(ISSN)2050-0904CCR3Clinical Case Reports2050-0904John Wiley and Sons Inc. Hoboken 10.1002/ccr3.1982CCR31982Case ReportCase ReportsNative kidney BK nephropathy: A case report AL ZEIN et al.Al Zein Said \n1\nPrice Hayley \n1\nChen Guoli \n1\nKaur Gurwant gkaur1@pennstatehealth.psu.edu \n1\n\n1 \nPenn State Health Milton S. Hershey Medical Center\nHershey\nPennsylvania\n* Correspondence\n\nGurwant Kaur, Penn State Milton S. Hershey Medical Centre, Hershey, PA.\n\nEmail: gkaur1@pennstatehealth.psu.edu\n09 1 2019 2 2019 7 2 10.1002/ccr3.2019.7.issue-2353 356 26 9 2018 20 11 2018 27 11 2018 © 2019 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.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.Key Clinical Message\n\nBK virus nephropathy (BKN) is uncommonly reported in native kidneys; mostly reported in bone marrow transplant patients. This case report represents an interesting clinical scenario of biopsy‐proven BKN in native kidneys, in the presence of more than one million copies/mL of BK virus in serum.\n\nBK virusbone marrow transplantimmunosuppressionkidney transplantnative BK virus nephropathy source-schema-version-number2.0component-idccr31982cover-dateFebruary 2019details-of-publishers-convertorConverter:WILEY_ML3GV2_TO_NLMPMC version:5.6.0 mode:remove_FC converted:25.02.2019\n\n\nAl Zein \nS \n, \nPrice \nH \n, \nChen \nG \n, \nKaur \nG \n. Native kidney BK nephropathy: A case report . Clin Case Rep . 2019 ;7 :353 –356 . 10.1002/ccr3.1982\n==== Body\n1 INTRODUCTION\nHistorically, BK virus nephropathy was thought to be a disease of kidney allografts that only affected renal transplant recipients. BKN is getting more frequently diagnosed as a cause of kidney disease in immunosuppressed patients. Here, we describe a biopsy‐proven native kidney BKN in an allogeneic stem cell transplant patient.\n\nThe BK virus was first isolated in 1971 from the urine of a renal transplant patient,1 but it was not until early 80s when Polyomavirus (BK and JC viruses) infections were described in renal transplant recipients.2, 3 At that time, native kidney BKN was considered to occur sporadically with few reports in lymphoma patients and solid organ transplant recipients. More cases of native kidney BKN have been reported in the new millennium with thoughts of under diagnoses of this entity.4\n\n\nIn the general population, 70%‐90% of individuals carry anti‐bodies to BK virus.5 The primary infection occurs as either a mild respiratory illness or asymptomatic infection during childhood, followed by viral latency usually in the urothelium and renal tubular epithelial cells.6, 7 Reactivation of BK infection may occur under conditions of immunosuppression, with usual manifestation being hematuria when it is limited to the urothelium.8, 9 Tissue diagnosis by a kidney biopsy is needed for detection of intrarenal Polyomavirus (PV) using SV40 stain.\n\n2 CLINICAL BACKGROUND\nSixty‐seven‐year‐old Caucasian male presented for progressive renal failure and was admitted to oncology floor. His past medical history included mantle cell lymphoma in remission with history of allogeneic hematopoietic stem cell transplant (HSCT) 5 years ago. HSCT is complicated by hypogammaglobulinemia with recurrent upper respiratory viral infections 3 years ago, so he was given monthly infusions of intravenous immunoglobulin G (IVIG) over a period of 6 months. Few months later, he developed chronic, cutaneous graft‐versus‐host disease (GVHD) with manifestation as diffuse scleroderma extending from the lower extremities to the neck. His scleroderma did not improve with outpatient treatment with neither rituximab nor ruxolitinib; however, it did remit and regress to only lower extremity involvement with ibrutinib 280 mg. His clinical course had been complicated with frequent infections including pneumonia which responded to outpatient antibiotics, alongside of a steadily rising creatinine, the ibrutinib was discontinued in interval time.\n\nMedications included mycophenolate mofetil 500 mg twice daily, sirolimus 1 mg every other day, acyclovir 600 mg daily, trimethoprim‐sulfamethoxazole 800‐160 mg twice weekly, and prednisone 10 mg daily.\n\n3 CLINICAL COURSE\nHe was chronically ill appearing. Examination was unremarkable with the exception of skin thickening and mottling in the lower extremities to the knees, consistent with known cutaneous scleroderma.\n\nHe presented for progressive renal failure with creatinine level of 4.84 mg/dL (0.7‐1.3 mg/dL), which had steadily risen over the past year from baseline creatinine of 1 mg/dL paralleling progressive fatigue and worsening dyspnea over the previous several months before admission. He had hyperkalemia of 5.7 mmol/L (normal range 3.5‐5 mmol/L) and metabolic acidosis. In the setting of renal failure, his acyclovir, trimethoprim‐sulfamethoxazole, and losartan were held. Urine revealed hematuria (moderate to large hemoglobin with 50+ red blood cells), and only trace proteinuria. Differential diagnosis for his hematuria and acute kidney injury (AKI) included septic/toxic acute tubular necrosis or acute interstitial nephritis, but was considered less likely as his AKI preceded the recent episode of pneumonia and antibiotic treatment. IgA nephropathy was also considered in differential for AKI with hematuria; uncommonly GVHD could also affect kidneys. Additional workup including Hepatitis B and C viral serologies, anti‐nuclear anti‐bodies (ANA < 1:80), C3, and C4 were normal, and antineutrophil cytoplasmic anti‐bodies (ANCA) were undetectable. His blood levels of BK virus yielded over one million copies. BK virus was detected in the urine with PCR showing >390 000 000 copies/mL of the virus DNA. Urine cytology was not done. This was followed by a renal biopsy which confirmed BK virus nephropathy with positive stain for SV 40. His mycophenolate mofetil was discontinued. He was started on leflunomide 100 mg for 3 days and 20 mg daily thereafter (adjusted for renal function). His creatinine slowly but steadily rose throughout his hospital course and was eventually started on hemodialysis (HD). His viral load remained high (BKV serum PCR > 1 000 000 copies/mL). After 2 months, the patient subsequently was started on cidofovir. After 6 weeks of initiating therapy, his viral load started to decline reaching 318 749 copies/mL but he remained HD dependent, became increasingly debilitated and deconditioned on dialysis and eventually passed away 2 weeks after his last clinic visit. The cause of death is unknown; he either passed away at home or at another hospital, likely due to an infection.\n\n4 KIDNEY BIOPSY PATHOLOGY\nTwo of 12 glomeruli were globally sclerotic on light microscopy. There was marked tubulointerstitial inflammation (Figure 1) including mainly lymphocytes mixed with plasma cells: Rare neutrophils and eosinophils were noted in a patchy pattern. It showed tubular atrophy and interstitial fibrosis in around 50% of the submitted specimen. Immunohistochemistry was positive for SV40 (Figure 2). Immunofluorescence had no specific staining of IgG, IgA, IgM, C3, kappa, and lambda light chains. Electron microscopy did not reveal any immune deposits.\n\nFigure 1 Light microscopy showing marked tubulointerstitial inflammation\n\nFigure 2 Immunohistochemistry showing positive stain for SV40\n\n5 DISCUSSION\nBK virus nephropathy is uncommonly reported in native kidneys with most of the reported cases occurring in bone marrow transplant patients.4 Most of the cases are seen in renal allografts, and most of the literature comes from small series in the transplant population. Diagnosis of BK virus nephropathy involves positive BK virus polymerase chain reaction (PCR) and tissue diagnosis by a kidney biopsy for detection of intrarenal Polyomavirus (PV) replication.10 This is done by the detection of T antigen of the Polyomavirus by immunochemistry. T antigen is the only viral protein required for viral replication as all other factors involved in pathogenesis are provided by the infected cells. This immunochemistry detection of T antigen is referred to as SV40‐positive staining, although it is most commonly seen in BK virus (80%) compared to other Polyomaviruses (PV) JC virus (20%) and rarely with simian virus 40 (SV40).11 SV40 staining is important to distinguish PV infection from other causes of tubule‐interstitial inflammation like allergic interstitial nephritis.\n\nThe usual treatment in transplant patients revolves around decreasing the immune suppression and assessing the response by trending the BK serum viral load which should start to improve within a month or two; full clearance of viremia may take several months. If decreasing immune suppression is not effective, a nonproven therapy, IVIG, is occasionally used12 as most IVIG preparations come from BKV exposed donors and contain BKV neutralizing anti‐bodies. Other anti‐viral approaches include the use of leflunomide, a drug that has both immunosuppressive and anti‐viral activity and has shown benefit in few small studies.13, 14, 15 Another alternative is cidofovir, an anti‐viral agent that has been used for HIV‐infected patients with progressive multifocal leukoencephalopathy (PML) resulting from Polyomavirus infection, although it is only Food and Drug Administration approved for treatment of Cytomegalovirus infections. cidofovir has shown benefit in few small studies in the treatment of BKVN16, 17 and in a retrospective analysis of 18 allo‐HSCT patients with reactivation of BK virus.18 Nephrotoxicity is the highest concern when cidofovir is used.\n\nIn our case, all immunosuppressive agents were discontinued and the patient was only kept on Leflunomide without much improvement in the serum BK viral load. Then, cidofovir was started and his viral load subsequently showed improving but still high levels. Multiple factors led to deconditioning in our patient including renal failure with dialysis in addition to persistent viremia.\n\n6 CONCLUSION\nBK Virus nephropathy should be considered as a cause of renal failure in immunocompromised patients who otherwise have no clear diagnosis.\n\nCONFLICT OF INTEREST\nNone of the authors’ have any conflicts of interest at the time of publication of this case report.\n\nAUTHOR CONTRIBUTION\nSAZ: contributed to writing of Discussion section. HP: contributed to writing of clinical case and background. GC: contributed to providing pathology slides. GK: contributed to creating the initial case report draft, clinical key message, pathology section, and editing it multiple times.\n==== Refs\nREFERENCES\n1 \n\nGardner \nSD \n, \nField \nAM \n, \nColeman \nDV \n, et al. New human papovavirus (B.K.) isolated from urine after renal transplantation . Lancet . 1971 ;1 :1253 ‐1257 .4104714 \n2 \n\nGardner \nSD \n, \nMacKenzie \nEF \n, \nSmith \nC \n, \nPorter \nAA \n. Prospective study of the human polyomaviruses BK and JC and cytomegalovirus in renal transplant recipients . J Clin Pathol . 1984 ;37 :578 ‐586 .6327777 \n3 \n\nHogan \nTF \n, \nBorden \nEC \n, \nMcBain \nJA \n, \nPadgett \nBL \n, \nWalker \nDL \n. Human polyomavirus infections with JC virus and BK virus in renal transplant patients . Ann Intern Med . 1980 ;92 :373 ‐378 .6243896 \n4 \n\nSharma \nSG \n, \nNickeleit \nV \n, \nHerlitz \nLC \n. BK polyoma virus nephropathy in the native kidney . Nephrol Dial Transplant . 2013 ;28 (3 ):620 ‐631 .23249622 \n5 \n\nHirsch \nHH \n, \nKnowles \nW \n, \nDickenmann \nM \n, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal‐transplant recipients . N Engl J Med . 2002 ;347 :488 ‐496 .12181403 \n6 \n\nRandhawa \nP \n, \nBrennan \nDC \n. BK virus infection in transplant recipients: an overview and update . Am J Transplant . 2006 ;6 :2000 ‐2005 .16771813 \n7 \n\nNickeleit \nV \n, \nMihatsch \nMJ \n. Polyomavirus nephropathy in native kidneys and renal allografts: an update on an escalating threat . Transpl Int . 2006 ;19 :960 ‐973 .17081225 \n8 \n\nNickeleit \nV \n, \nSteiger \nJ \n, \nMihatsch \nMJ \n. BK virus infection after kidney transplantation . Graft . 2005 ;5 :S46 ‐S47 .\n9 \n\nNickeleit \nV \n, \nHirsch \nHH \n, \nBinet \nIF \n, et al. Polyomavirus infection of renal allograft recipients: from latent infection to manifest disease . J Am Soc Nephrol . 1999 ;10 :1080 ‐1089 .10232695 \n10 \n\nColvin \nRB \n, \nNickeleit \nV \n. Renal transplant pathology In: Jennette JC , Olson JL , Schwartz MM , Silva FG , eds. Heptinstall's Pathology of the Kidney , 6th edn \nPhiladelphia, PA : Lippincott Williams and Wilkins ; 2006 :1347 ‐1490 .\n11 \n\nLusco \nMA \n, \nFogo \nAB \n, \nNajafian \nB \n, \nAlpers \nCE \n. AJKD atlas of renal pathology: polyomavirus nephropathy . Am J Kidney Dis . 2016 ;68 :e37 ‐e38 .27884285 \n12 \n\nSener \nA \n, \nHouse \nAA \n, \nJevnikar \nAM \n, et al. Intravenous immunoglobulin as a treatment for BK virus associated nephropathy: one‐year follow‐up of renal allograft recipients . Transplantation . 2006 ;81 :117 .16421486 \n13 \n\nNesselhauf \nN \n, \nStrutt \nJ \n, \nBastani \nB \n. Evaluation of leflunomide for the treatment of BK viremia and biopsy proven BK nephropathy; a single center experience . J Nephropathol . 2016 ;5 (1 ):34 ‐37 .27047808 \n14 \n\nFaguer \nS \n, \nHirsch \nHH \n, \nKamar \nN \n, et al. Leflunomide treatment for polyomavirus BK‐associated nephropathy after kidney transplantation . Transpl Int . 2007 ;20 (11 ):962 ‐969 .17666021 \n15 \n\nJosephson \nMA \n, \nGillen \nD \n, \nJavaid \nB \n, et al. Treatment of renal allograft polyoma BK virus infection with leflunomide . Transplantation . 2006 ;81 :704 .16534472 \n16 \n\nKuypers \nDR \n, \nVandooren \nAK \n, \nLerut \nE \n, et al. Adjuvant low‐dose cidofovir therapy for BK polyomavirus interstitial nephritis in renal transplant recipients . Am J Transplant . 2005 ;5 :1997 .15996251 \n17 \n\nVats \nA \n, \nShapiro \nR \n, \nSingh Randhawa \nP \n, et al. Quantitative viral load monitoring and cidofovir therapy for the management of BK virus‐associated nephropathy in children and adults . Transplantation . 2003 ;75 :105 .12544881 \n18 \n\nGanguly \nN \n, \nClough \nLA \n, \nDubois \nLK \n, et al. Low‐dose cidofovir in the treatment of symptomatic BK virus infection in patients undergoing allogeneic hematopoietic stem cell transplantation: A retrospective analysis of an algorithmic approach . Transpl Infect Dis . 2010 ;12 (5 ):406 ‐411 .20487411\n\n",
"fulltext_license": "CC BY",
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"issue": "7(2)",
"journal": "Clinical case reports",
"keywords": "BK virus; bone marrow transplant; immunosuppression; kidney transplant; native BK virus nephropathy",
"medline_ta": "Clin Case Rep",
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"title": "Native kidney BK nephropathy: A case report.",
"title_normalized": "native kidney bk nephropathy a case report"
} | [
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"literaturereference": "ZEIN S, PRICE H, CHEN G, KAUR G. NATIVE KIDNEY BK NEPHROPATHY: A CASE REPORT. CLIN CASE REP? HTTPS://DOI.ORG/10.1002/CCR3.1982. 2019?7:353-356.",
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{
"abstract": "The impact of lenalidomide treatment on long-term outcomes of patients with lower risk myelodysplastic syndromes (MDS) and chromosome 5q deletion (del(5q)) is unclear. This study used time-dependent multivariate methodology to analyse the influence of lenalidomide therapy on overall survival (OS) and acute myeloblastic leukaemia (AML) progression in 215 patients with International Prognostic Scoring System (IPSS) low or intermediate-1 risk and del(5q). There were significant differences in several relevant characteristics at presentation between patients receiving (n = 86) or not receiving lenalidomide (n = 129). The 5-year time-dependent probabilities of OS and progression to AML were 62% and 31% for patients receiving lenalidomide and 42% and 25% for patients not receiving lenalidomide; differences were not statistically significant in multivariate analysis that included all variables independently associated with those outcomes (OS, P = 0·45; risk of AML, P = 0·31, respectively). Achievement of RBC transfusion independency (P = 0·069) or cytogenetic response (P = 0·021) after lenalidomide was associated with longer OS in multivariate analysis. These data clearly show that response to lenalidomide results in a substantial clinical benefit in lower risk MDS patients with del(5q). Lenalidomide treatment does not appear to increase AML risk in this population of patients.",
"affiliations": "IMIBIC/Reina Sofía University Hospital/University of Córdoba, Córdoba, Spain.",
"authors": "Sánchez-García|Joaquín|J|;Del Cañizo|Consuelo|C|;Lorenzo|Ignacio|I|;Nomdedeu|Benet|B|;Luño|Elisa|E|;de Paz|Raquel|R|;Xicoy|Blanca|B|;Valcárcel|David|D|;Brunet|Salut|S|;Marco-Betes|Victor|V|;García-Pintos|Marta|M|;Osorio|Santiago|S|;Tormo|Mar|M|;Bailén|Alicia|A|;Cerveró|Carlos|C|;Ramos|Fernando|F|;Diez-Campelo|María|M|;Such|Esperanza|E|;Arrizabalaga|Beatriz|B|;Azaceta|Gemma|G|;Bargay|Joan|J|;Arilla|María J|MJ|;Falantes|José|J|;Serrano-López|Josefina|J|;Sanz|Guillermo F|GF|;|||",
"chemical_list": "D020533:Angiogenesis Inhibitors; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "England",
"delete": false,
"doi": "10.1111/bjh.12876",
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"issn_linking": "0007-1048",
"issue": "166(2)",
"journal": "British journal of haematology",
"keywords": "deletion 5q; lenalidomide; myelodysplastic syndrome; prognosis; treatment",
"medline_ta": "Br J Haematol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D020533:Angiogenesis Inhibitors; D002872:Chromosome Deletion; D002895:Chromosomes, Human, Pair 5; D018450:Disease Progression; D004341:Drug Evaluation; D017707:Erythrocyte Transfusion; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D053208:Kaplan-Meier Estimate; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009190:Myelodysplastic Syndromes; D011379:Prognosis; D012189:Retrospective Studies; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "0372544",
"other_id": null,
"pages": "189-201",
"pmc": null,
"pmid": "24716538",
"pubdate": "2014-07",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Multivariate time-dependent comparison of the impact of lenalidomide in lower-risk myelodysplastic syndromes with chromosome 5q deletion.",
"title_normalized": "multivariate time dependent comparison of the impact of lenalidomide in lower risk myelodysplastic syndromes with chromosome 5q deletion"
} | [
{
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"literaturereference": "SANCHEZ-GARCIA J, DEL CANIZO C, LORENZO I, NOMDEDEU B, LUNO E, DE PAZ R. MULTIVARIATE TIME-DEPENDENT COMPARISON OF THE IMPACT OF LENALIDOMIDE IN LOWER-RISK MYELODYSPLASTIC SYNDROMES WITH CHROMOSOME 5Q DELETION.. BR J HAEMATOL. 2014;189-201.",
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{
"abstract": "Endometrial small cell carcinoma (ESCC) is an extremely rare and aggressive tumor with poor prognosis. It is characterized by early regional and systemic spread leading to rapid development of lymph nodes, pelvic and extrapelvic metastasis and compromising the outcome. In this paper, we reported three cases of ESCC confirmed by pathological and immunohistochemistry studies. In one case, ESCC was associated with endometrioid carcinoma and carcinosarcoma, while the other two cases were pure ESCC. Two cases were diagnosed at early stage IA of the International Federation of Gynecology and Obstetrics (FIGO) cancer staging system. They were treated by surgery followed by pelvic external radiation and brachytherapy with favorable outcome (no recurrence was confirmed and a survival was 1 and 5years, respectively). The third case was diagnosed with visceral metastasis and was treated with 6 cycles of cisplatin plus etoposide. She died 8months after diagnosis. Due to its rarity, there is no standard guideline for the management of ESCC. Its treatment is extrapolated from that of both, the conventional endometrial carcinoma and the small cell carcinoma of the lungs, which share similarities with ESCC. Thus, multimodal therapeutic including surgery, radiation therapy and chemotherapy, seems to be the best therapeutic approach. Randomized clinical trials with multiples cases of ESCC are encouraged to clearly define the optimal therapeutic approach to this rare tumor.",
"affiliations": "Université libre de Bruxelles, institut Jules-Bordet, Brussels, Belgium; Centre hospitalier universitaire Hassan II, Department of medical oncology, Fez, Morocco. Electronic address: fatsi_2@hotmail.com.;Centre hospitalier universitaire Hassan II, Department of medical oncology, Fez, Morocco.;Université libre de Bruxelles, institut Jules-Bordet, Brussels, Belgium.;Centre hospitalier universitaire Hassan II, Department of medical oncology, Fez, Morocco.;Université libre de Bruxelles, institut Jules-Bordet, Brussels, Belgium.;Université libre de Bruxelles, institut Jules-Bordet, Brussels, Belgium.;Université libre de Bruxelles, institut Jules-Bordet, Brussels, Belgium.",
"authors": "Sidibe|Fatoumata Matokoma|FM|;Traore|Zakaria|Z|;Georgala|Aspasia|A|;Kanab|Rajae|R|;Larsimont|Denis|D|;Awada|Ahmad|A|;Piccart-Gebhart|Martine|M|",
"chemical_list": null,
"country": "France",
"delete": false,
"doi": "10.1016/j.bulcan.2018.06.007",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0007-4551",
"issue": "105(9)",
"journal": "Bulletin du cancer",
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{
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{
"abstract": "BACKGROUND\nApproximately, 70 % of adult patients with de novo acute myeloid leukemia (AML) achieve a complete remission (CR) while 10-20 % of AML are refractory to induction chemotherapy. Furthermore, a significant proportion of AML patients in CR will relapse during or after consolidation treatment. There is no evidence for a standard salvage regimen and most centers use a combination of an anthracycline and cytarabine (AraC). The aim of this study was to investigate the impact of two age-adjusted regimens containing AraC and cyclophosphamide applied for the treatment of relapsed or refractory AML.\n\n\nMETHODS\nWe retrospectively analyzed 60 patients (24 male, 36 female; median age 56 years) with relapsed or refractory AML who were treated with a combination of AraC and cyclophosphamide monocentrically between October 2000 and January 2013. Two different protocols containing either high-dose (hAC) or intermediate-dose cytarabin (iAC) have been applied dependent on age and performance status.\n\n\nRESULTS\nWe demonstrate an overall response rate (CR + PR) induced by hAC and iAC of 56.7 %. Importantly, a complete remission rate (CR + CRp) of 52.2 % was found in patients who received the hAC regimen while only 8.8 % of patients achieved a CR following the iAC protocol (p < 0.001). The rate of refractory disease was 26.1 and 47.1 %, respectively. High-risk cytogenetics, i.e., a complex aberrant or monosomal karyotype had no effect on achievement of CR after hAC. In addition, there was no impact of activating FLT3 mutations on response to treatment according to the hAC regimen. In the cohort of patients treated with the iAC protocol, treatment-related mortality of 11.8 % within 60 days was observed but none of the patients who received the hAC regimen died within the first 2 months following chemotherapy. The toxicity profile was acceptable at both cytarabine dose levels. Importantly, 19 patients (82.6 %) of the hAC cohort underwent allogeneic hematopoietic stem cell transplantation (HSCT) as consecutive treatment.\n\n\nCONCLUSIONS\nThe hAC regimen represents a promising therapeutic approach to induce a second CR in younger patients with relapsed or refractory AML prior to HSCT without using anthracyclines.",
"affiliations": "Abteilung Hämatologie und Internistische Onkologie, Klinik für Innere Medizin II, Universitätsklinikum Jena, Erlanger Allee 101, 07747, Jena, Germany.",
"authors": "Schnetzke|Ulf|U|;Fix|Peter|P|;Spies-Weisshart|Baerbel|B|;Schrenk|Karin|K|;Glaser|Anita|A|;Fricke|Hans-Joerg|HJ|;La Rosée|Paul|P|;Hochhaus|Andreas|A|;Scholl|Sebastian|S|",
"chemical_list": "D003561:Cytarabine; D003520:Cyclophosphamide; C497970:FLT3 protein, human; D019009:Proto-Oncogene Proteins c-kit; D051941:fms-Like Tyrosine Kinase 3",
"country": "Germany",
"delete": false,
"doi": "10.1007/s00432-014-1666-7",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0171-5216",
"issue": "140(8)",
"journal": "Journal of cancer research and clinical oncology",
"keywords": null,
"medline_ta": "J Cancer Res Clin Oncol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D003520:Cyclophosphamide; D003561:Cytarabine; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D005240:Feasibility Studies; D005260:Female; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D019009:Proto-Oncogene Proteins c-kit; D012189:Retrospective Studies; D016879:Salvage Therapy; D016019:Survival Analysis; D016896:Treatment Outcome; D055815:Young Adult; D051941:fms-Like Tyrosine Kinase 3",
"nlm_unique_id": "7902060",
"other_id": null,
"pages": "1391-7",
"pmc": null,
"pmid": "24728467",
"pubdate": "2014-08",
"publication_types": "D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "7459811;19776405;15742336;1588374;15572587;9053511;15976757;24070241;3589690;8078551;23610610;12707726;23287624;24309527;12598308;18473961;23841729;21331073;22096250;19880497;18798533;11535508;23071272;9665189;22585697;19509382;19008455;15632409;23526416;22965967;19602710;20628653;18695255;19776406;22383796;20110655;21910721;21410371",
"title": "Efficacy and feasibility of cyclophosphamide combined with intermediate- dose or high-dose cytarabine for relapsed and refractory acute myeloid leukemia (AML).",
"title_normalized": "efficacy and feasibility of cyclophosphamide combined with intermediate dose or high dose cytarabine for relapsed and refractory acute myeloid leukemia aml"
} | [
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},
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},
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{
"abstract": "Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is an uncommon yet serious adverse cutaneous drug reaction that results from a hypersensitivity reaction. Drug reaction with eosinophilia and systemic symptoms is often misdiagnosed because of vague and confounding signs and symptoms. The most common clinical manifestations of DRESS are shared with many other diseases and include rash, lymphadenopathy, and fever. Because the syndrome can be difficult to diagnose, patients are often in the late stages of the disease process before treatment is initiated. The mainstay of treatment is stopping the culprit medication. Drug reaction with eosinophilia and systemic symptoms is associated with a high mortality rate, most often from liver failure and failure to diagnose. Emergency providers should be able to recognize the clinical manifestations of DRESS, know what diagnostic studies are indicated, and be familiar with the appropriate treatment.",
"affiliations": "College of Nursing, University of South Alabama, Mobile, Alabama.",
"authors": "Myers|Charlene M|CM|;Miller|Jennifer J|JJ|;Davis|Wesley D|WD|",
"chemical_list": "D006074:Gout Suppressants; D000493:Allopurinol",
"country": "United States",
"delete": false,
"doi": "10.1097/TME.0000000000000298",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1931-4485",
"issue": "42(2)",
"journal": "Advanced emergency nursing journal",
"keywords": null,
"medline_ta": "Adv Emerg Nurs J",
"mesh_terms": "D000368:Aged; D000493:Allopurinol; D063926:Drug Hypersensitivity Syndrome; D004802:Eosinophilia; D006074:Gout Suppressants; D006801:Humans; D008297:Male",
"nlm_unique_id": "101285075",
"other_id": null,
"pages": "108-118",
"pmc": null,
"pmid": "32358426",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Allopurinol-Induced Drug Reaction With Eosinophilia and Systemic Symptoms: A Case Report.",
"title_normalized": "allopurinol induced drug reaction with eosinophilia and systemic symptoms a case report"
} | [
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"reactionmeddraversionpt": "24.0",
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},
{
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},
{
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{
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},
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"literaturereference": "MYERS CM, MILLER JJ, DAVIS WD. ALLOPURINOL?INDUCED DRUG REACTION WITH EOSINOPHILIA AND SYSTEMIC SYMPTOMS: A CASE REPORT. ADVAN?EMERG?NURS?J 2020?42(2):108?118.",
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},
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},
{
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}
],
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}
] |
{
"abstract": "The prevalence of newborns with neonatal abstinence syndrome (NAS) is rising sharply. To respond to this crisis, our institution re-examined our policies and procedures regarding our approach to the management of newborns with prenatal opioid exposure. Our 6-pronged approach included: (1) a commitment to nonpharmacologic care as first-line treatment; (2) a simplified function-based approach to observation of the infant (Eat-Sleep-Console); (3) improved prenatal education to prepare parents for the newborn's postnatal course; (4) a cuddler program; (5) strategies to help parents remain at the bedside; and (6) change from morphine to methadone for infants who require medication for NAS. Our obstetrics collaborators and outpatient pediatric colleagues have partnered with us to prepare mothers for delivery by strengthening them in their recovery prenatally and helping them maintain their recovery after discharge. Among many improvements, our changes resulted in a decrease in medication treatment for NAS (from 87% to 40%), a decrease in the need for adjuvant medication (from 34% to 2%), and a decrease in length of hospital stay (from 18 days to 10 days). The 3 most significant factors that have contributed to our success have been: (1) a committed champion leader; (2) a strong collaborative multidisciplinary team; and (3) a quality improvement approach that facilitates implementation of ideas easily and provides timely feedback to guide further change. Although we have seen notable improvements with our new approach, emerging data from our outpatient colleagues indicate that much more is needed to help improve the long-term health of these dyads.",
"affiliations": "Department of Pediatrics, Boston Medical Center, Boston, MA, USA. Electronic address: susan.minear@bmc.org.;Department of Pediatrics, Boston Medical Center, Boston, MA, USA.",
"authors": "Minear|Susan|S|;Wachman|Elisha M|EM|",
"chemical_list": "D000701:Analgesics, Opioid; D009020:Morphine; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1016/j.clinthera.2019.07.001",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0149-2918",
"issue": "41(9)",
"journal": "Clinical therapeutics",
"keywords": null,
"medline_ta": "Clin Ther",
"mesh_terms": "D000701:Analgesics, Opioid; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D007902:Length of Stay; D008691:Methadone; D009020:Morphine; D009357:Neonatal Abstinence Syndrome; D010045:Outpatients; D010290:Parents; D011247:Pregnancy; D058996:Quality Improvement",
"nlm_unique_id": "7706726",
"other_id": null,
"pages": "1663-1668",
"pmc": null,
"pmid": "31439335",
"pubdate": "2019-09",
"publication_types": "D016428:Journal Article; D013486:Research Support, U.S. Gov't, Non-P.H.S.",
"references": null,
"title": "Management of Newborns with Prenatal Opioid Exposure: One Institution's Journey.",
"title_normalized": "management of newborns with prenatal opioid exposure one institution s journey"
} | [
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},
{
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}
],
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},
{
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}
],
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"medicinalproduct": "CLONIDINE."
},
{
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},
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},
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}
],
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"reaction": [
{
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"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Neonatal disorder",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Foetal exposure during pregnancy",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug withdrawal syndrome neonatal",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Hypertonia",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Sneezing",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Infantile spitting up",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "High-pitched crying",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "MINEAR S AND WACHMAN EM. MANAGEMENT OF NEWBORNS WITH PRENATAL OPIOID EXPOSURE: ONE INSTITUTION^S JOURNEY. CLINICAL THERAPEUTICS. 2019?DOI:10.1016/J.CLINTHERA.2019.0",
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},
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}
] |
{
"abstract": "Permanent visual loss can be caused by improper use of immunosuppressive therapy in cases of uveitis without differential diagnosis of syphilitic uveitis. We present four cases of syphilitic uveitis that were incorrectly diagnosed as being secondary to rheumatic diseases and were subsequently treated with immunosuppressive therapy, leading to permanent visual loss. These cases highlight the importance of ruling out syphilis in the differential diagnosis of inflammatory ocular diseases before starting use of immunosuppressive therapy.",
"affiliations": "Department of Ophthalmology and Visual Sciences, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.;Department of Ophthalmology and Visual Sciences, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.;Department of Ophthalmology and Visual Sciences, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.;Department of Rheumatology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.;Department of Ophthalmology and Visual Sciences, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.;Department of Ophthalmology and Visual Sciences, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo, SP, Brazil.",
"authors": "Afonso|Vivian Cristina Costa|VC|;Nascimento|Heloisa|H|;Belfort|Rubens M|RM|;Sato|Emilia Inoue|EI|;Muccioli|Cristina|C|;Belfort|Rubens|R|",
"chemical_list": "D007166:Immunosuppressive Agents",
"country": "Brazil",
"delete": false,
"doi": null,
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"issn_linking": "0004-2749",
"issue": "78(3)",
"journal": "Arquivos brasileiros de oftalmologia",
"keywords": null,
"medline_ta": "Arq Bras Oftalmol",
"mesh_terms": "D003937:Diagnosis, Differential; D005260:Female; D016508:Fluorescent Treponemal Antibody-Absorption Test; D006801:Humans; D007166:Immunosuppressive Agents; D008297:Male; D008875:Middle Aged; D013587:Syphilis; D014605:Uveitis; D014786:Vision Disorders; D014792:Visual Acuity",
"nlm_unique_id": "0400645",
"other_id": null,
"pages": "185-6",
"pmc": null,
"pmid": "26222110",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Visual loss resulting from immunosuppressive therapy in patients with syphilitic uveitis.",
"title_normalized": "visual loss resulting from immunosuppressive therapy in patients with syphilitic uveitis"
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},
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"receivedate": "20160316",
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},
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},
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"seriousnessdeath": null,
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"seriousnesshospitalization": null,
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"transmissiondate": "20160526"
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}
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"literaturereference": "AFONSO VC, NASCIMENTO H, BELFORT RM, SATO EI, MUCCIOLI C, BELFORT JR R. VISUAL LOSS RESULTING FROM IMMUNOSUPPRESSIVE THERAPY IN PATIENTS WITH SYPHILITIC UVEITIS. ARQ-BRAS-OFTALMOL 2015?78(3):185-6.",
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},
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] |
{
"abstract": "A 43-year-old female was administered recombinant human thyrotropin-α (Thyrogen®; Genzyme Corp., Cambridge, Mass., USA) before a fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) scan as part of an evaluation of thyroid cancer recurrence. She was administered two doses of Thyrogen only 4 weeks before for stimulated thyroglobulin measurement. The PET/CT scan demonstrated enlarged ovaries which on subsequent conservative follow-up resolved. This transient hyperstimulated state of the ovaries was presumed to be related to Thyrogen injections received twice within a space of a month. Thyrogen is being increasingly used for raising the level of thyroid-stimulating hormone (TSH), besides thyroid hormone withdrawal for suspected recurrence of differentiated thyroid carcinoma. Ovarian hyperstimulation has been reported as an iatrogenic complication for in vitro fertilization with the presence of human chorionic gonadotropin being invariably associated. Transient gestational thyrotoxicosis has been reported to be related to promiscuous activation of the thyrotropin receptor by chorionic gonadotropin. In our case it is possible that due to the promiscuous stimulation, thyrotropin caused a follicle-stimulating hormone (FSH)-like action resulting in ovarian hyperstimulation. The reason behind this could be the shared sequence identity of the hormone-binding domains of TSH and FSH receptors, or some mutation in the FSH receptor. In conclusion, our case highlights a potential side effect of administering Thyrogen in females of the reproductive age group.",
"affiliations": "Nuclear Medicine Division, Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, Va., USA.;Nuclear Medicine Division, Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, Va., USA.",
"authors": "Rizvi|Tanvir|T|;Rehm|Patrice K|PK|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000360852",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2235-0640",
"issue": "3(2)",
"journal": "European thyroid journal",
"keywords": "Ovarian hyperstimulation; Positron emission tomography/computed tomography scan; Recombinant human thyrotropin",
"medline_ta": "Eur Thyroid J",
"mesh_terms": null,
"nlm_unique_id": "101604579",
"other_id": null,
"pages": "125-9",
"pmc": null,
"pmid": "25114876",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article",
"references": "9756273;3234176;11898394;3398841;9221989;11753180;8027262;11943741;9731906;9861544;12930928;20484385;12727936;2457586;16278261;18630995;15003269;12498425;19860577;10638405;9558473;9854118;2660037;11585858;9183570;8885814;2667498",
"title": "Recombinant human thyrotropin use resulting in ovarian hyperstimulation: an unusual side effect.",
"title_normalized": "recombinant human thyrotropin use resulting in ovarian hyperstimulation an unusual side effect"
} | [
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},
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"reaction": [
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{
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}
],
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}
},
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"literaturereference": "RIZVI T., REHM PK. RECOMBINANT HUMAN THYROTROPIN USE RESULTING IN OVARIAN HYPERSTIMULATION: AN UNUSUAL SIDE EFFECT. EUR. THYROID J. 2014 JUN 7; 3(2):125-129. DOI:10.1159/000360852.",
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"transmissiondate": "20150326"
},
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],
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}
},
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"literaturereference": "RIZVI T, REHM PK. RECOMBINANT HUMAN THYROTROPIN USE RESULTING IN OVARIAN HYPERSTIMULATION: AN UNUSUAL SIDE EFFECT. EUR THYROID J. 2014; 3:125-129. DOI: 10.1159/000360852",
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"transmissiondate": "20151125"
}
] |
{
"abstract": "Tocilizumab is a humanized monoclonal antibody targeting the interleukin-6 receptor that is frequently used for the treatment of refractory rheumatoid arthritis. Since patients with hepatitis B virus (HBV) infection were excluded from pivotal trials, the risk of HBV reactivation with this novel drug class remains uncertain. We present the first case of tocilizumab-associated HBV reactivation resulting in fulminant hepatic failure and a need for liver transplant. Our findings underscore the need for prophylactic antiviral therapy in patients being treated with novel immunosuppressive agents.",
"affiliations": "Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.;Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.;Viroscience, Erasmus MC University Medical Center, Rotterdam, The Netherlands.;Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands.",
"authors": "Sonneveld|Milan J|MJ|;Murad|S Darwish|SD|;van der Eijk|A A|AA|;de Man|R A|RA|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.14309/crj.0000000000000243",
"fulltext": "\n==== Front\nACG Case Rep J\nACG Case Rep J\nACGCRJ\nACGCRJ\nAC9\nACG Case Reports Journal\n2326-3253 Wolters Kluwer Maryland, MD \n\n32042838\nACGCR-19-0251\n10.14309/crj.0000000000000243\n00006\nCase Report\nLiver\nFulminant Liver Failure due to Hepatitis B Reactivation During Treatment With Tocilizumab\nSonneveld Milan J. MD, PhD1 Murad S. Darwish MD, PhD1 van der Eijk A.A. MD, PhD2 de Man R.A. MD, PhD1 1 Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Rotterdam, The Netherlands\n2 Viroscience, Erasmus MC University Medical Center, Rotterdam, The Netherlands\nCorrespondence: M.J. Sonneveld, Department of Gastroenterology and Hepatology, Erasmus MC University Medical Center, Mailbox 2040, 3000 CA Rotterdam, Rotterdam, the Netherlands (m.j.sonneveld@erasmusmc.nl).\n12 2019 \n09 12 2019 \n6 12 e0024313 4 2019 11 9 2019 © 2019 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.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.ABSTRACT\nTocilizumab is a humanized monoclonal antibody targeting the interleukin-6 receptor that is frequently used for the treatment of refractory rheumatoid arthritis. Since patients with hepatitis B virus (HBV) infection were excluded from pivotal trials, the risk of HBV reactivation with this novel drug class remains uncertain. We present the first case of tocilizumab-associated HBV reactivation resulting in fulminant hepatic failure and a need for liver transplant. Our findings underscore the need for prophylactic antiviral therapy in patients being treated with novel immunosuppressive agents.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nHepatitis B virus (HBV) reactivation is a serious and potentially fatal complication of immunosuppressive therapy. Current guidelines recommend screening for HBV markers in patients undergoing profound immunosuppression (eg, rituximab) and consideration of prophylactic therapy in patients at high risk. However, because HBV-infected patients are usually excluded from participation in clinical trials, the risk of HBV reactivation under emerging biologicals and novel immune modulators is largely unknown. Tocilizumab is a humanized monoclonal antibody targeting the interleukin-6 (IL-6) receptor. IL-6 is a proinflammatory cytokine that, among others, appears to have a major role in the pathogenesis of rheumatoid arthritis (RA). Tocilizumab has been shown to be very effective in patients with RA.1 Because IL-6 has a myriad of proinflammatory and antiviral properties, HBV reactivation is a potential concern with IL-6 antagonist therapy.2\n\nThere is no consensus on the magnitude of the risk of HBV reactivation with tocilizumab. We present, to our knowledge, the first case report of tocilizumab-associated HBV reactivation resulting in fulminant liver failure, necessitating urgent liver transplantation.\n\nCASE REPORT\nA 59-year-old Chinese woman with a medical history of RA for which she had been primarily treated with methotrexate 10 years before presented to another clinic. At that time, she was also diagnosed with an HBeAg-negative chronic HBV infection for which she received no treatment. After 2 years, she developed an HBV flare after which methotrexate was discontinued. Liver biopsy showed minimal fibrosis. After the flare, she was again not treated with antiviral agents. Two years later, azathioprine and low-dose prednisolone were started for a new episode of active RA without any liver-related adverse events. One year before the current presentation, she was switched to a combination of leflunomide, hydroxychloroquine, and low-dose prednisolone (10–15 mg/d). At this time, she was still hepatitis B surface antigen (HBsAg) positive, with unknown HBV DNA levels. She became HBsAg negative during the follow-up and developed borderline positive anti-HBs. She was also immunoglobulin G positive for cytomegalovirus (CMV) without detectable viremia.\n\nUnfortunately, her RA was insufficiently controlled and she was considered for treatment with tocilizumab. During screening, she was again HBsAg positive and anti-HBs negative and had an HBV DNA level of 88 IU/mL. Tocilizumab therapy was commenced with 8 mg/kg once every 4 weeks intravenously without concomitant prophylactic antiviral therapy based on the low viral load and perceived low risk of HBV reactivation with tocilizumab. Shortly after the start of tocilizumab, she developed a rapidly progressive hepatitis with a peak alanine aminotransferase (ALT) of 2,125 IU/L. At this time, she had an HBV DNA level of 3.6 × 108 IU/mL. Tocilizumab and leflunomide were discontinued, and she was started on entecavir 0.5 mg once daily. This resulted in a rapid decline of HBV DNA and ALT, but she developed marked jaundice (bilirubin 431 IU/L), coagulopathy (international normalized ratio 2.9), and grade 2 hepatic encephalopathy (Figure 1). She was subsequently transferred to our center for evaluation for liver transplantation. At the time of presentation, she complained of malaise, nausea, and vomiting. She was jaundiced and had asterixis and a grade 2 encephalopathy. Besides a distended abdomen with shifting dullness and mild peripheral edema, her physical examination was unremarkable. Additional biochemical investigations are shown in Table 1. She had no evidence of hepatitis A, C, D, or E infection but did have a detectable CMV polymerase chain reaction (1.99 × 104 IU/L). Her HBV DNA level was 1.31 × 103 IU/mL. Imaging showed marked ascites without evidence of portal vein thrombosis, no evidence of biliary obstruction or malignancy, and no signs of cirrhosis. She was treated with valganciclovir and received antibiotic and antimycotic therapy per the local protocol while entecavir was continued. Nevertheless, her health deteriorated and progressed to grade 3 encephalopathy. She was admitted to the intensive care unit and was listed for high urgency liver transplantation. She underwent an uncomplicated liver transplantation with a donation after brain death liver 5 days after. Posttransplant immunosuppression consisted of prednisolone, basiliximab (days 1 and 4), mycophenolate mofetil, and subsequently tacrolimus. She received anti-HBs immunoglobulin and entecavir posttransplant and was treated with valganciclovir until CMV DNA was undetectable. She remains well to this date, with her RA well controlled without additional RA medication. A pathological study of the explant showed a picture compatible with acute liver failure with completely distorted architecture and massive hepatic necrosis with ductular reaction. There was limited periportal fibrosis without evident cirrhosis. The findings were compatible with acute viral hepatitis but could also fit with toxic liver injury.\n\nFigure 1. An overview of ALT, bilirubin, HBV DNA, and INR. ALT, alanine aminotransferase; HBV, hepatitis B virus; Hydroxychl, hydroxychloroquine; INR, international normalized ratio; Lef, leflunomide; Pred, prednisolone; TOC, tocilizumab.\n\nTable 1. Laboratory findings at the time of transfer to our liver unit\n\nDISCUSSION\nCurrent treatment guidelines for the management of patients with HBV infection suggest beginning prophylactic antiviral therapy in all HBsAg-positive patients, regardless of the HBV DNA level when undergoing profound immunosuppression. Because patients with HBV infection were excluded from pivotal trials, it has been unclear whether this recommendation should include patients treated with IL-6 receptor antagonists.\n\nIL-6 has a myriad of proinflammatory and antiviral properties. Various studies have shown that IL-6 is upregulated in HBV-infected patients, IL-6 polymorphisms are associated with the clearance of HBV infection, and IL-6 also appears to have a role in hepatocarcinogenesis in HBV infected patients.2,3 Furthermore, IL-6 has also been shown to suppress HBV replication and to prevent the accumulation of HBV covalently closed circular DNA and HBV entry into hepatocytes.4,5 Despite the apparent importance of IL-6 for control of HBV infection, existing evidence has yielded contradictory results regarding the risk of HBV reactivation with tocilizumab. In a case report from 2008, Nagashima and Minota described a single HBeAg-positive patient who was treated with tocilizumab without any apparent issues.6 Furthermore, Chen et al studied 63 patients treated with tocilizumab, 48 of whom had evidence of (chronic or resolved) HBV infection.7 Three of 7 untreated HBsAg-positive patients developed HBV reactivation, whereas none of 41 HBsAg-negative, anti-HBc-positive patients experienced reactivation. None of the patients with HBV reactivation developed a rise in transaminases. In another study from Greece involving 30 tocilizumab-treated HBV-infected patients, none developed reactivation.8 Our case shows that HBV reactivation during tocilizumab can also cause severe hepatitis with subsequent fulminant liver failure.\n\nIt is important to note that tocilizumab itself has also been implicated as a cause of toxic liver injury. In the registration trials, up to 71% of patients experienced modest increases in ALT during treatment, with ALT elevations over 5 times the upper limit of normal reported in 2%.1 There are at least 2 case reports of severe liver toxicity attributed to tocilizumab.9,10\n\nAlthough it is impossible to conclusively determine the cause of liver failure in our patient, the course of events (development of an HBV DNA flare with subsequent hepatitis and resolution of hepatitis upon commencing antiviral therapy) suggest HBV reactivation as the primary cause. Concomitant toxic liver injury can, however, not be completely excluded. The role of CMV in the current clinical scenario is also unclear. CMV reactivation may occur in the context of acute hepatitis because of other causes, but CMV-related liver disease has been reported with tocilizumab and thus may have contributed to the rapid deterioration of liver function in our patient.11\n\nIn conclusion, we report the first case of tocilizumab-associated HBV reactivation resulting in liver failure and a need for liver transplantation. Our case underscores the need to consider prophylactic antiviral therapy in all HBsAg-positive patients undergoing IL-6 receptor antagonist therapy.\n\nDISCLOSURES\nAuthor contributions: All authors contributed equally to this manuscript. MJ Sonneveld is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n1. Scott LJ \nTocilizumab: A review in rheumatoid arthritis\n. Drugs. \n2017 ;77 :1865 –79\n.29094311 \n2. Lan T Chang L Wu L Yuan YF \nIL-6 plays a crucial role in HBV infection\n. J Clin Transl Hepatol. \n2015 ;3 :271 –6\n.26807383 \n3. Xia C Liu Y Chen Z Zheng M \nInvolvement of interleukin 6 in hepatitis B viral infection\n. Cell Physiol Biochem. \n2015 ;37 :677 –86\n.26343270 \n4. Kuo TM Hu CP Chen YL \nHBV replication is significantly reduced by IL-6\n. J Biomed Sci . 2009 ;16 :41 .19374779 \n5. Bouezzedine F Fardel O Gripon P \nInterleukin 6 inhibits HBV entry through NTCP down regulation\n. Virology. \n2015 ;481 :34 –42\n.25765005 \n6. Nagashima T Minota S \nLong-term tocilizumab therapy in a patient with rheumatoid arthritis and chronic hepatitis B\n. Rheumatology (Oxford). \n2008 ;47 :1838 –40\n.\n7. Chen LF Mo YQ Jing J Ma JD Zheng DH Dai L \nShort-course tocilizumab increases risk of hepatitis B virus reactivation in patients with rheumatoid arthritis: A prospective clinical observation\n. Int J Rheum Dis. \n2017 ;20 :859 –69\n.28160426 \n8. Papalopoulos I Fanouriakis A Kougkas N \nLiver safety of non-tumour necrosis factor inhibitors in rheumatic patients with past hepatitis B virus infection: An observational, controlled, long-term study\n. Clin Exp Rheumatol \n2018 ;36 :102 –9\n.\n9. Anger F Wiegering A Wagner J \nToxic drug-induced liver failure during therapy of rheumatoid arthritis with tocilizumab subcutaneously: A case report\n. Rheumatology (Oxford) . 2017 ;56 :1628 –9\n.28575416 \n10. Hiura M Abe S Tabaru A \nCase of severe liver damage after the induction of tocilizumab therapy for rheumatoid vasculitis\n. Hepatol Res. \n2011 ;41 :492 –6\n.21435128 \n11. Komura T Ohta H Nakai R \nCytomegalovirus reactivation induced acute hepatitis and gastric erosions in a patient with rheumatoid arthritis under treatment with an anti-IL-6 receptor antibody, tocilizumab\n. Intern Med. \n2016 ;55 :1923 –7\n.27432105\n\n",
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"title": "Fulminant Liver Failure due to Hepatitis B Reactivation During Treatment With Tocilizumab.",
"title_normalized": "fulminant liver failure due to hepatitis b reactivation during treatment with tocilizumab"
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{
"abstract": "High-energy trauma associated with calcaneal fracture or Lisfranc fracture dislocation and midfoot crushing injuries are known causes of compartment syndrome in the foot. Suppurative infection in the deep osseofascial compartments can also cause compartment syndrome. We describe the case of a 29-year-old female who had developed a suppurative local infection that resulted in acute compartment syndrome after receiving a local hydrocortisone injection for plantar fasciitis. We diagnosed the compartment syndrome, and fasciotomy was promptly undertaken. After more than 2 years of follow-up, she had a satisfactory functional outcome without substantial morbidity. To our knowledge, no other report in the English-language studies has described compartment syndrome due to abscess formation after a local injection of hydrocortisone. The aim of our report was to highlight this rare, but serious, complication of a routine outpatient clinical procedure.",
"affiliations": "Director and Head, Orthopedic Department, Noble Hospital, Hadapsar, Pune, Maharashtra, India. Electronic address: sampatdumbre@gmail.com.;Research Officer, Noble Hospital, Hadapsar, Pune, Maharashtra, India.;Consultant Orthopaedic Surgeon, Orthopedic Department, Abane Hospital, Hadapsar, Pune, Maharashtra, India.;Consultant Orthopaedic Surgeon, Orthopedic Department, Noble Hospital, Hadapsar, Pune, Maharashtra, India.;Consultant Orthopaedic Surgeon, Orthopedic Department, Noble Hospital, Hadapsar, Pune, Maharashtra, India.",
"authors": "Patil|Sampat Dumbre|SD|;Patil|Vaishali Dumbre|VD|;Abane|Sachin|S|;Luthra|Rohit|R|;Ranaware|Abhijit|A|",
"chemical_list": "D000893:Anti-Inflammatory Agents; D006854:Hydrocortisone",
"country": "United States",
"delete": false,
"doi": null,
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"issn_linking": "1067-2516",
"issue": "54(4)",
"journal": "The Journal of foot and ankle surgery : official publication of the American College of Foot and Ankle Surgeons",
"keywords": "abscess; complication of treatment; fasciotomy; muscle compartment; plantar fascia",
"medline_ta": "J Foot Ankle Surg",
"mesh_terms": "D000208:Acute Disease; D000328:Adult; D000893:Anti-Inflammatory Agents; D003161:Compartment Syndromes; D036981:Fasciitis, Plantar; D000071938:Fasciotomy; D005260:Female; D006801:Humans; D006854:Hydrocortisone; D007267:Injections; D018461:Soft Tissue Infections",
"nlm_unique_id": "9308427",
"other_id": null,
"pages": "692-6",
"pmc": null,
"pmid": "24838218",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Acute Compartment Syndrome of the Foot due to Infection After Local Hydrocortisone Injection: A Case Report.",
"title_normalized": "acute compartment syndrome of the foot due to infection after local hydrocortisone injection a case report"
} | [
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{
"abstract": "A 59-year-old man who presented with continuous fever, livedo reticularis, and left leg ischemia with multiple tibial artery stenosis and renal artery aneurysm, as demonstrated by arteriography, was diagnosed with polyarteritis nodosa (PAN) 6 years ago. Although he frequently relapsed in spite of intensive immunosuppressive therapies, the disease activity of PAN was controlled with repeated rituximab (RTX) therapies and steroid doses were tapered safely. Peripheral CD19+ B-cells disappeared soon after the 1st administration of RTX. Although CD19+ B-cells remained absent, 3.1% of CD3+CD20+ T-cells were observed in the peripheral blood prior to the 2nd administration of RTX. Recent studies have suggested the pathogenic role of CD3+CD20+ T-cells in autoimmune diseases in the context of RTX therapy; therefore, their roles in the pathogenesis of PAN also need to be considered.",
"affiliations": "a Department of Allergy and Rheumatology , Graduate School of Medicine, the University of Tokyo , Tokyo , Japan.;a Department of Allergy and Rheumatology , Graduate School of Medicine, the University of Tokyo , Tokyo , Japan.;a Department of Allergy and Rheumatology , Graduate School of Medicine, the University of Tokyo , Tokyo , Japan.;a Department of Allergy and Rheumatology , Graduate School of Medicine, the University of Tokyo , Tokyo , Japan.;a Department of Allergy and Rheumatology , Graduate School of Medicine, the University of Tokyo , Tokyo , Japan.;a Department of Allergy and Rheumatology , Graduate School of Medicine, the University of Tokyo , Tokyo , Japan.;a Department of Allergy and Rheumatology , Graduate School of Medicine, the University of Tokyo , Tokyo , Japan.",
"authors": "Seri|Yu|Y|;Shoda|Hirofumi|H|;Hanata|Norio|N|;Nagafuchi|Yasuo|Y|;Sumitomo|Shuji|S|;Fujio|Keishi|K|;Yamamoto|Kazuhiko|K|",
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"delete": false,
"doi": "10.3109/14397595.2015.1014153",
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"issue": "27(4)",
"journal": "Modern rheumatology",
"keywords": "B-cell; Polyarteritis nodosa; Rituximab; T-cell",
"medline_ta": "Mod Rheumatol",
"mesh_terms": "D001402:B-Lymphocytes; D006801:Humans; D007155:Immunologic Factors; D008297:Male; D008875:Middle Aged; D010488:Polyarteritis Nodosa; D000069283:Rituximab; D013601:T-Lymphocytes; D016896:Treatment Outcome",
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"pages": "696-698",
"pmc": null,
"pmid": "25671401",
"pubdate": "2017-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A case of refractory polyarteritis nodosa successfully treated with rituximab.",
"title_normalized": "a case of refractory polyarteritis nodosa successfully treated with rituximab"
} | [
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{
"abstract": "During therapy with imatinib, some patients with chronic myeloid leukemia (CML) develop chromosomal abnormalities in Philadelphia chromosome (Ph)-negative cells. These abnormalities are frequently transient and their clinical consequence is unclear. Although some reports have suggested that the abnormalities might be associated with secondary myelodysplastic syndrome (MDS), the diagnosis has not always been established using standard criteria. We report 3 cases of patients treated with imatinib for CML who were subsequently found to have chromosomal abnormalities in Ph-negative cells. One of them developed acute myelogenous leukemia (AML) and the other 2 developed high-risk MDS that rapidly transformed to AML. These cases were identified in a total study group of 1701 patients. Although these occurrences are rare, the findings highlight the need for close monitoring of patients with CML treated with imatinib.",
"affiliations": "Department of Leukemia, The University of Texas, M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 428, Houston, TX 77030, USA.",
"authors": "Kovitz|Craig|C|;Kantarjian|Hagop|H|;Garcia-Manero|Guillermo|G|;Abruzzo|Lynne V|LV|;Cortes|Jorge|J|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate",
"country": "United States",
"delete": false,
"doi": "10.1182/blood-2006-04-017400",
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"issn_linking": "0006-4971",
"issue": "108(8)",
"journal": "Blood",
"keywords": null,
"medline_ta": "Blood",
"mesh_terms": "D000970:Antineoplastic Agents; D001549:Benzamides; D002869:Chromosome Aberrations; D005260:Female; D006801:Humans; D000068877:Imatinib Mesylate; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive; D015470:Leukemia, Myeloid, Acute; D054438:Leukemia, Myeloid, Chronic, Atypical, BCR-ABL Negative; D008297:Male; D008875:Middle Aged; D009190:Myelodysplastic Syndromes; D010879:Piperazines; D011743:Pyrimidines; D012307:Risk Factors",
"nlm_unique_id": "7603509",
"other_id": null,
"pages": "2811-3",
"pmc": null,
"pmid": "16809614",
"pubdate": "2006-10-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't; D016454:Review",
"references": null,
"title": "Myelodysplastic syndromes and acute leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia.",
"title_normalized": "myelodysplastic syndromes and acute leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia"
} | [
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"drugindication": "MYELODYSPLASTIC SYNDROME",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "VIDAZA"
}
],
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"patientonsetage": "51",
"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Acute myeloid leukaemia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KOVITZR C. MYELODYSPLASTIC SYNDROMES AND ACUTE LEUKEMIA DEVELOPING AFTER IMATINIB MESYLATE THERAPY FOR CHRONIC MYELOID LEUKEMIA. BLOOD. 2006 JUN 29;2006:2811-2813.",
"literaturereference_normalized": "myelodysplastic syndromes and acute leukemia developing after imatinib mesylate therapy for chronic myeloid leukemia",
"qualification": "5",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20150212",
"receivedate": "20150212",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10789651,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150721"
}
] |
{
"abstract": "To date, the Toxicology Section of the Montgomery County Coroner's Office/Miami Valley Regional Crime Laboratory has identified six synthetic cathinones, commonly found in bath salt products, in 43 cases. Thirty-two cases will be reviewed here, including all of the postmortem cases, all of the human performance cases that had blood specimens submitted, and one urine-only human performance case. The following compounds have been confirmed: 3,4-methylenedioxypyrovalerone (MDPV), 3,4-methylenedioxymethcathinone (methylone), pyrovalerone, pentylone, alpha-pyrrolidinopentiophenone (alpha-PVP) and methedrone. The method also screens for mephedrone, butylone and 3-fluoromethcathinone. Case demographics show 42 white males and females ranging in age from 19 to 53 years. The remaining case was that of a 34-year-old Hispanic male. The 43 cases represent 17 driving under the influence, two domestic violence, four suicides, 12 overdoses, six accidents, one drug-facilitated assault and one homicide. Data will be presented on the distribution of some of these cathinones in various matrices. After review, blood concentration does not appear to predict outcome regarding fatalities or impairment. The highest MDPV concentration occurred in a suicide by hanging and the highest methylone concentration was in a driver. The confirmation method is a liquid-liquid extraction with detection by liquid chromatography triple quadrupole mass spectrometry using electrospray ionization in multiple reaction monitoring mode.",
"affiliations": "Montgomery County Coroner's Office (MCCO)/Miami Valley Regional Crime Laboratory (MVRCL), Dayton, OH, USA. marinettil@mcohio.org",
"authors": "Marinetti|Laureen J|LJ|;Antonides|Heather M|HM|",
"chemical_list": "D000470:Alkaloids; D000697:Central Nervous System Stimulants; D015198:Designer Drugs; C023665:cathinone",
"country": "England",
"delete": false,
"doi": "10.1093/jat/bks136",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0146-4760",
"issue": "37(3)",
"journal": "Journal of analytical toxicology",
"keywords": null,
"medline_ta": "J Anal Toxicol",
"mesh_terms": "D000328:Adult; D000470:Alkaloids; D001334:Automobile Driving; D001344:Autopsy; D001494:Baths; D002138:Calibration; D002423:Cause of Death; D000697:Central Nervous System Stimulants; D002853:Chromatography, Liquid; D015198:Designer Drugs; D017579:Domestic Violence; D005260:Female; D005431:Florida; D053593:Forensic Toxicology; D006708:Homicide; D006801:Humans; D008297:Male; D008875:Middle Aged; D012015:Reference Standards; D021241:Spectrometry, Mass, Electrospray Ionization; D015813:Substance Abuse Detection; D019966:Substance-Related Disorders; D013405:Suicide; D055815:Young Adult",
"nlm_unique_id": "7705085",
"other_id": null,
"pages": "135-46",
"pmc": null,
"pmid": "23361867",
"pubdate": "2013-04",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology: method development, drug distribution and interpretation of results.",
"title_normalized": "analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology method development drug distribution and interpretation of results"
} | [
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"drugindication": "PRODUCT USED FOR UNKNOWN INDICATION",
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"medicinalproduct": "FENTANYL."
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "TRAZODONE HYDROCHLORIDE"
},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "TRAZODONE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "METHYLENEDIOXYPYROVALERONE HYDROCHLORIDE"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
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"drugcharacterization": "1",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "3, 4- METHYLENEDIOXYPYROVALERONE"
},
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GABAPENTIN"
},
"drugadditional": null,
"drugadministrationroute": null,
"drugauthorizationnumb": null,
"drugbatchnumb": null,
"drugcharacterization": "1",
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"drugtreatmentdurationunit": null,
"medicinalproduct": "GABAPENTIN."
}
],
"patientagegroup": null,
"patientonsetage": "43",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Toxicity to various agents",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "MARINETTI L, ANTONIDES H. ANALYSIS OF SYNTHETIC CATHINONES COMMONLY FOUND IN BATH SALTS IN HUMAN PERFORMANCE AND POSTMORTEM TOXICOLOGY: METHOD DEVELOPMENT, DRUG DISTRIBUTION AND INTERPRETATION OF RESULTS. J ANAL TOXICOL. 2013?37:135-46.",
"literaturereference_normalized": "analysis of synthetic cathinones commonly found in bath salts in human performance and postmortem toxicology method development drug distribution and interpretation of results",
"qualification": null,
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "UM",
"receiptdate": "20190522",
"receivedate": "20190522",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 16341113,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": 1,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20190711"
}
] |
{
"abstract": "OBJECTIVE\nCarbamazepine, a widely used antiepileptic drug that has been used for the treatment of both partial and generalized seizures, for trigeminal neuralgia, as a mood stabilizer and for treatment of neuropathic pain syndromes, may have negative chronotropic and dromotropic effects on the cardiac conduction system.\n\n\nMETHODS\nWe report a case of cardiac syncope due to atrial tachycardia combined with complete atrioventricular block as a consequence of carbamazepine administration for trigeminal neuralgia.\n\n\nCONCLUSIONS\nAlthough sinus tachycardia is the most frequently observed cardiac side effect of carbamazepine, sinus and nodal bradycardia, atrioventricular block, premature ventricular contractions, ventricular tachycardia and junctional escape rhythms have been reported in patients due to carbamazepine toxicity.",
"affiliations": "Cardiology Department, General Hospital of Halkidiki, Polygyros, Halkidiki, Greece.;Cardiology Department, General Hospital of Halkidiki, Polygyros, Halkidiki, Greece.;Cardiology Department, General Hospital of Halkidiki, Polygyros, Halkidiki, Greece.;Cardiology Department, General Hospital of Halkidiki, Polygyros, Halkidiki, Greece.",
"authors": "Koutsampasopoulos|K|K|;Zotos|A|A|;Papamichalis|M|M|;Papaioannou|K|K|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1108-4189",
"issue": "18(2)",
"journal": "Hippokratia",
"keywords": "Carbamazepine; atrial tachycardia; complete atrioventricular block",
"medline_ta": "Hippokratia",
"mesh_terms": null,
"nlm_unique_id": "101296613",
"other_id": null,
"pages": "185-6",
"pmc": null,
"pmid": "25336888",
"pubdate": "2014-04",
"publication_types": "D002363:Case Reports",
"references": "1653123;17473503;11753195;3774685;1728915;15974971;3362374;8355320",
"title": "Carbamazepine induced atrial tachycardia with complete AV block.",
"title_normalized": "carbamazepine induced atrial tachycardia with complete av block"
} | [
{
"companynumb": "PHHY2014GR107206",
"fulfillexpeditecriteria": "1",
"occurcountry": "GR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "CARBAMAZEPINE"
},
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"drugdosagetext": "400 MG, TID",
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"drugindication": "TRIGEMINAL NEURALGIA",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "TEGRETOL"
},
{
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},
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"drugdosagetext": "3.125 MG, QD",
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"drugindication": "CORONARY ARTERY DISEASE",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "CARVEDILOL."
},
{
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},
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"medicinalproduct": "ENALAPRIL"
},
{
"actiondrug": "5",
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"activesubstancename": "ATORVASTATIN"
},
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"drugcharacterization": "2",
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"drugdosageform": null,
"drugdosagetext": "40 MG, QD",
"drugenddate": null,
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"drugindication": "CORONARY ARTERY DISEASE",
"drugintervaldosagedefinition": "804",
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"medicinalproduct": "ATORVASTATIN"
},
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ASPIRIN"
},
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"drugcharacterization": "2",
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"drugdosageform": null,
"drugdosagetext": "100 MG, QD",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "CORONARY ARTERY DISEASE",
"drugintervaldosagedefinition": "804",
"drugintervaldosageunitnumb": "1",
"drugrecurreadministration": "3",
"drugrecurrence": null,
"drugseparatedosagenumb": "1",
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"medicinalproduct": "ASPIRIN."
}
],
"patientagegroup": null,
"patientonsetage": "82",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Death",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "Cardiac failure congestive",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Arrhythmia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Syncope",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Loss of consciousness",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Atrioventricular block",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Hypotension",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Fatigue",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Bradycardia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Atrial tachycardia",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "KOUTSAMPASOPOULOS K, ZOTOS A, PAPAMICHALIS M, PAPAIOANNOU K.. CARBAMAZEPINE INDUCED ATRIAL TACHYCARDIA WITH COMPLETE AV BLOCK.. HIPPOKRATIA. 2014;18 (2):185-186",
"literaturereference_normalized": "carbamazepine induced atrial tachycardia with complete av block",
"qualification": "3",
"reportercountry": "GR"
},
"primarysourcecountry": "GR",
"receiptdate": "20141003",
"receivedate": "20140904",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10430810,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"transmissiondate": "20150528"
}
] |
{
"abstract": "The authors describe a case of a 76-year-old male with a medical history of Merkel cell carcinoma (MCC) of the right lower eyelid. He was admitted to the emergency department due to abdominal pain in the right hypochondrium, nauseas, asthenia, and choluria with 3 days of evolution. Biochemical liver workup revealed a cytocholestase pattern as well as a prolonged prothrombin time. After admission, the patient developed hepatic encephalopathy, and a clinical and analytical worsening was observed. Abdominal ultrasound showed a reduction in the caliber of the hepatic veins, in apparent relation to a parenchymal compression. Liver biopsy was performed and showed an extensive infiltration of the hepatic parenchyma by a solid neoplasm, which, upon immunohistochemical study, was compatible with a diffuse metastization of a MCC. We report this clinical case due to its rarity of presentation and to show the important role of liver biopsy in cases of acute hepatitis.",
"affiliations": "Gastroenterology Department, Centro Hospitalar de São João, Porto, Portugal.;Gastroenterology Department, Hospital Central do Funchal, Madeira, Portugal.;Gastroenterology Department, Centro Hospitalar de São João, Porto, Portugal.;Gastroenterology Department, Centro Hospitalar de São João, Porto, Portugal.;Gastroenterology Department, Centro Hospitalar de São João, Porto, Portugal.;Porto Medical School, University of Porto, Porto, Portugal.;Gastroenterology Department, Centro Hospitalar de São João, Porto, Portugal.",
"authors": "Santos|Ana Luísa|AL|;Magno Pereira|Vítor|V|;Coelho|Rosa|R|;Gaspar|Rui|R|;Cardoso|Hélder|H|;Lopes|Joanne|J|;Macedo|Guilherme|G|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000503150",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2387-1954",
"issue": "27(3)",
"journal": "GE Portuguese journal of gastroenterology",
"keywords": "Hepatic encephalopathy; Liver biopsy; Liver failure; Liver metastases; Neuroendocrine carcinoma",
"medline_ta": "GE Port J Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101685861",
"other_id": null,
"pages": "203-206",
"pmc": null,
"pmid": "32509927",
"pubdate": "2020-04",
"publication_types": "D002363:Case Reports",
"references": "21144740;28417882;18280333;28540062;29891526;19638070;30992953;26257075",
"title": "A Rare Cause of Acute Liver Failure: Diffuse Liver Metastization of Merkel Cell Carcinoma.",
"title_normalized": "a rare cause of acute liver failure diffuse liver metastization of merkel cell carcinoma"
} | [
{
"companynumb": "PT-AUROBINDO-AUR-APL-2020-027223",
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"activesubstancename": "AMOXICILLIN\\CLAVULANIC ACID"
},
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}
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"reaction": [
{
"reactionmeddrapt": "Drug-induced liver injury",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Metastases to liver",
"reactionmeddraversionpt": "23.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "SANTOS A.L. ET AL.. A RARE CAUSE OF ACUTE LIVER FAILURE: DIFFUSE LIVER METASTIZATION OF MERKEL CELL CARCINOMA. GE - JOURNAL PORTUGU?S DE GASTRENTEROLOGIA. 2020?27(3):203-206",
"literaturereference_normalized": "a rare cause of acute liver failure diffuse liver metastization of merkel cell carcinoma",
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},
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"receivedate": "20200609",
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},
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}
] |
{
"abstract": "We evaluated our 16-year single-center experience of pediatric post-transplant lymphoproliferative disorder (PTLD) cases who underwent liver transplantation between 2001 and 2017.\n\n\n\nOf the 236 pediatric patients who underwent liver transplantation between 2001 and 2017, the clinical and laboratory data of eight patients diagnosed with PTLD were reviewed. The pre-transplant Epstein-Barr virus (EBV) status of 172 patients was also recorded.\n\n\n\nThe total incidence of PTLD was 3.4%. The incidence of PTLD was 10% in pre-transplant EBV immunoglobulin G (IgG)-seronegative patients and 0.8% in pre-transplant EBV IgG-seropositive patients. The mean age of the patients at liver transplantation was 2.71±3.21 years, and four patients were aged below 1 year at the time of transplantation. PTLD was diagnosed at 21.81±18.1 months after transplantation. The primary site of involvement was variable among patients: peripheral and mediastinal lymph nodes, stomach and intestine, transplanted graft, bone marrow, and nasopharynx. The eosinophil count varied greatly among patients, with a mean value of 524.62±679/mm3. Three patients had a food allergy and were administered an elimination diet at the time of PTLD diagnosis. Six patients had PTLD of B-cell origin. One patient died due to neutropenic sepsis during chemotherapy, whereas seven patients were followed up in full remission for 7.75±4 years.\n\n\n\nPTLD is a life-threatening complication of solid-organ transplantation with a heterogeneous clinical spectrum. Food allergy had a close association with PTLD. A close follow-up of patients with risk factors and an early diagnosis with appropriate treatment may lead to a better outcome.",
"affiliations": "Department of Pediatric Gastroenterology, Başkent University Hospital, Ankara, Turkey.;Department of Pediatric Gastroenterology, Başkent University Hospital, Ankara, Turkey.;Department of Pediatric Allergy, Başkent University Hospital, Ankara, Turkey.;Department of Pathology, Başkent University Hospital, Ankara, Turkey.;Department of Pediatric Oncology, Başkent University Hospital, Ankara, Turkey.;Department of General Surgery and Transplant Surgery, Başkent University Hospital, Ankara, Turkey.",
"authors": "Barış|Zeren|Z|;Özçay|Figen|F|;Yılmaz Özbek|Özlem|Ö|;Haberal|Nihan|N|;Sarıalioğlu|Faik|F|;Haberal|Mehmet|M|",
"chemical_list": null,
"country": "Turkey",
"delete": false,
"doi": "10.5152/tjg.2018.17731",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1300-4948",
"issue": "29(3)",
"journal": "The Turkish journal of gastroenterology : the official journal of Turkish Society of Gastroenterology",
"keywords": null,
"medline_ta": "Turk J Gastroenterol",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D004804:Eosinophils; D020031:Epstein-Barr Virus Infections; D005260:Female; D005500:Follow-Up Studies; D005512:Food Hypersensitivity; D004854:Herpesvirus 4, Human; D006801:Humans; D015994:Incidence; D007223:Infant; D007958:Leukocyte Count; D016031:Liver Transplantation; D008232:Lymphoproliferative Disorders; D008297:Male; D011183:Postoperative Complications; D011184:Postoperative Period; D057234:Preoperative Period; D012307:Risk Factors",
"nlm_unique_id": "9515841",
"other_id": null,
"pages": "354-360",
"pmc": null,
"pmid": "29755021",
"pubdate": "2018-05",
"publication_types": "D016428:Journal Article",
"references": "16611339;17683183;18929796;19239659;20963522;21193979;22489822;23696264;23802715;24025083;26270449;26767488;27110023;27683629;28302005;28392824;9649460",
"title": "A single-center experience of post-transplant lymphoproliferative disorder (PTLD) cases after pediatric liver transplantation: Incidence, outcomes, and association with food allergy.",
"title_normalized": "a single center experience of post transplant lymphoproliferative disorder ptld cases after pediatric liver transplantation incidence outcomes and association with food allergy"
} | [
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},
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],
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"reactionoutcome": "2"
}
],
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"literaturereference": "BARIS Z, OZCAY F, YILMAZ OZBEK O, HABERAL N, SARIALIOGLU F, HABERAL M. A SINGLE-CENTER EXPERIENCE OF POST-TRANSPLANT LYMPHOPROLIFERATIVE DISORDER (PTLD) CASES AFTER PEDIATRIC LIVER TRANSPLANTATION: INCIDENCE, OUTCOMES, AND ASSOCIATION WITH FOOD ALLERGY. TURK-J-GASTROENTEROL 2018?29(3):354-360.",
"literaturereference_normalized": "a single center experience of post transplant lymphoproliferative disorder ptld cases after pediatric liver transplantation incidence outcomes and association with food allergy",
"qualification": "3",
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},
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20190205"
},
{
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
},
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},
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"drugdosagetext": "20 MG/KG, QD",
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"drugindication": "LIVER TRANSPLANT",
"drugintervaldosagedefinition": "804",
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"reaction": [
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"reactionmeddraversionpt": "21.1",
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},
{
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}
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},
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},
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": 1,
"seriousnessother": null,
"transmissiondate": "20190205"
},
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"patient": {
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"drugdosagetext": "1 MILLIGRAM/KILOGRAM",
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"abstract": "BACKGROUND\nEpidural analgesia is commonly used for management of pain during childbirth. Need for emergent Caesarean section e.g. because of signs of foetal distress or lack of progress is however not an uncommon event. In females having an established epidural; general anaesthesia, top-up of the epidural or putting a spinal are all possible options. Dosing of the spinal anaesthesia in females having epidural is a matter of discussion.\n\n\nMETHODS\nWe describe a healthy 32 years, 0 para mother in gestation week 36 having labour epidural analgesia but due to foetal distress scheduled for an emergent Caesarean section category 2 that developed upper extremity weakness and respiratory depression after administration of standard dose high density bupivacaine/morphine/fentanyl intrathecal anaesthesia. She was emergent intubated and resumed motor function after 15-20min.\n\n\nCONCLUSIONS\nA too extensive cephalic spread was the most plausible explanation to the event. Whether or not reducing the dose for a spinal anaesthesia in mothers having an established labour epidural analgesia is a matter of discussion. It is of course of importance to achieve a rapid and effective surgical anaesthesia but also avoiding overdosing with the risk for a too high cephalic spread.\nTo perform spinal anaesthesia for emergent Caesarean in patients having an epidural for labour pain is a feasible option and should be considered in category 2-3 section. The dose for a convert spinal block should be assessed on an individual basis and reasonably reduced.",
"affiliations": "Department of Anaesthesia & Intensive CareInstitution for Clinical Science, Karolinska Institutet, Danderyds University Hospital, SE 182 88 Stockholm, Sweden. Electronic address: helena.virgin@ds.se.;Department of Anaesthesia & Intensive CareInstitution for Clinical Science, Karolinska Institutet, Danderyds University Hospital, SE 182 88 Stockholm, Sweden. Electronic address: eva.oddby-muhrbeck@ds.se.;Department of Anaesthesia & Intensive CareInstitution for Clinical Science, Karolinska Institutet, Danderyds University Hospital, SE 182 88 Stockholm, Sweden. Electronic address: jan.jakobsson@ki.se.",
"authors": "Virgin|H|H|;Oddby|E|E|;Jakobsson|J G|JG|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2016.09.018",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(16)30359-510.1016/j.ijscr.2016.09.018ArticleSuspected total spinal in patient having emergent Caesarean section, a case report and literature review Virgin H. MDSenior Consultanthelena.virgin@ds.seOddby E. MD PhDSenior Consultanteva.oddby-muhrbeck@ds.seJakobsson J.G. Adj. Professor Senior Consultant Director of Doctoral Education Clinical Research and Developmentjan.jakobsson@ki.se⁎Department of Anaesthesia & Intensive CareInstitution for Clinical Science, Karolinska Institutet, Danderyds University Hospital, SE 182 88 Stockholm, Sweden⁎ Corresponding author at: Department of Anaesthesia & Intensive Care, Danderyds Hospital, 18288 Danderyd, Sweden. jan.jakobsson@ki.se03 10 2016 2016 03 10 2016 28 173 175 15 7 2016 1 9 2016 6 9 2016 © 2016 The Author(s)2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Emergent Caesarean section should be classified in accordance to the treat of mother and child, e.g. with the Lucas grading score.\n\n• Anaesthetic technique for emergent Caesarean section is not well defined.\n\n• Category 1 emergent Caesarean section should preferentially be formed with general anaesthesia to ascertain shortest decision-to-delivery interval.\n\n• Anaesthetic technique for category 2/3 emergent Caesarean section should be based on an individual assessment, top-up epidural and convert spinal are both feasible option.\n\n• When convert spinal is used the dose should possibly reduced considering the risk for too high block caused by cephalic spread.\n\n\n\nIntroduction\nEpidural analgesia is commonly used for management of pain during childbirth. Need for emergent Caesarean section e.g. because of signs of foetal distress or lack of progress is however not an uncommon event. In females having an established epidural; general anaesthesia, top-up of the epidural or putting a spinal are all possible options. Dosing of the spinal anaesthesia in females having epidural is a matter of discussion.\n\nPresentation of case\nWe describe a healthy 32 years, 0 para mother in gestation week 36 having labour epidural analgesia but due to foetal distress scheduled for an emergent Caesarean section category 2 that developed upper extremity weakness and respiratory depression after administration of standard dose high density bupivacaine/morphine/fentanyl intrathecal anaesthesia. She was emergent intubated and resumed motor function after 15–20 min.\n\nDiscussion\nA too extensive cephalic spread was the most plausible explanation to the event. Whether or not reducing the dose for a spinal anaesthesia in mothers having an established labour epidural analgesia is a matter of discussion. It is of course of importance to achieve a rapid and effective surgical anaesthesia but also avoiding overdosing with the risk for a too high cephalic spread.\n\nConcluiosn\nTo perform spinal anaesthesia for emergent Caesarean in patients having an epidural for labour pain is a feasible option and should be considered in category 2–3 section. The dose for a convert spinal block should be assessed on an individual basis and reasonably reduced.\n\nKeywords\nCaesarean sectionEpidural analgesiaSpinal anaesthesiaTotal spinal\n==== Body\n1 Introduction\nAnaesthesia for emergent Caesarean section (CS) in females having an epidural analgesia is a matter of discussion. In critical situations general anaesthesia is preferred increasing speed of induction and time to achieving surgical anaesthesia. In situations where the time to delivery is urgent, but not critical within minutes, spinal or top-up of the epidural anaesthesia may be safe, safer option avoiding the risk for regurgitation and aspiration associated to rapid sequence induction if a pregnant none-fasting female.\n\n2 Case presentation\nA healthy mother of 32 years was 36 weeks pregnant with her first baby. Labour had been induced for reasons of intrauterine growth restriction. An epidural catheter had been administered earlier in the labour process. A decision to perform an acute caesarean was taken due to signs of foetal distress during contractions. The obstetrician assessed the section to be grade 2. An epidural catheter had been administered earlier in the labour process, but the intermittent injections were reported to have had no or very limited effect on labour pain. The agents used for epidural anaesthesia were bupivacaine 1 mg/ml and sufentanil 0,5 mcg/ml, in volumes of 10 ml administered as a bolus at need with a minimum time laps of 60 min. A total of 55 ml had been administered over the course of 7 h. Last administrated dose was 135 min before spinal anaesthesia. The decision by the attending anaesthetist was therefore to perform a spinal anaesthesia.\n\nIn a sitting position, a dose of bupivacaine (with added glucose, “heavy” 5 mg/ml) 13 mg, fentanyl 25 mcg and morphine 0.4 mg/ml, 100 mcg was administrated intrathecally according to local routines. The patient was then immediately helped to supine position, with a left side tilt. Within one minute of administration, she showed signs of upper extremity weakness also became sluggish and was slow to respond to verbal stimuli. When vigorously stimulated with touch and speech, she could give eye contact and tried to form words, but made no sound. There were progressive signs of respiratory insufficiency and saturation started to decrease, and at saturation (SpO2) of 85% she became unconscious. Decision was made for immediate intubation – which was performed without any need of muscle relaxation. The baby was delivered immediately, cried seconds after delivery and proved good health afterwards. Within 8 min, the mother could open her eyes, and a few minutes later flex the fingers of both hands and accomplish voluntary breathing on request. After approximately 20 min she regained spontaneous breathing. Hemodynamic was controlled throughout the episode; systolic blood pressure of 100–115, and a pulse above 90. After closing the wound she was kept sedated and a CT scan of brain and thorax was performed to rule out the differential diagnosis e.g. cerebral insult or pulmonary embolus. Both turned out normal. There were no signs or laboratory deviations suggesting toxicosis. She was shortly after the negative CT extubated and could soon thereafter with her baby be transferred to a general maternity ward. The mother and child had a further completely uncomplicated course.\n\n3 Discussion\nThe choice of anaesthetic technique for emergent CS should be based on the urgency for delivery of the neonate. A classification of urgency of CS was described by Lucas et al. in 2000 and this grading has become accepted in many institutions. ‘Emergency’ and ‘elective’ CS equate to categories 1–3 and category 4 respectively. Category 1 defined as immediate threat to life of woman or fetus; category 2 maternal or fetal compromise which is not immediately life-threatening, category 3 as needing early delivery but no maternal or fetal compromise and a category 4 as at a time to suit the patient and maternity team, thus merely elective eventi. This grading system has become the recommended for national use by e.g. the National Institute for Clinical Excellence (NICE) in the UK since 2004 [2]. General anaesthesia is reasonably the preferred in the most urgent once (category 1) cases while it seems more than reasonable to consider both top-up of epidural or spinal in situation where some additional minutes are available; category 2–4. Kinsella et al. published in 2010 the results of a survey around anaesthetic techniques for emergent CS in England. They found some inconsistencies with regards to definitions. They saw that the terms emergency/urgent/scheduled/elective as described by Lucas et al. [1] to accompany the numeric categories from 1 to 4 in The Caesarean Section guideline as published by NICE were not explicitly used [2]. They found the median general anaesthetic rate to be 51%, 12% and 4%, for category the three categories 1, categories 2–3 (non-elective/emergency CS) and category-4 (elective), respectively and with rather huge variability.\n\nThere are general recommendations for decision to delivery time interval but no firm guide around anaesthetic technique to be used. The present NICE guidelines states1; Decision-to-delivery interval for unplanned CS; Use the following decision-to-delivery intervals to measure the overall performance of an obstetric unit: 30 min for category 1 CS both 30 and 75 min for category 2 CS. However there is no guide for anaesthetic technique. Tyner and Rayburn published in 2013 a review concluding that classification and time guidance is clear but explicit comments on techniques is vague. They found however sparse recommendations around explicit techniques to be used. US practice was described being regional anaesthesia as preferred technique for elective CS however general anaesthesia, although carrying risk, being commonly used practice for emergent cases [2]. Regan and O’Sullivan conducted a survey in UK published in 2009 [3]. They found a varying practice. Top-up was not uncommonly used but the top-up drug, volume and mixture as well as when/how the top-up was administered, in the labour ward or after transfer to the operating theatre varied considerable. The practice showed several aspects for improvement; Of the 161 respondents thirty-three respondents reported a total of 43 adverse incidents associated with the extension of epidural blockade. These included high blocks, inadequate blocks and possible intravascular injections, the latter resulting in two seizures and one cardiac arrest.\n\nCombining spinal and epidural anaesthesia in obstetrics has been described since long. Raval et al. showed in 1988 the combined technique to be effective, providing better intraoperative anaesthesia than epidural and with no difference in side effects [4] while Ithnin et al. showed a more extensive block associated to the combined spinal epidural technique [5]. They injected a 10 mg hyperbaric bupivacaine at L3–L4 as single spinal or in conjunction to loss of resistance epidural. The maximal sensory block achieved in group combined technique was statistically higher than that in single spinal group (median C6 interquartile range, C5 to C8 versus median T3, T2 to T4, P < 0.001). Goy et al. conducted a sophisticated study looking for effective dose comparing single spinal and combined spinal epidural technique [6]. Blocks were put at L3–L4 with hyperbaric bupivacaine. They defined “successful” spinal anaesthesia outcome arbitrarily as sensory anaesthesia at or above the T6 dermatome lasting for 60 min. Median effective bupivacaine dose was found to be 9.18 mg (95% confidence interval, 8.89–9.47 mg) for the combined spinal epidural technique as compared with 11.37 mg (95% confidence interval, 10.88–11.86 mg) for single spinal (P < 0.001). Thus combined technique required 19.3% less local anaesthetic to achieve the defined clinical target. Horstman et al. studied also whether the combined spinal epidural technique was associated to changes in the epidural pressure and thus possibly could cause a more pronounced cephalic spread of the spinal anaesthesia [7]. They did not see any difference. The single spinal and the combined spinal and epidural techniques inserted in the lateral decubitus position resulted in similar extent of sensory blockade and cerebrospinal fluid pressure. They concluded that altering the intrathecal dose is not necessary and that any difference in intrathecal pressure associated with initial placement of an epidural needle in the epidural space during combined spinal epidural anaesthesia is clinically inconsequential.\n\nThere are also studies in none-obstetric patients suggesting that the combined technique is associated with a higher level of sensory block and thus a reduced need for local anaesthetic as compared with a single-shot spinal anaesthesia. Goy et al. studied the effects, spinal versus combined spinal epidural also in females undergoing minor gynaecological surgery [8]. They concluded that induction of subarachnoid block (10 mg hyperbaric bupivacaine) by a combined-spinal epidural technique produces a greater sensor motor anaesthesia and results in prolonged recovery when compared with a single-shot spinal technique. They found also more frequent incidence of hypotension with the combined technique. Leo et al. [9] conducted a study comparing 7, 8 and 9 mg hyperbaric bupivacaine in combination with 100 μg morphine injected in combination spinal epidural technique for Caesarean section [9]. They found the lowest dose of hyperbaric bupivacaine (7 mg) to provided equally rapid onset and effective anaesthesia for Caesarean delivery while reducing the incidence of hypotension compared with 8 and 9 mg. The 9 mg dose had a high median spread; T1 [C8-T2].\n\nThere are no explicit guidelines available for how to manage the emergent Caesarean class 1–3 in females having an established epidural analgesia. The use of top-up when feasible is not uncommon, but conversion to spinal anaesthesia has also become reasonably accepted. There are two recent papers describing the safe use of conversion. Visser et al. published in 2009 a retrospective analysis of females having had Caesarean section. Of the 693 patients, 508 (73.3%) had no epidural analgesia and received spinal anaesthesia. There were 128 patients received, converting to spinal anaesthesia, following epidural anaesthesia for labour, 19 had a top-up epidural, and 38 received general anaesthesia. When comparing both spinal anaesthesia groups, no clinically relevant differences were observed regarding the incidence of total spinal block (0% in both groups) or high spinal block (0.2 vs 0.8%, P = 0.36). The number of hypotensive episodes, the total amount of ephedrine administered, and the Apgar scores recorded at 5 and 10 min were similar amongst groups. Huang et al. has recently published their clinical experience with spinal as an alternative for anaesthesia in prurient requiring section [10]. In all 2341 had labour epidural and 334 of them were converted to have a Caesarean section. Spinal anaesthesia was used with 163 parturients and epidural anaesthesia with 96. No high-level block or total blocks was noted. The time from anaesthesia to surgical incision and the total anaesthesia time were shorter, hypotension episodes were more frequent, the rate of perioperative ephedrine administration was higher, and the rate of midazolam was lower in the spinal anaesthesia group as compared to top-up epidural. They found no side-effects, more than somewhat more a more profound cardiovascular depression but they still consider transition to spinal a safe and effective practice.\n\nPublic domain literature contains very sparse reports of “total spinal” in conjunction to Wagner describes in 1994 a patient having a total spinal associated with rather minor cardiovascular effects following injection of 1.5 ml of 0.75 mg/ml hyperbaric bupivacaine some 7 h following accidental dura puncture [11]. Furst and Reisner describe two cases of high spinal anaesthesia following failed epidural block in obstetric patients scheduled for Caesarean delivery [12]. They also performed a retrospective chart review and estimated the incidence of high spinal anaesthesia to be 11% in patients after prior failed epidural blockade versus less than 1% in patients undergoing spinal anaesthesia alone. Gupta et al. published in 1994 a paper suggesting spinal anaesthesia as contraindicated following labour analgesia based on 3 cases with unintended high spinal [13] . In all 3 cases, caesarean section was required for failure to progress. Hyperbaric bupivacaine was given in doses of 10 mg, 12.5 mg and 15 mg respectively. Within 2–4 min all 3 patients had a high block, complained of difficulty in breathing and subsequently developed apnoea.\n\nThe decision to convert to spinal anaesthesia was based on the fact that this was a category 2/3 Caesarean section and that the epidural had not had optimal effect. The spinal anaesthesia drugs and doses were administered in accordance to routines of the department. We are not able to give any explicit reason for the described event. We are prone to believe that it was an effect of local anaesthetic cephalic spread possibly related to the prior epidural and doses administered. CT imaging of brain and thorax was found normal, and patient resumed muscle strength in reasonable time fashion. No signs of eclampsia were seen and patient had a subsequent complete unremarkable course.\n\nIn summary, it seems reasonably well-accepted to perform spinal anaesthesia in patients having or having had an epidural for labour pain “when needed”. Top-up epidural is a likewise attractive alternative. The dose for a convert spinal block should reasonably be assessed on an individual basis but possibly reduced.\n\nConflicts of interest\nNone of authors have any conflict of interest in relation to the present case report, Spinal anaesthesia for emergent Caesarean section in patient having a labour epidural causing high spinal block, a case report and review of the literature.\n\nFunding\nThis paper has been supported by Department of Anaesthesia Danderyds Hospital, no external funding has been recieved.\n\nEthical approval\nNot applicable, Ptainte has provided informed conset to publication of the case report.\n\nConsent\nPatient has provided explicit informed consent.\n\nAuthor contribution\nAll authors have contributed equal to the preparation of the present paper; Spinal anaesthesia for emergent Caesarean section in patient having a labour epidural causing high spinal block, a case report and review of the literature.\n\nGuarantor\nJan G. Jakobsson has the role as main Guarantor.\n\n1 https://www.nice.org.uk/guidance/cg132/chapter/ftn.footnote _1.\n==== Refs\nReferences\n1 Lucas D.N. Yentis S.M. Kinsella S.M. Urgency of caesarean section: a new classification J. R. Soc. Med. 93 2000 346 350 10928020 \n2 Tyner J.E. Rayburn W.F. Emergency cesarean delivery: special precautions Obstet. Gynecol. Clin. North Am. 40 1 2013 37 45 23466135 \n3 Regan K.J. O'Sullivan G. The extension of epidural blockade for emergency Caesarean section: a survey of current UK practice Anaesthesia 63 February (2) 2008 136 142 18211443 \n4 Rawal N. Schollin J. Wesström G. Epidural versus combined spinal epidural block for cesarean section Acta Anaesthesiol. Scand. 32 1 1988 61 66 3278500 \n5 Ithnin F. Lim Y. Sia A.T. Ocampo C.E. Combined spinal epidural causes higher level of block than equivalent single-shot spinal anesthesia in elective cesarean patients Anesth. Analg. 102 February (2) 2006 577 580 16428564 \n6 Goy R.W. Chee-Seng Y. Sia A.T. Choo- Kok K. Liang S. The median effective dose of intrathecal hyperbaric bupivacaine is larger in the single- shot spinal as compared with the combined spinal-epidural technique Anesth. Analg. 100 May (5) 2005 1499 1502 (table of contents) 15845714 \n7 Horstman D.J. Riley E.T. Carvalho B. A randomized trial of maximum cephalad sensory blockade with single-shot spinal compared with combined spinal-epidural techniques for cesarean delivery Anesth. Analg. 108 January (1) 2009 240 245 19095857 \n8 Goy R.W. Sia A.T. Sensorimotor anesthesia and hypotension after subarachnoid block: combined spinal-epidural versus single-shot spinal technique Anesth. Analg. 98 2004 491 496 14742393 \n9 Leo S. Sng B.L. Lim Y. Sia A.T. A randomized comparison of low doses of hyperbaric bupivacaine in combined spinal-epidural anesthesia for cesarean delivery Anesth. Analg. 109 November (5) 2009 1600 1605 19843797 \n10 Huang C.H. Hsieh Y.J. Wei K.H. Sun W.Z. Tsao S.L. A comparison of spinal and epidural anesthesia for cesarean section following epidural labor analgesia: a retrospective cohort study Acta Anaesthesiol. Taiwan 53 March (1) 2015 7 11 25736588 \n11 Wagner D.L. Total spinal anesthesia during cesarean section hours after previous unintentional dural puncture Anesthesiology 81 July (1) 1994 260 261 \n12 Furst S.R. Reisner L.S. Risk of high spinal anesthesia following failed epidural block for cesarean delivery J. Clin. Anesth. 7 February (1) 1995 71 74 7772363 \n13 Gupta A.1 Enlund G. Bengtsson M. Sjöberg F. Spinal anaesthesia for caesarean section following epidural analgesia in labour: a relative contraindication Int. J. Obstet. Anesth. 3 July (3) 1994 153 156 15636940\n\n",
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{
"abstract": "Treatment for ulcerative colitis often requires the administration of immunosuppressive therapy. Shortly after rescue therapy with infliximab for acute severe colitis, a patient who was also taking corticosteroids, azathioprine and adalimumab became rapidly unwell with atypical pneumonia, which did not respond to conventional antimicrobials. Re-examining the travel history revealed a prior caving trip to Costa Rica. Dimorphic fungal serology was thus tested and a diagnosis of paracoccidioidomycosis was made. After a lengthy intensive care unit admission, the patient made a recovery after the administration of appropriate antifungal therapy and was discharged home on long-term oral antifungals.",
"affiliations": "Department of Gastroenterology, Weston Area Health NHS Trust, Weston-super-Mare, England, UK schealey@doctors.org.uk.;Department of Gastroenterology, Weston Area Health NHS Trust, Weston-super-Mare, England, UK.;Department of Gastroenterology, Weston Area Health NHS Trust, Weston-super-Mare, England, UK.;Department of Gastroenterology, Weston Area Health NHS Trust, Weston-super-Mare, England, UK.",
"authors": "Healey|Scott|S|http://orcid.org/0000-0002-9156-2572;Said|Waseem|W|;Fayyaz|Faisal|F|;Bell|Andrew|A|http://orcid.org/0000-0002-1581-2736",
"chemical_list": "D000305:Adrenal Cortex Hormones; D000935:Antifungal Agents; D005765:Gastrointestinal Agents; D007166:Immunosuppressive Agents; D000069285:Infliximab; D000068879:Adalimumab; D001379:Azathioprine",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2019-234125",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "13(7)",
"journal": "BMJ case reports",
"keywords": "inflammatory bowel disease; pneumonia (infectious disease); travel medicine; tropical medicine (infectious disease); ulcerative colitis",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000068879:Adalimumab; D000305:Adrenal Cortex Hormones; D000935:Antifungal Agents; D001379:Azathioprine; D003093:Colitis, Ulcerative; D005765:Gastrointestinal Agents; D006801:Humans; D007166:Immunosuppressive Agents; D000069285:Infliximab; D007362:Intensive Care Units; D008297:Male; D008875:Middle Aged; D010229:Paracoccidioidomycosis; D014195:Travel; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32616533",
"pubdate": "2020-07-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "First report of paracoccidioidomycosis reactivation as a complication of immunosuppressive therapy for acute severe colitis in a caving enthusiast.",
"title_normalized": "first report of paracoccidioidomycosis reactivation as a complication of immunosuppressive therapy for acute severe colitis in a caving enthusiast"
} | [
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{
"abstract": "Hepatitis E virus (HEV) infection has been recognized as an acute condition. However, recent reports have shown that immunocompromised patients, such as those receiving solid-organ transplantation, can develop chronic hepatitis with HEV infection. We report two cases of chronic hepatitis E after kidney transplantation (KT) who were successfully treated with ribavirin monotherapy. Several years after KT, both patients had sustained elevations in the levels of liver enzymes for a period of more than 6 months. Both patients had HEV infection, genotype 3a. Histological studies showed infiltration of inflammatory cells without fibrosis. Treatment included ribavirin monotherapy at a dosage of 600 mg daily for 3 months. One month after therapy initiation, HEV-RNA turned to negative, and remained negative at 24 weeks after ribavirin therapy without severe complications. Although the treatment of chronic hepatitis E is not fully established, ribavirin therapy can be a safe and effective treatment for chronic hepatitis E.",
"affiliations": "Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan.;Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan.;Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan.;Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan.;Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan.;Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan.;Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.;Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.;Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.;Division of Urology, Department of Regenerative and Transplant Medicine, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan.;Division of Gastroenterology and Hepatology, Graduate School of Medical and Dental Science, Niigata University, Niigata City, Japan.",
"authors": "Yoshida|Tomoaki|T|;Takamura|Masaaki|M|https://orcid.org/0000-0001-6773-4613;Goto|Ryo|R|;Takeuchi|Suguru|S|;Tsuchiya|Atsunori|A|;Kamimura|Kenya|K|;Tasaki|Masayuki|M|;Nakagawa|Yuki|Y|;Saito|Kazuhide|K|;Tomita|Yoshihiko|Y|;Terai|Shuji|S|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1111/hepr.13363",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1386-6346",
"issue": "49(10)",
"journal": "Hepatology research : the official journal of the Japan Society of Hepatology",
"keywords": "chronic hepatitis; hepatitis E virus; immunocompromised patient; kidney transplantation; ribavirin",
"medline_ta": "Hepatol Res",
"mesh_terms": null,
"nlm_unique_id": "9711801",
"other_id": null,
"pages": "1244-1248",
"pmc": null,
"pmid": "31077507",
"pubdate": "2019-10",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Efficacy and safety of ribavirin therapy for chronic hepatitis E after kidney transplantation.",
"title_normalized": "efficacy and safety of ribavirin therapy for chronic hepatitis e after kidney transplantation"
} | [
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{
"abstract": "Combination therapy with direct acting antiviral agents (DAAs) without interferon (IFN) has emerged as a treatment for chronic hepatitis C because of its high overall sustained virologic response rates and favorable side effect profile as compared to that with interferon. We report the first case of drug-induced lung injury (DLI) associated with IFN-free therapy with the DAAs, daclatasvir (NS5A inhibitor) and asunaprevir (NS3/4A protease inhibitor). Although this combination therapy of DAAs has been considered to have fewer side effects than IFN, more attention should be paid to DLI as an important side effect.",
"affiliations": "Department of Respiratory Medicine, Kobe City Medical Center West Hospital, Japan. Electronic address: takahiro00920619@gmail.com.;Department of Respiratory Medicine, Kobe City Medical Center West Hospital, Japan. Electronic address: k.furuta0113@gmail.com.;Department of Respiratory Medicine, Kobe City Medical Center West Hospital, Japan. Electronic address: htomy@kobe-nishishimin-hospi.jp.",
"authors": "Kamada|Takahiro|T|;Furuta|Kenjiro|K|;Tomioka|Hiromi|H|",
"chemical_list": "D000998:Antiviral Agents; D002219:Carbamates; D007093:Imidazoles; D007546:Isoquinolines; D011759:Pyrrolidines; D013449:Sulfonamides; D011239:Prednisolone; D014633:Valine; C549273:daclatasvir; C571889:asunaprevir",
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2212-5345",
"issue": "54(3)",
"journal": "Respiratory investigation",
"keywords": "Asunaprevir; Chronic hepatitis C; Daclatasvir; Direct acting antiviral agents; Drug-induced lung injury",
"medline_ta": "Respir Investig",
"mesh_terms": "D000998:Antiviral Agents; D002219:Carbamates; D004359:Drug Therapy, Combination; D019698:Hepatitis C, Chronic; D006801:Humans; D007093:Imidazoles; D007546:Isoquinolines; D008171:Lung Diseases; D008297:Male; D008875:Middle Aged; D011239:Prednisolone; D011759:Pyrrolidines; D013902:Radiography, Thoracic; D013449:Sulfonamides; D014057:Tomography, X-Ray Computed; D014633:Valine",
"nlm_unique_id": "101581124",
"other_id": null,
"pages": "207-10",
"pmc": null,
"pmid": "27108017",
"pubdate": "2016-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Drug-induced lung injury associated with combination therapy of daclatasvir and asunaprevir: The first case report.",
"title_normalized": "drug induced lung injury associated with combination therapy of daclatasvir and asunaprevir the first case report"
} | [
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"abstract": "BACKGROUND\nDirect oral anticoagulants (DOACs) are now standard of care for the management of thromboembolic risk. A prevalent issue of concern is how to manage direct oral anticoagulant (DOAC)-associated bleeding for which there is no specific antidote available for clinical use. We conducted a retrospective case series to describe the Toronto, Canada multicenter experience with bleeding from dabigatran or rivaroxaban.\n\n\nMETHODS\nRetrospective chart review of DOAC bleeding necessitating referral to hematology and/or transfusion medicine services at five large University of Toronto affiliated academic hospitals from January 2011 to December 2013.\n\n\nRESULTS\nTwenty-six patients with DOAC bleeding were reviewed; 42 % bleeds intracranial and 50 %, gastrointestinal. All patients had at least one risk factor associated with DOAC bleeding reported in previous studies. Inconsistent bleed management strategies were evident. Median length of hospital stay was 11 days (1-90). Five thromboembolic events occurred after transfusion based-hemostatic therapy and there were six deaths.\n\n\nCONCLUSIONS\nManagement of DOAC bleeding is variable. Clinical trial data regarding DOAC reversal is needed to facilitate optimization and standardization of bleeding treatment algorithms.",
"affiliations": "Division of Hematology, Department of Medicine and Department of Laboratory Medicine and Pathobiology, St. Michael's Hospital, University of Toronto, 30 Bond Street, Room 2-007G Core Lab, Carter Wing, Toronto, ON M5B-1 W8 Canada.;Division of Hematology, Department of Medicine and Department of Laboratory Medicine and Pathobiology St. Michael's Hospital, University of Toronto, Toronto, Ontario Canada.;Departments of Medicine and Laboratory Medicine and Pathobiology, Mount Sinai Hospital, University of Toronto, Toronto, ON Canada.;Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, ON Canada.;Department of Clinical Pathology, Sunnybrook Health Sciences Centre; and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada.",
"authors": "Sholzberg|Michelle|M|;Pavenski|Katerina|K|;Shehata|Nadine|N|;Cserti-Gazdewich|Christine|C|;Lin|Yulia|Y|",
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"fulltext": "\n==== Front\nBMC HematolBMC HematolBMC Hematology2052-1839BioMed Central London 3910.1186/s12878-015-0039-zResearch ArticleBleeding complications from the direct oral anticoagulants Sholzberg Michelle 416-864-5389sholzbergm@smh.ca Pavenski Katerina pavenskik@smh.ca Shehata Nadine nshehata@mtsinai.on.ca Cserti-Gazdewich Christine christine.cserti-gazdewich@sunnybrook.ca Lin Yulia yulia.lin@sunnybrook.ca Division of Hematology, Department of Medicine and Department of Laboratory Medicine and Pathobiology, St. Michael’s Hospital, University of Toronto, 30 Bond Street, Room 2-007G Core Lab, Carter Wing, Toronto, ON M5B-1 W8 Canada Division of Hematology, Department of Medicine and Department of Laboratory Medicine and Pathobiology St. Michael’s Hospital, University of Toronto, Toronto, Ontario Canada Departments of Medicine and Laboratory Medicine and Pathobiology, Mount Sinai Hospital, University of Toronto, Toronto, ON Canada Department of Laboratory Medicine and Pathobiology, University Health Network, University of Toronto, Toronto, ON Canada Department of Clinical Pathology, Sunnybrook Health Sciences Centre; and Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON Canada 24 12 2015 24 12 2015 2015 15 181 7 2015 5 12 2015 © Sholzberg et al. 2015\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nDirect oral anticoagulants (DOACs) are now standard of care for the management of thromboembolic risk. A prevalent issue of concern is how to manage direct oral anticoagulant (DOAC)-associated bleeding for which there is no specific antidote available for clinical use. We conducted a retrospective case series to describe the Toronto, Canada multicenter experience with bleeding from dabigatran or rivaroxaban.\n\nMethods\nRetrospective chart review of DOAC bleeding necessitating referral to hematology and/or transfusion medicine services at five large University of Toronto affiliated academic hospitals from January 2011 to December 2013.\n\nResults\nTwenty-six patients with DOAC bleeding were reviewed; 42 % bleeds intracranial and 50 %, gastrointestinal. All patients had at least one risk factor associated with DOAC bleeding reported in previous studies. Inconsistent bleed management strategies were evident. Median length of hospital stay was 11 days (1–90). Five thromboembolic events occurred after transfusion based-hemostatic therapy and there were six deaths.\n\nConclusions\nManagement of DOAC bleeding is variable. Clinical trial data regarding DOAC reversal is needed to facilitate optimization and standardization of bleeding treatment algorithms.\n\nKeywords\nAnticoagulantsBlood transfusionDabigatranHemorrhageRivaroxabanhttp://dx.doi.org/10.13039/100001003Boehringer Ingelheim (US)http://dx.doi.org/10.13039/100008322CSL Behring (US)http://dx.doi.org/10.13039/100007658Baxter Healthcare Corporation (US)issue-copyright-statement© The Author(s) 2015\n==== Body\nBackground\nVitamin K antagonists have long been the mainstay of prophylactic or therapeutic anticoagulation for thromboembolism. The cumbersome disadvantages of warfarin from both the patient and physician perspective have led to the development, and now standard use, of direct oral anticoagulants (DOACs) that do not require laboratory monitoring and have fewer food and drug interactions.Table 1 Risk factors associated with direct oral anticoagulant bleeding\n\nClinical Variable\tNumber of patients\t\n>80 years of age\t12\t\nWeight < 63 kg\t4\t\nSevere (<30 ml/min) or moderate (30–50 ml/min) impairment in creatinine clearance\t9\t\nDiabetes mellitus\t5\t\nConcomitant aspirin\t5\t\nConcomitant NSAIDa\n\t5\t\nConcomitant strong P-gpb inhibitors\t3\t\nHigher than recommended dose of dabigatran\t1\t\n\nanon-steroidal anti-inflammatory drug\n\n\nbp-glycoprotein\n\nTable 2 Hemostatic therapy according to bleed site\n\nIntracranial Hemorrhage (ICH) Events (N = 11) 2 combined ICH and GIB\tGastrointestinal Bleed (GIB) Events (N = 12) 2 combined ICH and GIB\t\n6 (54 %) received aPCCa\n\t1 (8 %) received aPCC\t\n0 (0 %) received PCCb\n\t2 (17 %) received PCC\t\n\t2 (17 %) received both aPCC and PCC\t\n7 (64 %) received hemostatic support of any kind\t9 (75 %) received hemostatic support of any kind\t\n4 (36 %) did not receive hemostatic therapy\t3 (25 %) did not receive hemostatic therapy\t\n\naactivated prothrombin complex concentrate\n\n\nbprothrombin complex concentrate\n\nFig. 1 Bleed sites (N = 27 bleeding episodes in 26 patients)\n\n\n\nLarge clinical trials comparing the DOACs to vitamin K antagonists have demonstrated similar efficacy in the management and prevention of thromboembolism and similar or reduced major bleeding rates [1–3]. As indications for DOACs expand, an issue of concern is how to manage real-world DOAC-associated bleeding for which no antidote is currently available. Guidelines and reviews have extrapolated bleeding management principles from results of animal and human volunteer studies with laboratory, not clinical, parameters as primary outcomes [4–7]. Since no evidence-based, standard therapeutic algorithm for DOAC bleeding is available, the primary objective of our study was to determine how patients are currently being managed in this setting. We focused on the experience with hemorrhage from dabigatran, a direct thrombin inhibitor, and rivaroxaban, a direct factor Xa inhibitor, as apixaban, a direct factor Xa inhibitor, was not yet approved for use in Canada.\n\nMethods\nWe conducted a retrospective chart review of DOAC bleeding necessitating referral to hematology and/or transfusion medicine services at five large University of Toronto affiliated academic hospitals (St. Michael’s Hospital, Toronto General Hospital, Toronto Western Hospital, Sunnybrook Health Sciences Centre, Mount Sinai Hospital) from January 2011 to December 2013. Patients were included if they were: over the age of 18 years, documented to have a DOAC associated hemorrhage and identified to hematology and/or transfusion medicine services.\n\nThe following data were abstracted from medical records: age and sex; body weight; DOAC type; indication for DOAC; duration of time on DOAC therapy until bleeding event (days); concomitant medication use; initial blood work (including complete blood cell count, activated partial thromboplastin time (aPTT), prothrombin time (PT), fibrinogen (Claus method), liver enzymes (aspartate aminotransferase [AST], alanine transaminase [ALT], alkaline phosphatase [ALP]), albumin, bilirubin, estimated creatinine clearance (Cockcroft-Gault formula); description of bleeding episode (site, date/time documented, red blood cell (RBC) transfusion, severity of bleed – major or minor). Major bleeding was defined according to the International Society on Thrombosis and Haemostasis (ISTH)’s recommendations [8] as either involvement of a critical organ, fall in haemoglobin of more than 20 g/L or requirement of greater than two RBC transfusions. Of note, aforementioned data points included those known to be associated with increased risk of DOAC bleeding.\n\nAdditional data collected included: management of bleeding (DOAC held, site compression, surgical management, fluids/adequate urine output, charcoal, haemodialysis, transfusion [activated prothrombin complex concentrate (aPCC), prothrombin complex concentrate (PCC), activated recombinant factor VII, frozen plasma, platelets, cryoprecipitate, fibrinogen concentrate] and non-transfusion based [tranexamic acid, desmopressin, vitamin K] hemostatic support; coagulation based test results post-transfusion therapy; bleeding outcome (decrease, increase, no change, cessation); venous or arterial thromboembolic (TE) event (with supportive imaging results and/or blood work); length of hospital stay; and hospital discharge status (alive, dead).\n\nData were analyzed using descriptive statistics (mean, median, range and standard deviation) and inferential statistics (confidence interval). All analyses were performed using SAS statistical software, version 9.2 (SAS Institute Inc). Approval to perform this study and to report the results was obtained from St Michael’s Hospital Research Ethics Board, University Health Network Research Ethics Board associated with Toronto General Hospital and Toronto Western Hospital, the Human Research Protections Program associated with Sunnybrook Health Sciences Centre, and Mount Sinai Hospital Research Ethics Board. The aforementioned list of research ethics committees approved this study and granted access to medical records and databases at their respective hospital sites. Approval to publicize the data set was not obtained by the hospital Research Ethics Boards. Hospitals are required to protect the privacy of citizens whose information they collect. The hospitals strive to comply with the Personal Health Information Protection Act (PHIPA). Therefore data supporting the study findings are unavailable.\n\nResults\nTwenty-seven bleeding events were captured upon retrospective review; one patient had two events hence a total of 26 patients were reviewed. Nine bleeding events occurred with rivaroxaban while 18 occurred with dabigatran. All except four patients were over the age of 70 years with a median age of 78 years (range 52–91 years). Approximately 69 % (18/26) of patients were male. Three individuals were underweight (less than 60 kilograms) while the median weight was 78.3 (range 50–150) kilograms. The median time taking the DOAC prior to bleeding was 120 days (range 5–810). The indications for DOAC therapy included the following: atrial fibrillation (n = 24), deep vein thrombosis (n = 1), and two patients (7 %) treated for an off-label indication (one for cancer associated pulmonary embolism and the other for prophylaxis for an automated implantable cardioverter-defibrillator. Of the nine rivaroxaban associated bleeds, five occurred at a dosage of 20 mg daily and four at 15 mg daily. Of the 18 dabigatran bleeds, eight occurred at a dosage of 150 mg twice per day and ten at 110 mg twice per day. The median number of concomitant medications was 7 (range 1–16). Five bleeding events occurred while the patient was taking concomitant aspirin therapy, five events with non-steroidal anti-inflammatory drugs (NSAIDs) and three occurred with concomitant P-glycoprotein (P-gp) inhibitors.\n\nEighty-nine percent of the bleeding events were classified as a major hemorrhage with 50 % requiring RBC transfusion. Of those who were transfused with RBCs, a median of 2.5 units (range 1–9) was required. Half of the dabigatran patients were transfused with RBCs (median 3 units, range 1–3) compared to 44 % treated with rivaroxaban (median 2 units, range 1–4).\n\nEleven (42 %) bleeding events were intracranial (ICH) and 13 (50 %) were gastrointestinal (GI) in origin. Of note, two of these events were combined ICH and GI hemorrhages. Of the 13 GI hemorrhages, nine were associated with dabigatran use and four with rivaroxaban. There were 11 ICH events, six occurred in dabigatran users and five in rivaroxaban users. There was no statistically significant association between dabigatran versus rivaroxaban use and type of hemorrhage using a two-tailed Fischer’s exact test (p = 0.68). More patients with GI bleeds received RBC transfusion (62 %), as compared to ICH (27 %).\n\nThe remaining four bleeds involved the following sites: vaginal, pulmonary, subcutaneous or musculoskeletal with some occurring in combination. One of these events was associated with a motor vehicle collision (Fig. 1).\n\nData were reviewed for risk factors (found in previous observational studies) associated with DOAC bleeding. In this study, all bleeding events occurred in the context of at least one previously identified associating factor and 63 % occurred with more than one. Specifically, 50 % of subjects were above 80 years of age and 33 % of cases occurred with severe (<30 ml/min) or moderate (30–50 ml/min) impairment in creatinine clearance at time of bleeding. Five subjects had comorbid diabetes mellitus, five were on concomitant aspirin and another 19 % were taking a NSAID (Table 1). Of the 26 patients, 14 were on a reduced dose of dabigatran (110 mg) or rivaroxaban (15 mg). All of those patients were either of older age or had impaired renal function. Fifty percent of those on standard dose DOAC were older or had abnormal kidney function.\n\nOf the 18 dabigatran related bleed events (in 17 patients), five (28 %) received aPCC alone, two (11 %) received aPCC and PCC, 13 (72 %) received at least one hemostatic support of any kind and five (28 %) did not receive any hemostatic therapy. Of the nine rivaroxaban related bleeding events, six (67 %) received at least one hemostatic support (two (22 %) received aPCC, two (22 %) received PCC) and three (33 %) did not receive any hemostatic therapy.\n\nAPCC tended to be administered to a larger number of patients with ICH - six (54 %) - compared with isolated GI hemorrhage - one (8 %). However, a similar proportion of individuals received hemostatic therapy of any kind (63 % for ICH and 69 % for GI bleed) (Table 2).\n\nHemostatic response to aPCC and/or PCC seemed to differ according to the DOAC. Of the nine total patients that received aPCC, three (all dabigatran related) had resolution of bleeding within 12 to 24 h of administration. Of the five total patients that received PCC, one bleed (rivaroxaban related) had resolution of bleeding at 24 h and there was no abnormal intra-operative bleeding in another rivaroxaban related case. CBC, PT and aPTT were the most commonly ordered initial laboratory tests. However, the frequency of repeated testing was highly variable. Concise summarization of laboratory data was not possible. Furthermore, we cannot comment on the pattern of coagulation study normalization due to inconsistencies within the dataset.\n\nThere were five TE events in subjects who received transfusion based hemostatic therapy (i.e. aPCC, PCC, FP and/or platelets). All of the events were arterial in nature involving either myocardial infarction or bowel ischemia. A single arterial TE event occurred within 24 h of hemostatic transfusion (aPCC). There were no TE events in patients who did not receive transfusion based hemostatic therapy.\n\nThe median length of hospital stay was 11 days (range 1–90). There were six deaths (four dabigatran and two rivaroxaban) (23 % of cases). The cause of death was ICH in five patients and one death occurred secondary to multi-organ failure and myocardial infarction. The proportion of ICH resulting in death was 45 %.\n\nDiscussion\nWe found, in this case series, that the management of DOAC bleeding is highly variable. A large proportion of patients in this study required prolonged hospitalization and experienced TE complications. Additionally, a substantial proportion of patients died. Of interest, 33 % of the patients in this case series would not have qualified for enrolment in the studies on the respective drugs.\n\nThis study is limited by the lack of control and denominator data, however, it highlights the importance of ‘risk’ factors for major DOAC related bleeding namely, advanced age, renal impairment, diabetes mellitus and concomitant treatment with aspirin and NSAIDs [9–12]. Despite reassuring recent evidence from a meta-analysis reviewing the bleeding rates in the elderly from published randomized controlled trials comparing DOACs with standard anticoagulant therapy, this study suggests that careful patient selection for treatment with DOACs remains paramount [12]. Interestingly, data from this case series is in contrast to the recently published data on rivaroxaban bleeding from the Dresden registry [13]. Most notably, this case series confirms that a high proportion of patients who experience anticoagulant associated ICH die [14].\n\nConclusion\nIn summary, this case series shows that there is considerable variation in the treatment used to control DOAC associated bleeding. This study also highlights the importance of proper patient selection for DOAC therapy. In conclusion, management of DOAC bleeding needs to be optimized and standardized once clinical trial data regarding reversal becomes available.\n\nAbbreviations\nALPAlkaline phosphatase\n\nALTAlanine transaminase\n\nASTAspartate aminotransferase\n\naPCCActivated prothrombin complex concentrate\n\naPTTActivated partial thromboplastin time\n\nDOACDirect oral anticoagulants\n\nGIGastrointestinal\n\nICHIntracranial hemorrhage\n\nISTHInternational society of thrombosis and haemostasis\n\nNSAIDNon-steroidal anti-inflammatory drug\n\nPCCProthrombin complex concentrate\n\nP-gpP-glycoprotein\n\nPTProthrombin time\n\nRBCRed blood cell\n\nTEThromboembolic\n\nCompeting interests\n\nThe conduct of this multicenter case series was supported by unrestricted research/educational grants from the following pharmaceutical sponsors: Baxter, Octapharma, Boehringer-Ingelheim and CSL Behring. Research assistant salary support was provided in part by a grant from Boehringer-Ingelheim (Canada) Ltd.\n\nAuthors’ contributions\n\nMS participated in the study design, data collection, analysis, analysis interpretation, and manuscript preparation. KP participated in study design, data collection, analysis interpretation, and manuscript editing. NS participated in study design, data collection, analysis interpretation, and manuscript editing. CCG participated in study design, data collection, analysis interpretation, and manuscript editing. YL participated in study design, data collection, analysis interpretation, and manuscript editing. All authors read and approved the final manuscript.\n\nAcknowledgements\nWe would like to acknowledge the unrestricted research/educational grant support from Baxter, Octapharma and CSL Behring. Research assistant salary support was provided in part by a grant from Boehringer-Ingelheim (Canada) Ltd. We would also like to acknowledge support from our research coordinators, Ms. Daisy Dastur, Mr. Aziz Jiwajee, Ms. Jessica Petrucci, Ms. Lorna Sampson, Ms. Nusrat Zaffar, Ms. Cassandra Ottawa, Mr. Syed Mahamad, Ms. Natalya O'Neill and Mr. Joshua Tseng.\n==== Refs\nReferences\n1. Dentali F, Riva N, Crowther M, Turpie AG, Lip GY,Ageno W. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation. 2012;126(20):2381–91\n2. Fox BD Kahn SR Langleben D Eisenberg MJ Shimony A Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials 2012 \n3. Chai-Adisaksopha C Crowther M Isayama T Lim W The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis Blood 2014 124 15 2450 8 10.1182/blood-2014-07-590323 25150296 \n4. Eerenberg ES Kamphuisen PW Sijpkens MK Meijers JC Buller HR Levi M Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects Circulation 2011 124 14 1573 9 10.1161/CIRCULATIONAHA.111.029017 21900088 \n5. Heidbuchel H Verhamme P Alings M Antz M Hacke W Oldgren J EHRA Practical guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation: executive summary Eur Heart J 2013 27 2094 106 10.1093/eurheartj/eht134 23625209 \n6. Pernod G, Albaladejo P, Godier A, Samama CM, Susen S, Gruel Yet al. Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors: Proposals of the Working Group on Perioperative Haemostasis (GIHP) – March 2013. Archives of Cardiovascular Diseases. 2013;106(6–7):382–93. doi:http://dx.doi.org/10.1016/j.acvd.2013.04.009.\n7. Levy JH, Spyropoulos AC, Samama CM,Douketis J. Direct Oral Anticoagulants: New Drugs and New Concepts. JACC: Cardiovascular Interventions. 2014;7(12):1333–51. doi:http://dx.doi.org/10.1016/j.jcin.2014.06.014.\n8. Schulman S Kearon C Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non‐surgical patients Thromb Haemost 2005 3 4 692 4 10.1111/j.1538-7836.2005.01204.x \n9. Deedwania PC New oral anticoagulants in elderly patients with atrial fibrillation Am J Med 2013 126 4 289 96 10.1016/j.amjmed.2012.10.012 23369212 \n10. Harper P Young L Merriman E Bleeding risk with dabigatran in the frail elderly N Engl J Med 2012 366 9 864 6 10.1056/NEJMc1112874 22375994 \n11. Jacobs JM Stessman J New anticoagulant drugs among elderly patients is caution necessary? Comment on “The use of dabigatran in elderly patients” Arch Intern Med 2011 171 14 1287 8 10.1001/archinternmed.2011.308 21788546 \n12. Sardar P Chatterjee S Chaudhari S Lip GY New oral anticoagulants in elderly adults: evidence from a meta‐Analysis of randomized trials J Am Geriatr Soc 2014 62 5 857 64 10.1111/jgs.12799 24786913 \n13. Beyer-Westendorf J Förster K Pannach S Ebertz F Gelbricht V Thieme C Rates, management, and outcome of rivaroxaban bleeding in daily care: results from the Dresden NOAC registry Blood 2014 6 955 62 10.1182/blood-2014-03-563577 24859362 \n14. Alonso A Bengtson LGS MacLehose RF Lutsey PL Chen LY Lakshminarayan K Intracranial hemorrhage mortality in atrial fibrillation patients treated with dabigatran or warfarin Stroke 2014 45 8 2286 91 10.1161/STROKEAHA.114.006016 24994722\n\n",
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},
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}
] |
{
"abstract": "Psychotropic medications are an essential component of treating pediatric mental health disorders, and pediatricians are increasingly likely to prescribe them. Commonly used psychotropic medications include stimulants and nonstimulants used in the treatment of attention-deficit/hyperactivity disorder (ADHD); antidepressants used in the treatment of anxiety and depression; and antipsychotics indicated for use in autism, schizophrenia, mood disorders, severe impulsivity, and aggression. Stimulants are commonly associated with appetite suppression and initial insomnia and nonstimulants for ADHD are associated with sedation. Antidepressants are generally well tolerated; adverse effects include behavioral activation early in treatment and, rarely, treatment-emergent mania and suicidal ideation. Potential adverse effects of atypical antipsychotics include weight gain and metabolic syndrome. Monitoring strategies are reviewed. [Pediatr Ann. 2020;49(10):e431-e435.].",
"affiliations": null,
"authors": "Romba|Courtney|C|;Perez-Reisler|Marisa|M|",
"chemical_list": "D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D011619:Psychotropic Drugs",
"country": "United States",
"delete": false,
"doi": "10.3928/19382359-20200922-03",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0090-4481",
"issue": "49(10)",
"journal": "Pediatric annals",
"keywords": null,
"medline_ta": "Pediatr Ann",
"mesh_terms": "D000928:Antidepressive Agents; D014150:Antipsychotic Agents; D001289:Attention Deficit Disorder with Hyperactivity; D000697:Central Nervous System Stimulants; D002648:Child; D006801:Humans; D011619:Psychotropic Drugs",
"nlm_unique_id": "0356657",
"other_id": null,
"pages": "e431-e435",
"pmc": null,
"pmid": "33034658",
"pubdate": "2020-10-01",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Management of Adverse Effects of Psychotropic Medications.",
"title_normalized": "management of adverse effects of psychotropic medications"
} | [
{
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}
],
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"literaturereference": "Romba C, Perez-Reisler M.. Management of Adverse Effects of Psychotropic Medications. PEDIATRIC ANNALS. 2020;49(10):E431-E435",
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},
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"transmissiondate": "20220303"
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] |
{
"abstract": "BACKGROUND\nOutcome and toxicity data in adolescent-adult Ewing sarcoma (AA-ES) patients are sparse and merits exploration.\n\n\nMETHODS\nHistopathologically confirmed, nonmetastatic AA-ES patients, who received standard institutional combination chemotherapy regimen (Ewing's family of tumors-2001 [EFT-2001]) comprising of ifosfamide plus etoposide and vincristine, doxorubicin plus cyclophosphamide, lasting a total of 12 months between 2013 and 2018, were analyzed for treatment-related toxicities, event-free survival (EFS), and overall survival (OS).\n\n\nRESULTS\nThere were 235 patients (primary safety cohort [PSC]) with median age of 23 (15-61) years; 159 (67.7%) were males, 155 (65.9%) had skeletal primary and 114 (48.5%) had extremity tumors. One hundred ninety-six (83.4%) were treatment naïve (primary efficacy cohort [PEC]) and of these 119 (60.7%) had surgery. In PEC, at a median follow-up of 36.4 (interquartile range [IQR] 20-55) months, estimated 3-year EFS and OS were 67.3% (95% CI 60.3-75.1%) and 91.1% (95% CI 86.7-95.7%), respectively. Of these, 158 (80.6%) complying with intended treatment, at a median follow-up of 39 (IQR 26-57) months had an estimated 3-year EFS of 68.2% (95% CI 60.3-76.1%). In multivariable analysis, good prognostic factors included longer symptom(s) duration (HR 0.93, 95% CI 0.86-0.994), ≥99% necrosis (HR 0.30, 95% CI 0.11-0.77), and treatment completion (HR 0.32, 95% CI 0.14-0.74). Among PSC, grade 3-4 toxicities were febrile neutropenia (119, 50.6%), anemia (130, 55.3%), peripheral neuropathy (37, 15.7%), with three (1.3%) chemo-toxic deaths.\n\n\nCONCLUSIONS\nThe outcomes of AA nonmetastatic ES patients treated with EFT-2001 regimen were comparable to those reported by others, with acceptable toxicity. This regimen can be considered a standard of care in AA-ES.",
"affiliations": "Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.;Tata Memorial Hospital, Homi Bhabha National Institute (HBNI), Mumbai, Maharashtra, India.",
"authors": "Bajpai|Jyoti|J|https://orcid.org/0000-0001-7657-3460;Panda|Goutam Santosh|GS|https://orcid.org/0000-0003-1393-8607;Chandrasekharan|Arun|A|https://orcid.org/0000-0001-5373-0558;Bhargava|Prabhat|P|;Srinivas|Sujay|S|;Laskar|Siddhartha|S|https://orcid.org/0000-0001-8558-4225;Dandekar|Sonal|S|;Mokal|Smruti|S|;Rekhi|Bharat|B|;Khanna|Nehal|N|;Menon|Nandini|N|;Patil|Vijay|V|;Noronha|Vanita|V|;Joshi|Amit|A|;Prabhash|Kumar|K|;Banavali|Shripad D|SD|;Gupta|Sudeep|S|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1002/pbc.29081",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1545-5009",
"issue": "68(9)",
"journal": "Pediatric blood & cancer",
"keywords": "EFT-2001; Ewing sarcoma; adolescent-adult; low and middle-income countries (LMICs); nonmetastatic",
"medline_ta": "Pediatr Blood Cancer",
"mesh_terms": null,
"nlm_unique_id": "101186624",
"other_id": null,
"pages": "e29081",
"pmc": null,
"pmid": "33991401",
"pubdate": "2021-09",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Adolescent-adult nonmetastatic Ewing sarcoma-Experience from a large developing country.",
"title_normalized": "adolescent adult nonmetastatic ewing sarcoma experience from a large developing country"
} | [
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"companynumb": "IN-AMNEAL PHARMACEUTICALS-2021-AMRX-02147",
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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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"transmissiondate": "20220303"
},
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{
"abstract": "Antiviral resistance frequently complicates the treatment of herpes simplex virus (HSV) infections in immunocompromised patients. Here we present the case of an adolescent boy with dedicator of cytokinesis 8 (DOCK8) deficiency, who experienced recurrent infections with resistant HSV-1. We used both phenotypic and genotypic methodologies to characterize the resistance profile of HSV-1 in the patient and conclude that genotypic testing outperformed phenotypic testing. We also present the first analysis of intrahost HSV-1 evolution in an immunocompromised patient. While HSV-1 can remain static in an immunocompetent individual for decades, the virus from this patient rapidly acquired genetic changes throughout its genome. Finally, we document a likely case of transmitted resistance in HSV-1 between the patient and his brother, who also has DOCK8 deficiency. This event demonstrates that resistant HSV-1 is transmissible among immunocompromised persons.",
"affiliations": "Department of Medicine, University of Washington, Seattle, Washington, USA.;Department of Pediatrics, Children's Mercy, Kansas City, Missouri, USA.;Department of Pathology and Laboratory Medicine, Children's Mercy, Kansas City, Missouri, USA.;Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.;School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.;School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.;Department of Pathology and Laboratory Medicine, Children's Mercy, Kansas City, Missouri, USA.;Department of Laboratory Medicine, University of Washington, Seattle, Washington, USA.;School of Medicine, University of Missouri-Kansas City, Kansas City, Missouri, USA.",
"authors": "Casto|Amanda M|AM|;Stout|Sean C|SC|;Selvarangan|Rangaraj|R|;Freeman|Alexandra F|AF|;Newell|Brandon D|BD|;Stahl|Erin D|ED|;Ahmed|Atif A|AA|;Greninger|Alexander L|AL|;Yin|Dwight E|DE|",
"chemical_list": "D000998:Antiviral Agents; D004279:DNA, Viral; C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors",
"country": "United States",
"delete": false,
"doi": "10.1093/infdis/jiaa020",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1899",
"issue": "221(12)",
"journal": "The Journal of infectious diseases",
"keywords": "DOCK8 deficiency; HSV-1; genotypic antiviral resistance; immunodeficiency; intrahost evolution; phenotypic antiviral resistance; transmitted resistance",
"medline_ta": "J Infect Dis",
"mesh_terms": "D000293:Adolescent; D000998:Antiviral Agents; D004279:DNA, Viral; D024882:Drug Resistance, Viral; D060005:Genotyping Techniques; D020662:Guanine Nucleotide Exchange Factors; D006561:Herpes Simplex; D018259:Herpesvirus 1, Human; D006801:Humans; D016867:Immunocompromised Host; D008297:Male; D008826:Microbial Sensitivity Tests; D020641:Polymorphism, Single Nucleotide; D012720:Severity of Illness Index; D012867:Skin",
"nlm_unique_id": "0413675",
"other_id": null,
"pages": "2035-2042",
"pmc": null,
"pmid": "31970398",
"pubdate": "2020-06-11",
"publication_types": "D002363:Case Reports; D023362:Evaluation Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D052060:Research Support, N.I.H., Intramural",
"references": "27306564;29057909;26433780;12525428;25204613;25218782;11238837;17713155;28625885;29898986;9716390;23329690;14715760;22543367;12829822;22417106;14670581",
"title": "Evaluation of Genotypic Antiviral Resistance Testing as an Alternative to Phenotypic Testing in a Patient with DOCK8 Deficiency and Severe HSV-1 Disease.",
"title_normalized": "evaluation of genotypic antiviral resistance testing as an alternative to phenotypic testing in a patient with dock8 deficiency and severe hsv 1 disease"
} | [
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"abstract": "A 76-year-old Japanese man was admitted to hospital for treatment of fever and skin lesion at the implantation site of his pacemaker. During his hospitalization, vancomycin-intermediate Staphylococcus aureus (MIC 4 μg/mL) with reduced susceptibility to daptomycin was isolated from venous blood. This isolate was identified as methicillin-resistant S. aureus with SCCmec IV and was genotyped as sequence type 81, coa VIIa and spa type t7044, harbouring blaZ, aac(6')-aph(2″) and enterotoxin(-like) genes sea, seb, sek, sel, selx and selw. The patient was successfully treated with daptomycin, minocycline and sulfamethoxazole/trimethoprim. We describe the identification of sequence type 81/SCCmec IV vancomycin-intermediate S. aureus from pacemaker-associated septicaemia.",
"affiliations": "Department of Pharmacy, Sapporo Medical University School of Medicine, Sapporo, Japan.;Department of Pharmacy, Sapporo Medical University School of Medicine, Sapporo, Japan.;Department of Pharmacy, Sapporo Medical University School of Medicine, Sapporo, Japan.;Department of Laboratory, Sapporo Medical University School of Medicine, Sapporo, Japan.;Department of Paediatrics, Hakodate Municipal Hospital, Hakodate, Japan.;Department of Hygiene, Sapporo Medical University School of Medicine, Sapporo, Japan.;Department of Hygiene, Sapporo Medical University School of Medicine, Sapporo, Japan.;Department of Hygiene, Sapporo Medical University School of Medicine, Sapporo, Japan.",
"authors": "Sakurada|M|M|;Sumi|H|H|;Kaji|K|K|;Kobayashi|N|N|;Sakai|Y|Y|;Aung|M S|MS|;Urushibara|N|N|;Kobayashi|N|N|",
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"doi": "10.1016/j.nmni.2020.100656",
"fulltext": "\n==== Front\nNew Microbes New Infect\nNew Microbes New Infect\nNew Microbes and New Infections\n2052-2975 2052-2975 Elsevier \n\nS2052-2975(20)30008-1\n10.1016/j.nmni.2020.100656\n100656\nNew Resistant Microbes in Human\nPacemaker-associated infection caused by ST81/SCCmec IV methicillin-resistant, vancomycin-intermediate Staphylococcus aureus in Japan\nSakurada M. 1 Sumi H. 1 Kaji K. 1 Kobayashi N. nkobayas@sapmed.ac.jp2∗ Sakai Y. 3 Aung M.S. 4 Urushibara N. 4 Kobayashi N. 4 1) Department of Pharmacy, Sapporo Medical University School of Medicine, Sapporo, Japan\n2) Department of Laboratory, Sapporo Medical University School of Medicine, Sapporo, Japan\n3) Department of Paediatrics, Hakodate Municipal Hospital, Hakodate, Japan\n4) Department of Hygiene, Sapporo Medical University School of Medicine, Sapporo, Japan\n∗ Corresponding author: N. Kobayashi, Department of Hygiene, Sapporo Medical University School of Medicine, S-1 W-17, Chuo-ku, Sapporo, 060-8556, Japan. nkobayas@sapmed.ac.jp\n14 2 2020 \n5 2020 \n14 2 2020 \n35 1006569 12 2019 20 1 2020 10 2 2020 © 2020 The Author(s)2020This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).A 76-year-old Japanese man was admitted to hospital for treatment of fever and skin lesion at the implantation site of his pacemaker. During his hospitalization, vancomycin-intermediate Staphylococcus aureus (MIC 4 μg/mL) with reduced susceptibility to daptomycin was isolated from venous blood. This isolate was identified as methicillin-resistant S. aureus with SCCmec IV and was genotyped as sequence type 81, coa VIIa and spa type t7044, harbouring blaZ, aac(6′)-aph(2″) and enterotoxin(-like) genes sea, seb, sek, sel, selx and selw. The patient was successfully treated with daptomycin, minocycline and sulfamethoxazole/trimethoprim. We describe the identification of sequence type 81/SCCmec IV vancomycin-intermediate S. aureus from pacemaker-associated septicaemia.\n\nKeywords\nJapanMRSApacemaker-associated infectionST81vancomycin-intermediate Staphylococcus aureus(VISA)\n==== Body\nIntroduction\nMethicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of nosocomial infections worldwide. MRSA has a genetic element SCCmec in its chromosome which has been classified into several types. Generally, SCCmec of hospital-acquired MRSA is mostly assigned to types I to IV, while community-acquired MRSA is assigned to types Ⅳ and Ⅴ [1]. A glycopeptide antibiotic, such as vancomycin (VCM), is one of the representative anti-MRSA drugs and is frequently used as first-choice therapy to treat MRSA infections. However, VCM intermediate-resistant S. aureus (VISA) was first reported in Japan in 1996 [2]. VISA is defined as S. aureus showing VCM MIC of 4 to 8 μg/mL, according to Clinical and Laboratory Standards Institute criteria [3]. Despite its low incidence, VISA has been detected worldwide, and it poses a growing public health concern [4]. Occurrence of VISA is considered to be related to persistent infections and prolonged hospitalization with the provision of VCM [5]. In Japan, although prevalence is extremely low, VISA has been identified for SCCmec II-MRSA [6], SCCmec IV–sequence type (ST) 8 MRSA [7] and SCCmec IV-ST72 MRSA [8]. Here we report the detection of VISA with SCCmec IV-ST81 from a case of pacemaker-associated septicaemia.\n\nCase report\nA 76-year-old Japanese man was transferred to our hospital. He was suspected to have bacteraemia and pacemaker-associated infection. Because he had fever (temperature 39.2°C) associated with redness and swelling that appeared in the skin of the pacemaker implantation site on the left chest wall, ceftriaxone and VCM had been administered by a former doctor, although no bacterial examination had been performed. The patient had had a pacemaker implanted when he was 72 years old for bradycardic atrial fibrillation, and haemodialysis had been performed for chronic renal failure.\n\nAt admission (day 1), physical examinations showed the following: blood pressure 116/83 mm Hg, body temperature 37.5°C, respiratory rate 20 breaths/min, heart rate 86 beats/min (arrhythmia/self-pulse), SpO2 92%, clear consciousness (JCS0, GCS15), no rale in breathing sound, flat and soft abdomen and no muscular defense. Blood tests revealed an increase in white blood cell count (11.7 × 109/L), C-reactive protein (13.34 mg/dL) and procalcitonin (27.66 ng/mL).\n\nMRSA was isolated from venous blood on days 1 and 2, as well as from the pacemaker (surface in contact with wounded part, atrial and ventricular lead wires) on day 9, when the pacemaker was removed. Treatment with ceftriaxone and VCM was continued, but ceftriaxone was discontinued on day 6 after hospitalization, and VCM was administered until day 27. Blood culture results were negative on day 21. Surgery to reimplant the pacemaker was carried out on day 42; the postoperative course was uneventful, but slight fever persisted. On day 48, the patient had a temperature of 38.4°C, and blood culture revealed the presence of MRSA. Therefore, VCM was readministered on day 50. However, the patient's platelet count decreased, and MRSA isolated from blood samples taken on day 50 showed VCM MIC 2 μg/mL. VCM was changed to daptomycin (DAP). On day 61, increased VCM MIC, to 4 μg/mL, was observed for the MRSA isolate grown from blood taken on day 58, so minocycline and sulfamethoxazole/trimethoprim were added to the treatment. On day 63, negative blood culture was confirmed; DAP and minocycline were discontinued on day 73. Because the inflammatory reaction continued, teicoplanin (TEC) was administered for 12 days from day 81. Thereafter the patient fully recovered, without recurrence for 3 months.\n\nThe MRSA isolated on day 61 (strain HV2019-1) was confirmed to be VISA by MIC measured by broth microdilution test using Dry Plate ‘Eiken’ (192 plate), E-EP02 (Eiken Chemical, Tokyo, Japan). This strain exhibited slightly higher MICs than TEC and DAP (2 μg/mL each) than those isolated at admission (day 1) until day 9 (Table 1). Accordingly, this strain was judged to be nonsusceptible to DAP. The VISA strain was resistant to penicillin, cephalosporins, aminoglycosides and quinolones while being susceptible to macrolides, clindamycin, linezolid and sulfamethoxazole/trimethoprim. Except for VCM, TEC and DAP, strain HV2019-1 showed the same susceptibility pattern to those of MRSA isolated on days 1 and 9. The SCCmec type of strain HV2019-1 was identified as IV according to multiplex PCR by using previously published primers and conditions [9]. Strain HV2019-1 belonged to ST81 (clonal complex (CC) 1) based on the scheme of multilocus sequencing typing [10], coagulase genotype (coa) VIIa, spa type t7044 and agr type III. Virulence determinants and drug resistance genes were detected by uniplex/multiplex PCR as described previously [11]. Although PVL genes (lukS-PV-lukF-PV) and ACME (arginine catabolic mobile element)-arcA were negative, this strain harboured the enterotoxin(-like) genes sea, seb, sek, sel, selx and selw, as well as epidermal differentiation factor A gene (edin-A) and blaZ and aac(6′)-aph(2″).Table 1 Genotypes, antimicrobial susceptibility, virulence factors and other genetic traits of VISA strain HV2019-1\n\nTable 1Characteristic\tValue\t\nGenotype\t\n\tcoa type\tVIIa\t\n\tMLST\tST81, CC1 (allelic profile: 1-1-1-9-1-1-1)\t\n\tspa type\tt7044 (repeat profile: 07-23-21-16-34-33-20-13)\t\n\tagr\tIII\t\n\tSCCmec\tIV, subtype-nontypeable (class B-mec, ccrA2B2)\t\nSusceptibility pattern\t\n\tResistant\tβ-Lactams,a AMK, GEN, LVX, CIP\t\n\tSusceptible\tABK, ERY, CLR, ATM, CLI, MIN, TEC, GRX, FOF, SXT, LZD\t\nMIC (μg/mL), MRSA/VISAb\t\n\tVCM\t<0.5∼1/4\t\n\tTEC\t≤0.5/2\t\n\tDAP\t0.25∼1/2\t\nVirulence factorc\t\nHaemolysin\t\thla, hlb, hld, hlg\t\nEnterotoxin\t\tsea, seb, sek, sel, selx, selw\t\nLeukocidin\t\tlukDE\t\nOther\t\tedinA, sak\t\nAdhesin genesd\tcna, eno, fnbA, fnbB, ebpS, fib, clfA, clfB, sdrC, sdrE, icaA, icaD\t\nResistance genese\tblaZ, aac(6′)-aph(2″)\t\nABK, arbekacin; AMK, amikacin; ATM, azithromycin; CC, clonal complex; CIP, ciprofloxacin; CLI, clindamycin; CLR, clarithromycin; DAP, daptomycin; ERY, erythromycin; FOF, fosfomycin; GEN, gentamycin; GRX, garenoxacin; LVX, levofloxacin; LZD, linezolid; MIN, minocycline; MLST, multilocus sequence typing; MRSA, methicillin-resistant Staphylococcus aureus; SXT, sulfamethoxazole/trimethoprim; TEC, teicoplanin; VCM, vancomycin; VISA, vancomycin-intermediate S. aureus.\n\na β-Lactams included: amoxicillin/clavulanic acid, ampicillin/sulbactam, cefaclor, cefazolin, cefdinir, cefepime, cefmetazole, cefotaxime, cefotiam, cefoxitin, cefpodoxime, ceftazidime, ceftriaxone, flomoxef, imipenem, meropenem, penicillin G, oxacillin, piperacillin/tazobactam, sulbactam/cefoperazone.\n\nb Data shown as MRSA (days 1∼9)/VISA (day 61). MRSA was isolated from venous blood (day 1, day 2) and pacemaker (surface in contact with wounded part and lead wires) (day 9). MRSA (VISA) was isolated from venous blood.\n\nc Negative for lukF-PV/lukS-PV, lukM, sec-see, seg-sej, sem-seu, sey, selz, se127, se128, eta, etb, etd, tst-1, edinB, bap, scn, chp.\n\nd Negative for sdrD, bbp.\n\ne Negative for tetK, tetL, tetM, erm(A), erm(B), msrA, ant(4′)-Ia, ant(6)-Ia, aph(3′)-IIIa.\n\n\n\nDiscussion\nIn the present study, genetic information of early MRSA isolates (days 1, 2 and 9) were not available. However, these MRSA isolates showed the same susceptibility patterns (except for VCM, TEC and DAP) to that of VISA strain HV2019-1, thus suggesting that HV2019-1 might be derived from the early MRSA isolated from blood and pacemaker, which presumably remained in any part of patient's body after treatment with VCM. Occurrence of VISA and its precursor, hetero-VISA (h-VISA), has been an obstacle in chemotherapy of MRSA infections. Globally, the most prevalent genotype of methicillin-resistant VISA is SCCmec II and III, and ST239 and ST5 [5]. Although other STs—ST72, ST59 and ST900—have also been found as less common types in VISA or hVISA [5], ST81 (CC 1) has never been detected. Thus, our present study is to our knowledge the first to report ST81 VISA, which was associated with SCCmec IV, a minor SCCmec type among VISA. ST81 S. aureus is rarely detected in human clinical isolates [[11], [12], [13]]; there is only a single report of ST81 MRSA that had the same genetic traits (SCCmec IV, coa-VIIa/agr-III) and similar spa type (t127, repeat profile 07-23-21-16-34-33-13) [11] to that of our present VISA strain. In contrast, ST81 methicillin-susceptible S. aureus appears to be commonly distributed in cows with or without mastitis and in rats in Japan [14,15].\n\nWe noted that the DAP MIC of the strain HV2019-1 increased and became nonsusceptible (associated with the occurrence of VISA on day 61) shortly after the provision of DAP. Similarly, DAP nonsusceptibility was reported for ST72 VISA (MRSA-IV) in Japan [8]. Reduced susceptibility to vancomycin in S. aureus has been revealed to be generated by accumulation of mutations in various genes represented by rpoB [2]. In case of nonsusceptibility to DAP, point mutations in mprF are associated [16]. One study indicated that a single mutation in mprF was related to reduced susceptibility to both vancomycin and DAP in vitro [17], which was also observed for a clinical MRSA isolate [18]. Therefore, it may be necessary to pay attention to provide DAP to patients with VISA infection.\n\nIn conclusion, we here present the isolation of ST81 VISA (MRSA-IV) from pacemaker-associated septicaemia. The findings underscore the careful monitoring of susceptibility to vancomycin and DAP for MRSA frequently isolated from patients with underlying diseases.\n\nConflict of Interest\nNone declared.\n\nAcknowledgements\nSupported in part by Japan Society for the Promotion of Science Kakenhi grant 17H04664. The authors thank M. Kimura, Y. Nobata, Y. Enami, T. Kohama and K. Nakashima, members of the infection control team at Hakodate Municipal Hospital, for their assistance.\n==== Refs\nReferences\n1 Bal A.M. Coombs G.W. Holden M.T.G. Lindsay J.A. Nimmo G.R. Tattevin P. Genomic insights into the emergence and spread of international clones of healthcare-, community- and livestock-associated meticillin-resistant Staphylococcus aureus : blurring of the traditional definitions J Glob Antimicrob Resist 6 2016 95 101 27530849 \n2 Hiramatsu K. Hanaki H. Ino T. Yabuta K. Oguri T. Tenover F.C. Methicillin-resistant Staphylococcus aureus clinical strain with reduced vancomycin susceptibility J Antimicrob Chemother 40 1997 135 136 9249217 \n3 Clinical and Laboratory Standards Institute Performance standards for antimicrobial susceptibility testing 2015 Clinical and Laboratory Standards Institute Wayne, PA 24th informational supplement M100-S25 \n4 Hiramatsu K. Kayayama Y. Matsuo M. Aiba Y. Saito M. Hishinuma T. Vancomycin-intermediate resistance in Staphylococcus aureus J Glob Antimicrob Resist 2 2014 213 224 27873679 \n5 Zhang S. Sun X. Chang W. Dai Y. Ma X. Systematic review and meta-analysis of the epidemiology of vancomycin-intermediate and heterogeneous vancomycin-intermediate Staphylococcus aureus isolates PLoS One 10 2015 e0136082 \n6 Hanaki H. Hososaka Y. Yanagisawa C. Otsuka Y. Nagasawa Z. Nakae T. Occurrence of vancomycin-intermediate–resistant Staphylococcus aureus in Japan J Infect Chemother 13 2007 118 121 17458681 \n7 Kino H. Suzuki H. Yamaguchi T. Notake S. Oishi T. Ito Y. Central nervous system infection caused by vancomycin-intermediate Staphylococcus aureus (SCCmec type IV, ST8) J Infect Chemother 20 2014 643 646 25012468 \n8 Tsukimori A. Nakamura I. Okamura S. Sato A. Fukushima S. Mizuno Y. First case report of vancomycin-intermediate sequence type 72 Staphylococcus aureus with nonsusceptibility to daptomycin BMC Infect Dis 14 2014 459 25149872 \n9 Kondo Y. Ito T. Ma X.X. Watanabe S. Kreiswirth B.N. Etienne J. Combination of multiplex PCRs for staphylococcal cassette chromosome mec type assignment: rapid identification system for mec, ccr, and major differences in junkyard regions Antimicrob Agents Chemother 51 2007 264 274 17043114 \n10 Enright M.C. Day N.P. Davies C.E. Peacock S.J. Spratt B.G. Multilocus sequence typing for characterization of methicillin-resistant and methicillin-susceptible clones of Staphylococcus aureus J Clin Microbiol 38 2000 1008 1015 10698988 \n11 Aung M.S. Urushibara N. Kawaguchiya M. Sumi A. Shinagawa M. Takahashi S. Clonal diversity and genetic characteristics of methicillin-resistant Staphylococcus aureus isolates from a tertiary care hospital in Japan Microb Drug Resist 25 2019 1164 1175 31107152 \n12 Piao C. Karasawa T. Totsuka K. Uchiyama T. Kikuchi K. Prospective surveillance of community-onset and healthcare-associated methicillin-resistant Staphylococcus aureus isolated from a university-affiliated hospital in Japan Microbiol Immunol 49 2005 959 970 16301806 \n13 Chongtrakool P. Ito T. Ma X.X. Kondo Y. Trakulsomboon S. Tiensasitorn C. Staphylococcal cassette chromosome mec (SCCmec ) typing of methicillin-resistant Staphylococcus aureus strains isolated in 11 Asian countries: a proposal for a new nomenclature for SCCmec elements Antimicrob Agents Chemother 50 2006 1001 1012 16495263 \n14 Hata E. Katsuda K. Kobayashi H. Uchida I. Tanaka K. Eguchi M. Genetic variation among Staphylococcus aureus strains from bovine milk and their relevance to methicillin-resistant isolates from humans J Clin Microbiol 48 2010 2130 2139 20392913 \n15 PubMLST Staphylococcus aureus MLST databases https://pubmlst.org/bigsdb?db=pubmlst_saureus_isolates&page=profiles \n16 Ernst C.M. Peschel A. MprF-mediated daptomycin resistance Int J Med Microbiol 309 2019 359 363 31182276 \n17 Chen F.J. Lauderdale T.L. Lee C.H. Hsu Y.C. Huang I.W. Hsu P.C. Effect of a point mutation in mprF on susceptibility to daptomycin, vancomycin, and oxacillin in an MRSA clinical strain Front Microbiol 9 2018 1086 29887848 \n18 Wüthrich D. Cuénod A. Hinic V. Morgenstern M. Khanna N. Egli A. Genomic characterization of inpatient evolution of MRSA resistant to daptomycin, vancomycin and ceftaroline J Antimicrob Chemother 74 2019 1452 1454 30726929\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2052-2975",
"issue": "35()",
"journal": "New microbes and new infections",
"keywords": "Japan; MRSA; ST81; pacemaker-associated infection; vancomycin-intermediate Staphylococcus aureus(VISA)",
"medline_ta": "New Microbes New Infect",
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"pmid": "32215211",
"pubdate": "2020-05",
"publication_types": "D016428:Journal Article",
"references": "10698988;16301806;16495263;25012468;17043114;26287490;9249217;30726929;25149872;31182276;17458681;31107152;29887848;27530849;20392913;27873679",
"title": "Pacemaker-associated infection caused by ST81/SCCmec IV methicillin-resistant, vancomycin-intermediate Staphylococcus aureus in Japan.",
"title_normalized": "pacemaker associated infection caused by st81 sccmec iv methicillin resistant vancomycin intermediate staphylococcus aureus in japan"
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"abstract": "We describe the sudden death of a middle-aged man while having a sauna under the influence of α-pyrrolidinovalerophenone (α-PVP) (PM blood concentration: 0.8 mg/L), amphetamine (0.34 mg/L), and other drugs (buprenorphine, benzodiazepines), and engaging in solitary sexual activities. The drugs' effects on the cardio-circulatory system and on body thermoregulation combined with the high temperatures are likely to have been central mechanisms leading to death. The high levels of adrenaline triggered by sexual arousal and the respiratory depression caused by buprenorphine, in association with benzodiazepines, may have also contributed to his death. This previously unreported type of accidental autoerotic death illustrates the risk of using amphetamine-like sympathomimetic drugs (e.g. cathinone derivates) in hot environments such as a sauna, and during sexual activities therein.",
"affiliations": "Department of Biomedicine, Forensic Medicine, University of Turku, Turku, Finland. philippe.lunetta@utu.fi.;Finnish Institute for Health and Welfare, Forensic Toxicology Unit, Helsinki, Finland.;Finnish Institute for Health and Welfare, Forensic Medicine Unit, Helsinki, Finland.;Finnish Institute for Health and Welfare, Forensic Toxicology Unit, Helsinki, Finland.",
"authors": "Lunetta|Philippe|P|;Kriikku|Pirkko|P|;Tikka|Julius|J|;Ojanperä|Ilkka|I|",
"chemical_list": "D015198:Designer Drugs; D011759:Pyrrolidines; C542924:alpha-pyrrolidinovalerophenone; D001569:Benzodiazepines; D002047:Buprenorphine; D000661:Amphetamine",
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"doi": "10.1007/s12024-020-00236-1",
"fulltext": "\n==== Front\nForensic Sci Med Pathol\nForensic Sci Med Pathol\nForensic Science, Medicine, and Pathology\n1547-769X 1556-2891 Springer US New York \n\n236\n10.1007/s12024-020-00236-1\nCase Report\nFatal α-PVP and amphetamine poisoning during a sauna and autoerotic practices\nLunetta Philippe philippe.lunetta@utu.fi 12 Kriikku Pirkko pirkko.kriikku@thl.fi 34 Tikka Julius julius.tikka@thl.fi 5 Ojanperä Ilkka ilkka.ojanpera@helsinki.fi 34 1 grid.1374.10000 0001 2097 1371Department of Biomedicine, Forensic Medicine, University of Turku, Turku, Finland \n2 grid.10858.340000 0001 0941 4873Department of Forensic Medicine, University of Oulu, Oulu, Finland \n3 Finnish Institute for Health and Welfare, Forensic Toxicology Unit, Helsinki, Finland \n4 grid.7737.40000 0004 0410 2071Department of Forensic Medicine, University of Helsinki, Helsinki, Finland \n5 Finnish Institute for Health and Welfare, Forensic Medicine Unit, Helsinki, Finland \n26 3 2020 \n26 3 2020 \n2020 \n16 3 493 497\n13 2 2020 © The Author(s) 2020Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.We describe the sudden death of a middle-aged man while having a sauna under the influence of α-pyrrolidinovalerophenone (α-PVP) (PM blood concentration: 0.8 mg/L), amphetamine (0.34 mg/L), and other drugs (buprenorphine, benzodiazepines), and engaging in solitary sexual activities. The drugs’ effects on the cardio-circulatory system and on body thermoregulation combined with the high temperatures are likely to have been central mechanisms leading to death. The high levels of adrenaline triggered by sexual arousal and the respiratory depression caused by buprenorphine, in association with benzodiazepines, may have also contributed to his death. This previously unreported type of accidental autoerotic death illustrates the risk of using amphetamine-like sympathomimetic drugs (e.g. cathinone derivates) in hot environments such as a sauna, and during sexual activities therein.\n\nKeywords\nAutoerotic deathSaunaHyperthermiaα-PVPAmphetamineContraction band necrosisUniversity of Turku (UTU) including Turku University Central HospitalOpen access funding provided by University of Turku (UTU) including Turku University Central Hospital.\n\nissue-copyright-statement© Springer Science+Business Media, LLC, part of Springer Nature 2020\n==== Body\nIntroduction\nDeaths associated with autoerotic activities have been described in the medical literature for over a century [1]. Although several definitions and criteria for classification exist [1–4], autoerotic fatalities can merely be seen as “deaths that occur as the result of or in association with masturbation or other autoerotic activity” [1]. Byard and Bramwell [2] have recommended that the use of this term is restricted to accidental deaths that occur “during individual, usually solitary, sexual activity in which a device, apparatus, or prop that was employed to enhance the sexual stimulation of the deceased in some way caused unintended death”. The most frequent autoerotic accidental death (AAD) occurs by asphyxia, usually by hanging, and is the one frequently defined as typical [1, 5], but descriptions cover a wide range of atypical AAD [1, 3, 6–9].\n\nWe describe an atypical AAD of a middle-aged man during a sauna while under the influence of α-pyrrolidinovalerophenone (α-PVP), amphetamine, and other drugs.\n\nCase report\nCase history\nA Caucasian male in his mid-40s was found dead, in late spring, in the sauna area of an apartment building, where he lived with his mother. The man had a history of multidrug abuse and was participating in a buprenorphine replacement therapy program (Suboxone®). He had been diagnosed also with attention deficit hyperactivity disorder (ADHD), for which his treatment was methylphenidate and diazepam. The victim’s mother had started an hour-long sauna-shift at 9:00 pm but returned to her apartment at 9:30 pm, at which time the victim began his sauna. After approximately midnight, the mother noticed that her son had not returned from the sauna. The sauna electrical heating system had shut off automatically at 10:00 pm and, simultaneously, the door to the sauna department was automatically closed by an electrical lock. At 1:48 am, the mother alerted the residence caretaker, who opened the sauna door at 2:30 am. The victim was found dead on the second highest bench of the sauna, in a supine position partially on his right side. He was unclothed except for a woman’s bra, which was placed around his hips. On the upper bench were a pornographic magazine and a wig. Beneath the benches were an anal dildo and two balloons that likely had been positioned under the victims’ bra.\n\nNo resuscitation attempts took place, as secondary signs of death were evident. At the time of police-scene investigation, around 3:00 am, the temperature in the sauna room was 43 °C. Police investigation revealed no suicide note nor any findings suggesting foul play.\n\nAutopsy findings\nA medico-legal autopsy was performed 11 days later. At external examination, the victim’s body showed mild to moderate burn-like lesions caused by exposure to heat in the sauna. In addition to a few scattered bruises and abrasions, no other external signs of mechanical trauma were detectable. At internal examination, the brain and lungs showed congestion and moderate edema. Microscopic examination of sections of the left ventricular wall and ventricular septum showed myocardial contraction band necrosis and fragmentation of myocardial cells and dissection at the intercalated disks, chronic hepatitis and moderate hepatic fibrosis as well as, in the lungs, some foreign body granulomas consistent with intravenous drug abuse.\n\nToxicological analysis\nPost-mortem (PM) blood samples from femoral veins were positive for α-PVP (0.81 mg/L), amphetamine (0.34 mg/L), alprazolam (<0.005 mg/L; therapeutic range 0.01–0.02 mg/L), and oxazepam (0.18 mg/L; therapeutic range 0.1–1.4 mg/L) (GC-MS), as well as buprenorphine (8.7 μg/L; therapeutic range 0.5-10 μg/L), and norbuprenorphine (57 μg/L). In addition, traces of naloxone were detectable in PM blood, which is in accordance with the victim having been in buprenorphine replacement therapy. Amphetamine, α-PVP, and oxazepam were also detectable in the vitreous humor. No alcohols or other positive findings were detected either in blood, urine, or vitreous humor.\n\nBased on circumstantial data, medical history, and autopsy findings, the cause of death was certified as “fatal poisoning by α-PVP and amphetamine” and the manner of death “unintentional”. “Effect of high temperature (hot air, sauna)” was deemed a contributing cause of death.\n\nDiscussion\nCases of AAD are often classified as either typical (resulting from different types of mechanical asphyxia), or atypical (involving sexual self-stimulation by other means) [1]. The latter include electrocution, foreign-body insertion, intoxication, and even drowning [6, 7, 9–14]. A few cases of AAD related to or associated with cold exposure have been reported [1, 14]. Conversely, we are aware of only one AAD directly linked to environmental hyperthermia. That male victim was found dead outdoors (39 °C) wearing female clothes, including seven layered pairs of pantyhose, and had used a prescription medication (benztropine) causing, as a side-effect, hyperthermia [11]. Moreover, in some AAD cases, ones characterized by body-wrapping causing asphyxia, hyperthermia may have been a contributing factor [15]. Most often, PM toxicology in AAD is negative [8]. However, in addition to alcohol-positive cases and fatalities involving gas mixtures, some medicinal and illicit drugs have sporadically been detectable [5–9, 14].\n\nIn the present case, PM toxicology revealed α-pyrrolidinovalerophenone (α-PVP, α-pyrrolidinopentiophenone) in the blood in addition to amphetamine, buprenorphine, and benzodiazepines. The synthetic cathinone-derivate α-PVP, which is structurally related to pyrovalerone, acts as a central nervous system stimulant with effects similar to those of amphetamines and cocaine. Cathinone occurs naturally in a plant known as “khat” (Catha edulis), which has traditionally been chewed in Eastern Africa and in some Arab countries for its stimulant effects [16–18]. During recent decades, synthetic cathinones have been meant to replace more strictly regulated stimulants (e.g. cocaine, MDMA, other amphetamines) and to provide legal chemicals with equal or greater effects and abuse potential [19, 20]. Synthetic cathinones are commonly self-administered by tablet ingestion or powder insufflation, more rarely by intravenous or -muscular injection [19, 21]. Synthetic α-PVP has its peak effect within 10 to 40 min after intake, and its effects last for up to 1–3 h [18]. Users of synthetic cathinones report enhanced energy, euphoria, and empathy in social interactions, as well as increased libido [21–23]. Although perceived as relatively safe, these drugs have adverse sympathomimetic effects including arrhythmias, hypertension, hyperthermia, and seizures, as well as psychotic symptoms such as agitation and hallucinations [17, 19, 21, 22, 24].\n\nThus far, no data exist that can substantiate the toxic and lethal concentrations of α-PVP in humans [18, 19]. In the current case, the α-PVP PM blood concentration (0.81 mg/L) was fairly high compared to those concentrations detected in 47 individuals who underwent a medico-legal autopsy in Finland from January 2010 to September 2019 (unpublished data) and who tested positive for α-PVP in their blood (age range: 19–62, mean: 26.6 years, male-to-female ratio: 8.4). In this Finnish series (28 accidents, 9 suicides, 7 natural deaths, 1 homicide, and 2 undetermined deaths), the α-PVP PM blood concentration ranged from <0.02 mg/L to 2 mg/L, but only three cases showed blood concentrations higher than the concentration detectable in our case (0.91 mg/L, 1.3 mg/L, 2.0 mg/L). Only two cases were classified as accidental poisoning due to α-PVP alone (2.0 mg/L; 0.04 mg/L). In the latter case, intravenous use of α-PVP led to multiple organ damage and eventually death at hospital. At the time of sampling, some time had elapsed from the administration of α-PVP to death, which explains the low concentration of the drug. In addition to the cases in which α-PVP was the primary intoxicant, 14 cases, excluding the present one, involved α-PVP at a fatal multi-drug intoxication level (blood concentrations up to 0.64 mg/L).\n\nThe medical literature reports relatively few data on fatal α-PVP poisonings. A European Union survey involving eight state members reported 115 deaths between 2012 and 2015 in which α-PVP was analytically confirmed in one or more biological samples [25]. In 23 of these cases, α-PVP was the cause or a contributing cause of death, and in 5 of these cases, it was the only drug detected. In a sudden death during restraint of an individual with symptoms of excited delirium after self-administration of α-PVP, the PM blood concentration was 0.41 mg/L [26], whereas in two other fatal α-PVP poisonings, the concentrations were 0.17 mg/L and 0.85 mg/L [27, 28]. A US study has reported three fatal α-PVP poisonings with a PM blood concentration of 0.033, 0.054, and > 20 mg/L, the last one occurring in custody after the victim swallowed the drug [29]. As for non-fatal concentrations, in a series of 18 subjects suspected of driving under the influence of drugs, the blood concentration of α-PVP ranged from 0.03 to >0.09 mg/L, but only 4 drivers reported side-effects consistent with those of synthetic cathinones [29].\n\nTo the best of our knowledge, although amphetamine and other illicit drugs have been sporadically detected in victims of sauna death [30], neither AADs in a sauna nor deaths in a sauna associated with use of α-PVP have been reported thus far.\n\nIn the present case, the sauna was electrical (as is generally the case in saunas located in residence buildings in Finland), and its heating was interrupted by a timer at the end of the final shift. As Finnish saunas are heated to 60–80 °C or more [31, 32], and the victim’s mother was sauna-bathing until 9:30 p.m. when the victim arrived at the sauna, the victim was likely exposed to significant heat prior his death, although the sauna had significantly cooled by the time the police arrived at the scene.\n\nDuring a Finnish sauna (temperature 80–100 °C, humidity 10–20%) the skin temperature rises within a few minutes to 40 °C, and the core temperature rises approximately 1 °C in 30 min, while the heart rate increases; heat is lost by increased cutaneous blood flow, vasodilatation, and sweating [32]. In most sauna deaths, a pre-existing cardiac disease or acute alcohol consumption, or both, represent the underlying or contributing cause of death [30, 31]. Exposure to sauna heat may also alter drug pharmacokinetics, especially for trans-dermally administered drugs such as nitroglycerine [32] and fentanyl (unpublished case). Medications and illicit drugs having a thermogenic effect (e.g. amphetamine-like drugs including synthetic cathinones), when associated with exposure to overheated environments and coupled with inadequate liquid intake, can impair body thermoregulatory mechanisms and lead to life-threatening hyperthermia [20, 33, 34]. Body temperatures up to 43.3 °C have been associated with such events as the use of MDMA (“ecstasy”) [33].\n\nIn the present case, the thermogenic effects of α-PVP and amphetamine, combined with sauna heat, likely caused a marked elevation of the victim’s body temperature. However, no PM diagnosis of hyperthermia was possible. Establishing hyperthermia as the cause of death at autopsy is indeed challenging, because changes are unspecific and occasional (brain and lung edema; cutaneous, pleural, pericardial petechiae), information on ambient temperature and on the victims’ rectal temperature at the scene is hardly available, and retrieval of victims in a sauna is often delayed. Diagnosis of death due to hyperthermia thus remains mostly one of exclusion, based on circumstantial and individual factors and the exclusion, at autopsy, of other causes of death [35–38].\n\nIt is likely that the victim described here took α-PVP before his sauna shift, while planning to engage in paraphilic activities, possibly foreseeing the drugs effects on heightening his sexual arousal. We are unaware whether this was the first time the victim had consumed drugs and engaged in sexual activities while having a sauna. The sympathomimetic effects of α-PVP and amphetamine, testified by the detection of myocardial contraction band necrosis [39] and the additive effects of α-PVP and amphetamine with sauna heat on the cardiovascular system and of dehydration, combined with an increasing body core temperature seemingly contributed to the fatal outcome. Moreover, respiratory depression caused by buprenorphine and enhanced by benzodiazepines, as well as the high levels of adrenaline associated with sexual activity, evoked by the sexual props found at the scene, may well have contributed to death. Buprenorphine, although found at a fairly high level, was not considered crucial, since the low buprenorphine to norbuprenorphine ratio did not suggest acute poisoning [40]. It can also be noted, as a matter of general prevention, that timer-regulated locking of a sauna door may delay first-aid intervention for solo sauna bathers who experience any acute incapacitating medical condition, although in our case this was not a relevant issue.\n\nIn conclusion, this case report highlights the risk of using allegedly safe designer drugs, for instance α-PVP, in a sauna, especially in association with other drugs and while engaging in sexual activity.\n\nKey points\n\nAutoerotic accidental deaths (AAD) result from mechanical asphyxia or can involve other types of sexual self-stimulation.\n\nWe describe a unique case of AADs during a sauna associated with use of α-PVP, amphetamine and other drugs.\n\nThe additive cardiovascular effects of α-PVP and amphetamine, sauna heat and dehydration contributed to the fatal outcome.\n\nIn saunas, using sympathomimetic and other drugs, especially while engaging in sexual activity can be life-threatening.\n\n\n\nPublisher’s note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n\nFunding Information\nOpen access funding provided by University of Turku (UTU) including Turku University Central Hospital.\n==== Refs\nReferences\n1. 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"keywords": "Amphetamine; Autoerotic death; Contraction band necrosis; Hyperthermia; Sauna; α-PVP",
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"mesh_terms": "D000661:Amphetamine; D001569:Benzodiazepines; D002047:Buprenorphine; D015198:Designer Drugs; D006801:Humans; D008297:Male; D008418:Masturbation; D008875:Middle Aged; D011759:Pyrrolidines; D012131:Respiratory Insufficiency; D029002:Steam Bath; D019966:Substance-Related Disorders",
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"pubdate": "2020-09",
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"title": "Fatal α-PVP and amphetamine poisoning during a sauna and autoerotic practices.",
"title_normalized": "fatal pvp and amphetamine poisoning during a sauna and autoerotic practices"
} | [
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"companynumb": "FI-ARBOR PHARMACEUTICALS, LLC-FI-2021ARB000486",
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"literaturereference": "LUNETTA P, KRIIKKU P, TIKKA J, OJANPERA I.. FATAL ??PVP AND AMPHETAMINE POISONING DURING A SAUNA AND AUTOEROTIC PRACTICES. FORENSIC SCI MED PATHOL. 2020?16:3:493?497",
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{
"abstract": "BACKGROUND\nCerebrovascular disorders have occurred more frequently in some Central Nervous System (CNS) disorders, such as epilepsy. Some CNS drugs have been associated with increased stroke risk. Our aim was to estimate the risk of ischaemic stroke in patients exposed to antiepileptic drugs (AED).\n\n\nMETHODS\nPopulation-based matched case-control study using SIDIAP database, based in electronic health records from primary healthcare from Catalonia, Spain. Cases were those patients with a registered diagnosis of first stroke during 2009-2014. Up to 10 controls were selected for each case and matched by sex, age, and geographic area and without a prior diagnosis of stroke. We considered global drug exposure to AED, past and current exposure and exposure in monotherapy to each AED.\n\n\nRESULTS\n2,865 cases and 19,406 controls were exposed to AED during the study period. Global exposure to levetiracetam [(ORadj3.3, CI95 % 2.8-4.0)], phenytoin [ORadj1.5, CI95 % 1.2-41.9)], and valproic acid [(ORadj 1.3, CI95 % 1.1-1.6)], showed significantly association to ischaemic stroke that was also maintained with current exposure of levetiracetam [ORadj4.1, CI95 % 3.3-5.2)] and valproic acid [ORadj1.4, CI95 % 1.1-1.9)]. Current levetiracetam monotherapy showed a very high risk of ischaemic stroke [(ORadj 5.1, CI95 % 3.7-6.9)].\n\n\nCONCLUSIONS\nDrugs used for other conditions than epilepsy (pregabalin, gabapentin) were the most used AED and both did not show a risk. Levetiracetam shows a risk for stroke even when assessed in current monotherapy. The lack of data regarding the link with diagnosis and severity in our study makes it necessary to conduct further studies to confirm or dismiss our results, focussing on levetiracetam.",
"affiliations": "Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Gran Via de les Corts Catalanes 587, àtic, 08007, Barcelona, Spain.;Unitat d'Epidemiologia, Servei de Cardiología, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, CIBERESP, Barcelona, Spain.;Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Gran Via de les Corts Catalanes 587, àtic, 08007, Barcelona, Spain. agomez@idiapjgol.info.;Fundació Institut Universitari per a la recerca a l'Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Gran Via de les Corts Catalanes 587, àtic, 08007, Barcelona, Spain.",
"authors": "Giner-Soriano|Maria|M|;Marsal|Josep Ramon|JR|;Gomez-Lumbreras|Ainhoa|A|;Morros|Rosa|R|",
"chemical_list": "D000927:Anticonvulsants",
"country": "England",
"delete": false,
"doi": "10.1186/s12883-021-02237-1",
"fulltext": "\n==== Front\nBMC Neurol\nBMC Neurol\nBMC Neurology\n1471-2377\nBioMed Central London\n\n2237\n10.1186/s12883-021-02237-1\nResearch\nRisk of ischaemic stroke associated with antiepileptic drugs: a population-based case-control study in Catalonia\nGiner-Soriano Maria 12\nMarsal Josep Ramon 3\nGomez-Lumbreras Ainhoa agomez@idiapjgol.info\n\n124\nMorros Rosa 125\n1 Fundació Institut Universitari per a la recerca a l’Atenció Primària de Salut Jordi Gol i Gurina (IDIAPJGol), Gran Via de les Corts Catalanes 587, àtic, 08007 Barcelona, Spain\n2 grid.7080.f Universitat Autònoma de Barcelona, Cerdanyola del Vallès Bellaterra, Spain\n3 grid.411083.f 0000 0001 0675 8654 Unitat d’Epidemiologia, Servei de Cardiología, Hospital Universitari Vall d’Hebron, Universitat Autònoma de Barcelona, CIBERESP, Barcelona, Spain\n4 grid.5319.e 0000 0001 2179 7512 Facultat de Medicina, Universitat de Girona, Girona, Spain\n5 grid.22061.37 0000 0000 9127 6969 Institut Català de la Salut, Barcelona, Spain\n24 5 2021\n24 5 2021\n2021\n21 20828 10 2020\n30 4 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\nCerebrovascular disorders have occurred more frequently in some Central Nervous System (CNS) disorders, such as epilepsy. Some CNS drugs have been associated with increased stroke risk. Our aim was to estimate the risk of ischaemic stroke in patients exposed to antiepileptic drugs (AED).\n\nMethods\n\nPopulation-based matched case-control study using SIDIAP database, based in electronic health records from primary healthcare from Catalonia, Spain. Cases were those patients with a registered diagnosis of first stroke during 2009–2014. Up to 10 controls were selected for each case and matched by sex, age, and geographic area and without a prior diagnosis of stroke. We considered global drug exposure to AED, past and current exposure and exposure in monotherapy to each AED.\n\nResults\n\n2,865 cases and 19,406 controls were exposed to AED during the study period. Global exposure to levetiracetam [(ORadj3.3, CI95 % 2.8-4.0)], phenytoin [ORadj1.5, CI95 % 1.2–41.9)], and valproic acid [(ORadj 1.3, CI95 % 1.1–1.6)], showed significantly association to ischaemic stroke that was also maintained with current exposure of levetiracetam [ORadj4.1, CI95 % 3.3–5.2)] and valproic acid [ORadj1.4, CI95 % 1.1–1.9)]. Current levetiracetam monotherapy showed a very high risk of ischaemic stroke [(ORadj 5.1, CI95 % 3.7–6.9)].\n\nConclusions\n\nDrugs used for other conditions than epilepsy (pregabalin, gabapentin) were the most used AED and both did not show a risk. Levetiracetam shows a risk for stroke even when assessed in current monotherapy. The lack of data regarding the link with diagnosis and severity in our study makes it necessary to conduct further studies to confirm or dismiss our results, focussing on levetiracetam.\n\nSupplementary Information\n\nThe online version contains supplementary material available at 10.1186/s12883-021-02237-1.\n\nKeywords\n\nAntiepileptic drugs\nStroke\nDrug exposure\nElectronic health records\nPrimary healthcare\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nStroke is the second leading cause of death worldwide [1]. There are four types: ischaemic stroke, primary intracerebral haemorrhage, subarachnoid haemorrhage and undefined, being the ischaemic type the most frequent one (80–85 %) in Caucasian population [2, 3]. Stroke patients are at highest risk of death in the first weeks after the event, and between 20 and 50 % die within the first month depending on type, severity, age, comorbidity and effectiveness of treatment of complications. Those who survive can remain with or without disabilities, such as loss of speech and movement, making strokes the third cause of disability [1]. Over the last decades the total number of age-standardized rates of stroke mortality have decreased meanwhile stroke survivors have made the burden of stroke Disability-Adjusted Life Year (DALY lost) increase [2].\n\nThe pooled proportional frequency of ischaemic stroke in 2000–2008 was lower in low to middle income countries than in high-income countries (67 and 82 %, respectively) [2]. In high income countries in 2000–2008, early (21 days to 1 month) case fatality was between 13 and 23 %, [2] being in Catalonia mortality rate standardized by age 29.2 deaths/100,000 inhabitants in 2016 [4].\n\nThe most important modifiable risk factors for ischaemic stroke are hypercholesterolemia, hypertension, diabetes and smoking [5, 6].\n\nCerebrovascular disorders have occurred more frequently in some Central Nervous System (CNS) disorders, such as epilepsy [7–10] and also some CNS drugs have been reported to increase the risk for stroke, such as antidepressants, [11] anti-dementia drugs, [12] antipsychotics [13, 14] or antiepileptic drugs (AED) [15–17]. The mechanism suggested for AED is that they would increase risk of vascular diseases by accelerating atherosclerosis; for example cytochrome P450 enzyme-inducing AED as carbamazepine increase serum levels of total cholesterol and LDL-cholesterol and lipoprotein [16]. Concurrently, AED are often administered after a stroke to treat seizures or other conditions [18–20].\n\nAs there has been an increase in the chronic use of AED, on account of its use for the treatment of diseases different from epilepsy, like chronic neuropathic pain, migraine, anxiety and as mood stabilizers, [21] we think it is relevant to confirm if the risks detected in other studies are confirmed in our population. The aim of this study was to estimate the risk of ischaemic stroke in patients exposed to AED.\n\nMethods\n\nStudy design\n\nPopulation-based matched case-control study using data from primary healthcare (PHC) electronic records.\n\nStudy source\n\nInformation System for Research in Primary Care (SIDIAP) database; which contains data from 279 PHC centres from the Catalan Health Institute (ICS), covering 5.8 million people (80 % of the Catalan population) [22]. SIDIAP contains anonymized clinical information originated from different data sources: (1) ECAP (electronic health records in PHC of the ICS), including information since 2006 on sociodemographic characteristics, health conditions registered as International Classification Diseases Tenth Revision (ICD-10) [23] code, general practitioners’ (GP) prescriptions, clinical parameters and toxic habits, (2) laboratory data, (3) pharmacy invoice data corresponding to GP’s prescriptions (available since 2005) including information on all pharmaceutical products dispensed by communities pharmacies with Catalan Health System prescriptions by Anatomic Therapeutic and Chemical (ATC) [24] codes, and 4), Minimum Data Set at Hospital Discharge (CMBD-HA) [25] database for ICS hospitals, including diagnoses at hospital discharge registered as International Classification Diseases, Ninth Revision (ICD-9) codes [26].\n\nSelection of cases and controls\n\nCases were those patients ≥ 18 years old suffering a first ischaemic stroke (CMBD-HA hospital admission ICD 9th codes: 433, 434, 435, 436, 437, 438) during 2009–2014 attended in hospitals from the ICS in Catalonia, Spain. Index date was the day of hospital admission for a stroke from January 2009 to December 2014.\n\nA total of 10 controls were selected for each case, and matched by sex, age (+/- 1 year), geographic area and without previous diagnosis of stroke; any historic record of stroke before the selection year caused the exclusion as a control. The index date for controls was the same than for their respective case.\n\nVariables\n\nAge, sex, socioeconomic index (MEDEA) [27], body mass index (BMI), smoking status, alcohol intake, comorbidities, cardiovascular risk (classified as high, moderate, low or no risk), laboratory data including glomerular filtration rate (GFR) calculated per MDRD (Modification of Diet in Renal Disease), drug exposure and number of visits in PHC during the previous year to the index date.\n\nPatients diagnosed with ischaemic heart disease and/or peripheral artery disease and/or diabetes with complications were classified with a high cardiovascular risk. Among the unclassified patients in the high category, those with uncomplicated diabetes, treatment with antidiabetic drugs or two or three of the following diagnoses: dyslipidaemia, hypertension, and smoking (active or ex-smoking) were classified as moderate cardiovascular risk. Patients who were not classified in any category were considered to be at low cardiovascular risk (divided into two groups: very low cardiovascular risk if no risk factors registered and low cardiovascular risk if one risk factor registered).\n\nExposure definition\n\nThe drugs of interest were antiepileptics, N03A from the ATC classification. Information of exposure was obtained from GP’s prescriptions and pharmacy invoice data. Current comedications before index date were also collected: anticoagulants, antiplatelets, diabetes and cardiac therapy, lipid modifying agents, hormonal contraceptives, non-steroidal anti-inflammatory drugs (NSAID), analgesics, and psychotropic drugs.\n\nAs first SIDIAP registers begin in 2005, a minimum period of four years was selected in order to assess the AED exposure.\n\nWe considered drug exposure when there was a dispensation of at least three packages of an active substance of any of the study drugs (AED) during the study period. Past exposure was considered if the dispensation had taken place more than one year before the index date. Current exposure was considered if patients had at least one dispensation within the three months before the index date. Trying to avoid indication bias, patients with one dispensation within the same month of the index date were excluded for the current exposure analysis. Also, current exposure to only one AED was also ascertained as monotherapy exposure.\n\nPopulation size\n\nFor the study period SIDIAP had around 40,000 patients with a new stroke diagnosis registered. As CMBD-HA represents about a third of the SIDIAP total population (ICS hospitals and their primary care referral areas), we aimed to include approximately 12,000 cases. Assuming that the prevalence of exposure to the studied factors would be 1 % higher in cases, the available sample size would allow for detecting significant associations with OR ≥ 1.3 with a type I error of 5 % and an 80 % power.\n\nStatistical analysis\n\nWe conducted multivariate models of conditional logistic regression, and we calculated crude and adjusted odds ratios (OR, ORadj) and their 95 % confidence interval (CI 95 %). The crude model adjusted by age, sex, year of the index date and cardiovascular risk. The variables used in the adjusted model were: age, sex, year of the index date, MEDEA index, BMI, smoking status, number of visits to PHC, GFR, and diagnoses of: arthrosis, dementia, depression, diabetes, dyslipidaemia, epilepsy, fibromyalgia, hypertension, ischaemic heart disease, neuropathy, peripheral arterial disease and gastrointestinal ulcer. Co-treatments (insulin, antihypertensive drugs, NSAID…) and all study drugs included were added in this model.\n\nWe estimated the crude and adjusted effects of the current, past and global exposure to AED, and the effect of each AED for patients exposed in monotherapy.\n\nResults\n\nA total of 137,880 patients were included in the study; they were 12,616 cases with a first ischaemic stroke during 2009–2014 matched by sex, age and geographical region with 125,264 controls with no stroke history (Fig. 1). There were 56.3 % of men and their mean age was 72.6 (SD 13.2). Their baseline sociodemographic and clinical characteristics are described in Table 1 and their comedications at baseline, in Table 2. Cases and controls were different in most baseline characteristics highlighting the neuromental illness such as dementia (cases n = 828, 6.6 % and controls n = 6075, 4.8 %,), depression (853, 6.8 6870, 5.5) and epilepsy (cases n = 207, 1.6 % and controls n = 843, 0.7 %) and also in their ischaemic heart disease history (cases n = 1745, 13.8 % and controls n = 9656, 7.7 %), all statistically significant (p < 0,001). Also, the comedications at baseline showed differences (cardiac therapy for cases n = 2448, 19.4 % and for controls n = 15,565, 12.4 % and insulins cases n = 1276, 10.1 % and controls n = 4796, 3.8 %) but not for antidementia drugs (cases n = 2020, 16.0 % and controls n = 20,451, 16.3 %) and coxibs and oxicams (cases n = 2020, 16.0 % and controls n = 20,451, 16.3 %). Fig. 1 Study flowchart\n\nTable 1 Sociodemographic and clinical characteristics at baseline of patients exposed to Central Nervous System drugs\n\nN, %\tTotal N = 137,880\tCases N = 12,616\tControls N = 125,264\tp-value\t\nMean age, SD\t72.6, 13.2\t72.9, 13.2\t72.6, 13.2\t0.009\t\nSex, female\t60216, 43.7\t5486, 43.5\t54730, 43.7\t0.658\t\nN visits in PHC\t\nMissing values\t15165, 11.0\t682, 5.4\t14483, 11.6\t<0.001\t\n<5\t27055, 22.0\t1860, 15.6\t25195, 22.7\t<0.001\t\n5-9\t33155, 27.0\t2460, 20.6\t30695, 27.7\t\t\n10-24\t46191, 37.6\t4837, 40.5\t41354, 37.3\t\n≥25\t16314, 13.3\t2777, 23.3\t13537, 12.2\t\nSmoking status\t\nMissing values\t18895, 13.7\t1294, 10.3\t17601, 14.1\t<0.001\t\nCurrent smokers\t16172, 13.6\t2020, 17.8\t14152, 13.1\t<0.001\t\nBMI mean, SD\t28.9, 4.7\t28.8, 4.9\t28.9, 4.7\t0.273\t\nMissing values\t78443, 56.9\t6610, 52.4\t71833, 57.3\t<0.001\t\nObesity\t21708, 36.5\t2180, 36.3\t19528, 36.5\t<0.001\t\nMEDEA\t\t\t\t<0.001\t\nU\t8431, 6.1\t1216, 9.6\t7215, 5.8\t\nR\t25909, 18.8\t2343, 18.6\t23566, 18.8\t\nU1-U3\t58111, 42.1\t4955, 39.3\t53156, 42.4\t\nU4-U5\t45429, 32.9\t4102, 32.5\t41327, 33.0\t\nGFR\t\nMissing values\t56401, 40.9\t4186, 33.2\t52215, 41.7\t<0.001\t\n<30 mL/min/1.73m2\t1599, 2.0\t311, 3.7\t1288, 1.8\t<0.001\t\n30-44\t5357, 6.6\t802, 9.5\t4555, 6.2\t\t\n45-59\t12751, 15.6\t1568, 18.6\t11183, 15.3\t\n≥60\t61772, 75.8\t5749, 68.2\t56023, 76.7\t\nCardiovascular risk, high\t14978, 10.9\t2511, 19.9\t12467, 10.0\t<0.001\t\nComorbidities\t\nAnxiety\t12792, 9.3\t1177, 9.3\t11615, 9.3\t0.836\t\nArthrosis\t31921, 23.2\t2823, 22.4\t29098, 23.2\t0.031\t\nCancer\t24479, 17.8\t2306, 18.3\t22173, 17.7\t0.106\t\nCOPD\t16594, 12.0\t1822, 14.4\t14772, 11.8\t<0.001\t\nDementia\t6903, 5.0\t828, 6.6\t6075, 4.8\t<0.001\t\nDepression\t7723, 5.6\t853, 6.8\t6870, 5.5\t<0.001\t\nDiabetes\t29158, 21.1\t3890, 30.8\t25268, 20.2\t<0.001\t\nDyslipidaemia\t52057, 37.8\t5007, 39.7\t47050, 37.6\t<0.001\t\nEpilepsy\t1050, 0.8\t207, 1.6\t843, 0.7\t<0.001\t\nFibromyalgia\t1266, 0.9\t124, 1.0\t1142, 0.9\t<0.001\t\nHypertension\t73250, 53.1\t7626, 60.4\t65624, 52.4\t<0.001\t\nIschaemic heart disease\t11401, 8.3\t1745, 13.8\t9656, 7.7\t<0.001\t\nNeuropathies\t5067, 3.7\t575, 4.6\t4492, 3.6\t<0.001\t\nPeripheral artery disease\t3888, 2.8\t916, 7.3\t2972, 2.4\t<0.001\t\nUlcers\t4274, 3.1\t444, 3.5\t3830, 3.1\t0.005\t\nSD standard deviation, PHC primary healthcare, BMI body mass index, MEDEA socioeconomic index, (U unknown urban area, U# urban areas), R rural area, GFR glomerular filtration rate, COPD chronic obstructive pulmonary disease\n\nTable 2 Comedications at baseline of patients exposed to Nervous System drugs\n\nN, %\tTotal\nN = 137,880\tCases\nN = 12,616\tControls\nN = 125,264\tp-value\t\nAcetic acid derivatives\t58,208, 42.2\t5652, 44.8\t52,556, 42.0\t< 0.001\t\nAnalgesics (metamizol and paracetamol)\t109,801, 79.6\t10,771, 85.4\t99,030, 79.1\t< 0.001\t\nAnti-dementia agents\t8907, 6.5\t861, 6.8\t8046, 6.4\t0.080\t\nAntidepressants\t39,851, 28.9\t4465, 35.4\t35,386, 28.2\t< 0.001\t\nAntihypertensive agents\t3774, 2.7\t576, 4.6\t3198, 2.6\t< 0.001\t\nAntithrombotic drugs\t39,951, 29.0\t8613, 68.3\t31,338, 25.0\t< 0.001\t\nAntipsychotics\t20,024, 14.5\t2361, 18.7\t17,663, 14.1\t< 0.001\t\nAnxiolytics\t62,234, 45.1\t6536, 51.8\t55,698, 44.5\t< 0.001\t\nBeta-blockers\t18,022, 13.1\t2864, 22.7\t15,158, 12.1\t< 0.001\t\nBlood glucose-lowering drugs\t20,733, 15.0\t2896, 23.0\t17,837, 14.2\t< 0.001\t\nCalcium channel-blockers\t18,013, 13.1\t2448, 19.4\t15,565, 12.4\t< 0.001\t\nCardiac therapy\t13,233, 9.6\t2251, 17.8\t10,982, 8.8\t< 0.001\t\nCoxibs and oxicams\t22,471, 16.3\t2020, 16.0\t20,451, 16.3\t0.369\t\nDiuretics\t28,656, 20.8\t3794, 30.1\t24,862, 19.8\t< 0.001\t\nGastrointestinal tract\t2505, 1.8\t491, 3.9\t2014, 1.6\t< 0.001\t\nHypnotics and sedatives\t23,208, 16.8\t2607, 20.7\t20,601, 16.4\t< 0.001\t\nInsulins\t6072, 4.4\t1276, 10.1\t4796, 3.8\t< 0.001\t\nLipid-modifying agents\t42,897, 31.1\t6119, 48.5\t36,778, 29.4\t< 0.001\t\nOpioids (phentanil, buprenorphine and tramadol)\t33,489, 24.3\t3672, 29.1\t29,817, 23.8\t< 0.001\t\nPropionic acid derivatives\t93,012, 67.5\t8839, 70.1\t84,173, 67.2\t< 0.001\t\nPsychostimulants, ADHD-agents and nootropics\t11,948, 8.7\t1390, 11.0\t10,558, 8.4\t< 0.001\t\nRenin-angiotensin agents\t54,778, 39.7\t6657, 52.8\t48,121, 38.4\t< 0.001\t\nOther anti-inflammatories (glucosamine and chondroitin sulphate)\t17,342, 12.6\t1433, 11.4\t15,909, 12.7\t< 0.001\t\nADHD attention deficit hyperactivity disorder\n\nDuring the study period 2,865 (22.7 %) cases were exposed to AED (ATC classification N03) and 19,406 (15.5 %) were controls. Cases were more frequently exposed to all AED than controls (Table 3), except for pregabalin (38.4 % cases vs. 44.4 % controls exposed, p < 0.001). The drugs with the highest proportions of patients exposed were pregabalin (8,861 39.8 %) and gabapentin (9,720 43.6 %). Table 3 Exposure to antiepileptic drugs\n\nN, %\tTotal N = 22,271\tCases N = 2,865\tControls N = 19,406\tp-value\t\nCarbamazepine exposure\t1238, 5.6\t169, 5.9\t1069, 5.5\t0.407\t\nCurrent exposure\t321, 1.4\t52, 1.8\t269, 1.4\t\nPast exposure\t202, 0.9\t32, 1.1\t170, 0.9\t\nMonotherapy\t140, 0.6\t15, 0.5\t125, 0.6\t\nClonazepam\t4675, 21.0\t570, 19.9\t4105, 21.2\t0.128\t\nCurrent\t1089, 4.9\t135, 4.7\t954, 4.9\t\nPast\t1019, 4.6\t124, 4.3\t895, 4.6\t\nMonotherapy\t525, 2.4\t52, 1.8\t473, 2.4\t\nGabapentin\t8861, 39.8\t1138, 39.7\t7723, 39.8\t0.951\t\nCurrent\t1814, 8.1\t296, 10.3\t1518, 7.8\t\nPast\t1994, 9.0\t244, 8.5\t1750, 9,0\t\nMonotherapy\t1060, 4.8\t177, 6.2\t883, 4.6\t\nLamotrigine\t575, 2.6\t94, 3.3\t481, 2.5\t0.012\t\nCurrent\t191, 0.9\t38, 1.3\t153, 0.8\t\nPast\t146, 0.7\t21, 0.7\t125, 0.6\t\nMonotherapy\t72, 0.3\t14, 0.5\t58, 0.3\t\nLevetiracetam\t654, 2.9\t231, 8.1\t423, 2.2\t<0.001\t\nCurrent\t383, 1.7\t166, 5.8\t217, 1.1\t\nPast\t62, 0.3\t10, 0.3\t52, 0.3\t\nMonotherapy\t187, 0.8\t90, 3.1\t97, 0.5\t\nOxcarbazepine\t556, 2.5\t83, 2.9\t473, 2.5\t0.137\t\nCurrent\t149, 0.7\t27, 0.9\t122, 0.6\t\nPast\t131, 0.6\t20, 0.7\t111, 0.6\t\nMonotherapy\t66, 0.3\t11, 0.4\t55, 0.3\t\nPhenobarbital\t520, 2.3\t85, 3.0\t435, 2.2\t0.018\t\nCurrent\t205, 0.9\t39, 1.4\t166, 0.9\t\nPast\t124, 0.6\t28, 1.0\t96, 0.5\t\nMonotherapy\t58, 0.3\t10, 0.3\t48, 0.2\t\nPhenytoin\t610, 2.7\t128, 4.5\t482, 2.5\t<0.001\t\nCurrent\t232, 1.0\t49, 1.7\t183, 0.9\t\nPast\t121, 0.5\t25, 0.9\t96, 0.5\t\nMonotherapy\t96, 0.4\t17, 0.6\t79, 0.4\t\nPregabalin\t9720, 43.6\t1100, 38.4\t8620, 44.4\t<0.001\t\nCurrent\t1829, 8.2\t239, 8.3\t1590, 8.2\t\nPast\t2586, 11.6\t285, 9.9\t2301, 11.9\t\nMonotherapy\t1058, 4.8\t119, 4.2\t939, 4.8\t\nTopiramate\t1088, 4.9\t168, 5.9\t920, 4.7\t0.010\t\nCurrent\t176, 0.8\t36, 1.3\t140, 0.7\t\nPast\t285, 1.3\t45, 1.6\t240, 1.2\t\nMonotherapy\t77, 0.3\t9, 0.3\t68, 0.4\t\nValproic acid\t1037, 4.7\t192, 6.7\t845, 4.4\t<0.001\t\nCurrent\t367, 1.6\t92, 3.2\t275, 1.4\t\nPast\t214, 1.0\t28, 1.0\t186, 1.0\t\nMonotherapy\t175, 0.8\t39, 1.4\t136, 0.7\t\n\nThe effect of the AED exposure was adjusted for different baseline variables for the regression models (Fig. 2). Global exposure to AED showed a risk of 1.06 (95 % CI 0.99–1.13, p = 0.057) of ischaemic stroke and above all, the exposure to levetiracetam [(ORadj 3.3 CI95 % 2.8-4)], phenytoin [(ORadj 1.5 CI95 % 1.2–1.9)] and valproic acid [(ORadj 1.3 CI95 % 1.1–1.6)] did. Past exposure to lamotrigine [(ORadj 1.6 CI95 % 1.5–1.7)], phenobarbital [(ORadj 2.1 CI95 % 1.3–3.2)] and phenytoin [(ORadj 1.6 CI95 % 1-2.5)] showed a risk but only levetiracetam [(ORadj 4.1 CI95 % 3.3–5.2)] and valproic acid [(ORadj 1.4 CI95 % 1.1–1.9)] showed it when assessing current use. When the effect of AED in monotherapy was analysed, only levetiracetam (ORadj 5.1 CI95 % 3.7–6.9) was associated with a high risk of ischaemic stroke. Fig. 2 Risk of ischaemic stroke according to different exposures to antiepileptic drugs\n\nDiscussion\n\nMost studies assessing risk of stroke with use of AED were cohort studies which did not analyse different times of exposure as in our study, our research analyse global, past, current and current monotherapy exposures through a case-control design. We found that global exposure to AED was not significantly associated to ischaemic stroke (OR 1.06, CI95 % 0.998–1.128) [8–17].\n\nAmong the classic AED (phenobarbital, phenytoin, valproic acid, carbamazepine and clonazepam) only the exposure to phenytoin and valproic acid showed a risk for ischaemic stroke that was even higher for current exposure in the case of valproic acid. The highest risk for these classics was for the old phenobarbital past exposure showing an adjusted risk of 2.0 (CI95 % 1.3–3.2). Regarding phenytoin and valproic acid, they demonstrated higher risk of stroke when compared to carbamazepine in the study of Hsieh et al. [16]. A pharmacokinetic explanation, regarding the role as potent inducers of cytochrome P450 enzymes (involved in cholesterol synthesis) of carbamazepine or phenytoin could substantially increase the risk of cardiovascular and cerebrovascular disease [28]. When compared to the new AED, only past exposure to lamotrigine (ORadj 1.6 CI95 % 1.5–1.7) showed a risk for stroke. Renoux et al. analysing the past exposure to AED did not find an increased risk of ischaemic stroke (RR 0.89, CI95 % 0.78–1.01) [15]. In the case of those AED which were associated to an increased risk of stroke for the past exposure but not for the current, we are not able to conclude if this higher risk was caused by the epilepsy itself or by the drug exposure [7, 18, 19, 29].\n\nNevertheless, measuring current exposure to AED may be more accurate in order to assess the real increase of risk of ischaemic stroke caused by these drugs. In our study, levetiracetam exposure was associated with the highest risk of stroke [OR adj 3.3 (CI95 % 2.8- 4.0)] even higher when assessing monotherapy exposure [OR adj 5.1 (CI95 % 3.7–6.9] was assessed. Levetiracetam shows a risk for stroke when handle the indication bias taken only first incident stroke cases excluding prescriptions in the same month of the index date. To be considered that levetiracetam is used for the most severe and for refractory epilepsies when other AED fail, information not available in our database, what could address a risk of the epilepsy itself. We have not found any studies with similar results for levetiracetam. Deeper studies have to be conducted, analysing the AED indications what could be relevant to support our results.\n\nClonazepam is a benzodiazepine usually used as an “add-on” medication for people who continue to have seizures while taking other seizure medicines. Not having diagnosis linked to its prescription can refer to its use for psychiatric disorders and not really to prevent seizures. It can also be prescribed as “if needed” which wouldn’t reflect its use.\n\nThe AED studied with higher prevalence of use in our population were gabapentin and pregabalin, drugs which have other indications with a more frequent use than epilepsy; both are authorized for neuropathic pain and pregabalin is also authorized to treat anxiety disorders, which are more prevalent disorders than epilepsy. None of these drugs show a risk for stroke for the different exposures estimated.\n\nAmong AED those with a mainly use in our country for epilepsy, phenytoin and valproic acid, showed a global risk [OR adj 1.5 (CI95 % 1.2–1.9)] [OR adj 1.34 (CI95 % 1.1–1.6)] which are not maintained in the past exposures meanwhile lamotrigine and phenobarbital showed a risk for the past exposure [OR adj 1.58 (CI95 % 1.5–1.7) and OR adj 2.08 (CI95 % 1.3–3.2) respectively], thus we cannot rule out that the epilepsy itself is increasing stroke risk.\n\nOne of the main limitations of our data is the lack of association between a drug prescription and a diagnosis registered, or the lack of registry of the severity of epilepsy. We cannot know the diagnosis which led to the AED prescription, not only seizures but also the possibility of other diagnosis that could lead to AED prescription such as tumour, hypoxia, and neuropathic pain, among others. The main cause of seizures in the elderly is stroke (52.3 %), [30] what can point to an indication bias in our study, we have even tried to handle it by excluding those patients a first stroke episode and excluding those AED prescriptions in the same month of the index date. There are no diagnostic images available in our database, so we were not able to examine a possible ischemic lesion by imaging study in either the controls or the cases, thus, this remains as a limitation inherent to our study.\n\nConclusions\n\nDrugs used for other conditions than epilepsy were the most used AED (pregabalin, gabapentin). They didn’t show a risk for stroke.\n\nAn inherent risk of the epileptic condition for stroke cannot be dismissed with the present study results, but no link between drugs and diagnosis in our database made this a limitation in our research.\n\nLevetiracetam shows a risk for stroke global exposure, current and also monotherapy.\n\nEven our effort for handling the indication bias the lack of data regarding the diagnosis, severity and kind of epilepsy for it use should be address with further research focus on this active substance.\n\nSupplementary Information\n\nAdditional file 1: Table S1. Multivariate model.\n\nAbbreviations\n\nAED Antiepileptic drugs\n\nATC Anatomic Therapeutic and Chemical\n\nBMI Body mass index\n\nCI Confidence interval\n\nCMBD-HA Minimum Data Set at Hospital Discharge\n\nCNS Central Nervous System\n\nDALY Disability-Adjusted Life Year\n\nECAP Electronic health records in Primary healthcare\n\nGFR Glomerular filtration rate\n\nGP General Practitioner\n\nICD International Classification of Diseases\n\nICS Catalan Health Institute\n\nMDRD Modification of diet in renal disease\n\nMEDEA Socioeconomic index\n\nNSAID Non-steroidal anti-inflammatory drugs\n\nOR Odds ratio\n\nPHC Primary healthcare\n\nSD Standard deviation\n\nSIDIAP Information system for research in primary care\n\nAuthors’ contributions\n\nRosa Morros and Josep Ramon Marsal designed the study, Josep Ramon Marsal conducted the statistical analysis, all authors interpreted the results, Maria Giner-Soriano and Ainhoa Gomez-Lumbreras wrote the manuscript, all authors reviewed and approved the manuscript.\n\nFunding\n\nThis study has been funded by Bioibérica S.A.\n\nAvailability of data and materials\n\nAll datasets are available at request to the corresponding author.\n\nEthics approval and consent to participate\n\nThe present study follows national and international regulations: Declaration of Helsinki Ethical Principles for Medical Research Involving Human Subjects and Good Research Practice principles and guidelines. The study protocol has been approved by the Clinical Ethics Committee at IDIAPJGol, the reference institution for research in Primary Health Care of the ICS. Regarding the data contained in the databases and according to General Data Protection Regulation EU 2016/679, data included in SIDIAP are always anonymized. Thus, it is not necessary to ask for informed consent from the participants and so was waived by the Clinical Ethics Committee at IDIAPJGol.\n\nConsent for publication\n\nNot applicable.\n\nCompeting interests\n\nThe authors declare that they have no competing interests.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. Johnson W Onuma O Owolabi M Sachdev S Stroke: a global response is needed Bull World Health Organ 2016 94 634-634A 10.2471/BLT.16.181636 27708464\n2. 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Bohlken J Weber S Rapp MA Kostev K Continuous treatment with antidementia drugs in Germany 2003–2013: A retrospective database analysis Int Psychogeriatrics 2015 27 1335 42 10.1017/S1041610215000654\n13. Gareri P, Segura-García C, Manfredi VG, Bruni A, Ciambrone P, Cerminara G, De Sarro G, De Fazio P. Use of atypical antipsychotics in the elderly: a clinical review. Clin Interv Aging. 2014;9:1363–73.\n14. Zivkovic S, Koh CH, Kaza N, et al. Antipsychotic drug use and risk of stroke and myocardial infarction: a systematic review and meta-analysis. BMC Psychiatry 2019;19:189.\n15. Renoux C, Dell’Aniello S, Saarela O, Filion KB, Boivin JF. Antiepileptic drugs and the risk of ischaemic stroke and myocardial infarction: A population-based cohort study. BMJ Open. 2015;5(8):e008365.\n16. Hsieh C-Y Lai EC-C Yang Y-HK Lin S-J Comparative stroke risk of antiepileptic drugs in patients with epilepsy Epilepsia 2013 54 172 80 10.1111/j.1528-1167.2012.03693.x 23030457\n17. Olesen JB Abildstrøm SZ Erdal J Gislason GH Weeke P Andersson C Effects of epilepsy and selected antiepileptic drugs on risk of myocardial infarction, stroke, and death in patients with or without previous stroke: a nationwide cohort study Pharmacoepidemiol Drug Saf. 2011 20 964 71 10.1002/pds.2186 21766386\n18. Hassani M Cooray G Sveinsson O Cooray C Post-stroke epilepsy in an ischemic stroke cohort—Incidence and diagnosis Acta Neurol Scand 2020 141 141 7 10.1111/ane.13174 31580473\n19. Yang H Rajah G Guo A Wang Y Wang Q Pathogenesis of epileptic seizures and epilepsy after stroke Neurol Res 2018 40 426 32 10.1080/01616412.2018.1455014 29681214\n20. Hanaya R Arita K The new antiepileptic drugs: Their neuropharmacology and clinical indications Neurol Med Chir (Tokyo) 2016 56 205 20 10.2176/nmc.ra.2015-0344 26935782\n21. Agencia Española de Medicamentos y Productos Sanitarios. Utilización de medicamentos antiepilépticos en España durante el periodo 2008–2016. 2017.\n22. SIDIAP. Information System for Research in Primary Care CatalanCASpanishESEnglish (UK).\n23. WHO. ICD-10 Version: 2019. International Statistical Classification of diseases and Related Health Problems 10th Revision. 2019. https://icd.who.int/browse10/2019/en. Accessed 24 Apr 2020.\n24. WHO Collaborating Centre for Drug Statistics Methodology. ATC/DDD Index 2019. 2019. https://www.whocc.no/atc_ddd_index/. Accessed 14 Aug 2020.\n25. CatSalut. Servei Català de la Salut. Conjunt mínim bàsic de dades (CMBD). 2019. http://catsalut.gencat.cat/ca/proveidors-professionals/registres-catalegs/registres/cmbd/. Accessed 26 Nov 2020.\n26. Ministerio de Sanidad PS e I. CIE9. https://eciemaps.mscbs.gob.es/ecieMaps/browser/index_9_mc.html.\n27. Domínguez-Berjón M Borrell C Cano-Serral G Esnaola S Nolasco A Pasarin M Construcción de un índice de privación a partir de datos censales en grandes ciudades españolas (Proyecto MEDEA) Gac Sanit 2008 22 179 87 10.1157/13123961\n28. Mintzer S Skidmore CT Abidin CJ Morales MC Chervoneva I Capuzzi DM Effects of antiepileptic drugs on lipids, homocysteine, and C-reactive protein Ann Neurol 2009 65 448 56 10.1002/ana.21615 19296463\n29. Feyissa AM Hasan TF Meschia JF Stroke-related epilepsy Eur J Neurol 2019 26 18-e3 10.1111/ene.13813 30320425\n30. Leppik IE Status epilepticus in the elderly Epilepsia 2018 59 140 3 10.1111/epi.14497 30159881\n\n",
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"abstract": "Freezing of gait (FOG) is a common, disabling gait disturbance in Parkinson's disease (PD) and other Parkinsonian syndromes. Freezing also occurs during non-gait movements involving the upper limbs. The mechanisms underlying freezing are complex, likely involving motor, cognitive, and sensory systems that contribute to the episodes. Here, we reported a 60-year-old female with a 24-year history of parkinsonism who experienced significant FOG when ambulatory. Disease progression resulted in her permanent use of a powered wheelchair. While using the power chair, the patient experiences apparent paroxysmal freezing in the hand and arm used to steer and propel the chair. These episodes, some lasting up to several minutes, occur only in circumstances (e.g., entering and leaving an elevator) that are similar to environments known to elicit and exacerbate FOG. Episodes are transient and can be volitionally interrupted by the patient but sometimes require external assistance. Therapeutic intervention for this type of potential freezing has yet to be determined. This case may provide insight into the complex nature of freezing behavior and suggests a need for new approaches to treating non-traditional freezing behavior.",
"affiliations": "Program in Physical Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.;Program in Physical Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.;Program in Physical Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.;Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.;Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA.",
"authors": "Nemanich|Samuel T|ST|;McNeely|Marie E|ME|;Earhart|Gammon M|GM|;Norris|Scott A|SA|;Black|Kevin J|KJ|",
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"fulltext": "\n==== Front\nFront NeurolFront NeurolFront. Neurol.Frontiers in Neurology1664-2295Frontiers Media S.A. 10.3389/fneur.2017.00205NeuroscienceCase ReportA Case of Apparent Upper-Body Freezing in Parkinsonism while Using a Wheelchair Nemanich Samuel T. 1McNeely Marie E. 12Earhart Gammon M. 123Norris Scott A. 2Black Kevin J. 2345*1Program in Physical Therapy, Washington University School of Medicine in St. Louis, St. Louis, MO, USA2Department of Neurology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA3Department of Neuroscience, Washington University School of Medicine in St. Louis, St. Louis, MO, USA4Department of Radiology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA5Department of Psychiatry, Washington University School of Medicine in St. Louis, St. Louis, MO, USAEdited by: Marco Schieppati, University of Pavia, Italy\n\nReviewed by: Bettina H. Debû, Université Grenoble Alpes, France; Matthieu P. Boisgontier, KU Leuven, Belgium; Daniel Weiss, University of Tübingen, Germany\n\n*Correspondence: Kevin J. Black, kevin@wustl.eduSpecialty section: This article was submitted to Movement Disorders, a section of the journal Frontiers in Neurology\n\n15 5 2017 2017 8 20507 12 2016 27 4 2017 Copyright © 2017 Nemanich, McNeely, Earhart, Norris and Black.2017Nemanich, McNeely, Earhart, Norris and BlackThis 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) or licensor 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.Freezing of gait (FOG) is a common, disabling gait disturbance in Parkinson’s disease (PD) and other Parkinsonian syndromes. Freezing also occurs during non-gait movements involving the upper limbs. The mechanisms underlying freezing are complex, likely involving motor, cognitive, and sensory systems that contribute to the episodes. Here, we reported a 60-year-old female with a 24-year history of parkinsonism who experienced significant FOG when ambulatory. Disease progression resulted in her permanent use of a powered wheelchair. While using the power chair, the patient experiences apparent paroxysmal freezing in the hand and arm used to steer and propel the chair. These episodes, some lasting up to several minutes, occur only in circumstances (e.g., entering and leaving an elevator) that are similar to environments known to elicit and exacerbate FOG. Episodes are transient and can be volitionally interrupted by the patient but sometimes require external assistance. Therapeutic intervention for this type of potential freezing has yet to be determined. This case may provide insight into the complex nature of freezing behavior and suggests a need for new approaches to treating non-traditional freezing behavior.\n\nParkinson’s diseasehypokinesiaupper-limb freezingfreezingakinesiaNational Institutes of Health10.13039/100000002UL1TR000448American Parkinson Disease Association10.13039/100006309APDA Advanced Center for PD Research\n==== Body\nIntroduction\nFreezing of gait (FOG) is a common and disabling motor symptom of Parkinson’s disease (PD) and other Parkinsonian conditions. FOG is defined as a “brief, episodic absence or marked reduction of forward progression of the feet despite the intention to walk” (1). Approximately half of people with PD will experience FOG as the disease progresses (2). While it is typically associated with greater disease duration and dose of levodopa medication, FOG can affect some individuals earlier in the disease course (3). The health-related impact of FOG is concerning. FOG is associated with an increased risk of falling (4, 5), reduced quality of life (6), and cognitive impairment (7, 8). While pharmacologic and surgical treatment can alleviate freezing episodes in some patients, others continue to exhibit freezing behavior despite optimal treatment with these therapies (9, 10). These observations suggest that FOG may involve non-dopaminergic systems (3), but the causal pathways remain poorly understood.\n\nWhile freezing predominantly affects walking and stepping, recent work showed that freezing can affect non-gait motor systems as well (11). These data indicate that similar freezing can occur during upper-limb and finger movements (12–14), as well as during speech (15). While gait and non-gait freezing do not necessarily co-occur, these data suggest that some common mechanism underlies motor arrests in PD. As such, in the remainder of this case report, we will use the term “freezing” to include both gait and non-gait phenomena.\n\nVarious hypotheses describing potential mechanisms of freezing have been proposed, including impaired automaticity (16), perceptual impairments (17), and cognitive-motor decoupling (18), and this remains an active area of research. Furthermore, non-dopaminergic systems such as serotonergic neurons in the raphe nucleus and cholinergic neurons in the pedunculopontine nucleus may also play a role (3). Thus, freezing likely involves a widespread network of various brain regions. In this case report, we describe a patient with dopa-responsive parkinsonism who experienced gait freezing when ambulatory and currently experiences apparent freezing only when operating her powered wheelchair in situations that often elicit gait freezing. The purpose of this case is to present a novel task-specific case of potential freezing and to summarize and expand on the potential neurological mechanisms of freezing.\n\nCase Report\nThe patient is a 60-year-old woman with a 24-year history of parkinsonism currently residing in an assisted living facility. She initially presented to our movement disorder clinic in 1996 with a 4-year history of gradually progressive lower extremity pain and spasms, and blepharospasm following constipation and urinary urge. Baclofen and botulinum toxin targeting ocular muscles provided modest benefit for spasms. The differential remained broad and initial workup included normal brain magnetic resonance imaging (MRI), cervical, thoracic, and lumbar spine MRI, cerebrospinal fluid studies (cell count, protein, glucose, oligoclonal bands, Lyme titers), complete blood cell count, comprehensive metabolic panel, thyroid-stimulating hormone level, triiodothyronine (T3) levels, free thyroxine (T4) levels, serum immunofixation, ceruloplasmin, B12, Venereal Disease Research Laboratory, erythrocyte sedimentation rate, extractable nuclear antigen, antinuclear antibody (slightly elevated, but rheumatology follow-up revealed no association with clinical syndrome), vitamin E, human immunodeficiency virus, human T-cell lymphotropic virus, very long chain fatty acids, electromyography/nerve conduction studies, serum and urine amino acids, conjunctival biopsy for lipofuscinosis, urine samples for arylsulfatase A, negative gene testing for spinocerebellar ataxia-type 3, and Huntington disease.\n\nOver the next 2 years, she displayed progressive asymmetric (left more than right) leg and arm dystonia with concomitant development of asymmetric leg then arm rest tremor, rigidity, and impaired gait (asymmetric foot dragging) and balance. PD was diagnosed in 1998 following exquisite improvement of rest tremor, rigidity, dystonia, gait, and blepharospasm with initiation of carbidopa/levodopa (Unified Parkinson’s Disease Rating Scale motor subsection (UPDRS III) score improved from 38 to 15.5 with titration). Over the next several years, she developed motor fluctuations with painful OFF-state left arm/leg dystonia and peak-dose cervical dystonia (worse on the left). Trials with ropinerole provided initial relief of OFF-state dystonia, but in late 2001, she developed dose-limiting peak-dose dyskinesia and was unable to tolerate ropinerole or trials with pergolide, pramipexole, tolcapone, or entacapone in addition to amantadine and levodopa. Over the next 3 years, she experienced worsening gait (due in part to worsening left leg dystonia) with freezing that resulted in at least 2 falls per week by 2004. In 2006, on examination, gait impairment was characterized independent of dystonia by inability to lift her feet, particularly on the left side, resembling the akinetic subtype of FOG (19). At this time, FOG was severe enough that she used a wheelchair when outside of the home for safety.\n\nIn June 2006, she underwent successful implantation of bilateral subthalamic nucleus deep brain stimulation after OFF/ON evaluation revealed improvement of the UPDRS III score from 69 in the practically defined OFF state to 13.5 following ingestion of 600 mg levodopa. DBS resulted in markedly reduced rigidity and tremor, and relieved pain secondary to left arm and leg dystonia which allowed reduction of levodopa dosing over 50% during the first year. After DBS, the patient’s gait and mobility improved substantially, and she did not regularly use her power scooter. Three years following DBS, she required dose titrations and again developed motor fluctuations with worsening rest tremor, dystonia, and FOG. By July of 2009, she was still able to walk, but again preferred to use a power chair due to fear of falls in the context of worsening FOG. She was bound to her power chair in 2012 due to progression of gait instability and FOG with increased motor fluctuations.\n\nIn April 2015, the patient first reported intermittent right hand freezing while controlling her power wheelchair in specific situations. Three months later, this apparent freezing of the upper extremity began to interfere substantially with her ability to propel her power wheelchair, particularly when entering an elevator or passing through doorways. The apparent freezing was mostly in her fingers, which controlled the movement of her chair. During episodes, the patient does not display dystonic posturing of the wrist or hand typical of her OFF-period dystonia, or as an overflow phenomenon. As reported in May of 2016, the navigation-related upper-limb freezing episodes occur a few times per day. The suspected freezes observed in the clinic usually lasted just a few seconds, but the patient reports episodes may last for as long as 1–10 min. The patient is typically able to break the motor arrests using her other hand (left) to release fingers of the right hand from the steering knob. In cases where the episodes last several minutes, staff members at her living facility intervene to help break the motor arrest. These apparent freezing episodes occur when moving the wheelchair both forward and backward. Entering and exiting elevators are the most common triggers, though navigating around the dining room in the presence of other residents who make her feel nervous occasionally triggers these episodes of potential freezing. The patient reports that these navigation-related upper-limb freezing episodes are similar to gait freezing she experienced previously and are accompanied by similar sensations and feelings of panic without other panic attack features. These episodes can occur either at peak dose or in the off state, but are more frequent and last longer in the off state. Because the patient is no longer ambulatory, we cannot determine if she still experiences gait freezing. The patient does not report this potential upper-limb freezing during any other upper-limb tasks nor does the apparent upper-limb freezing occur during wheelchair steering in other circumstances, such as navigating a wide open space. This is consistent with observations in our clinic.\n\nOn examination, she had saccadic intrusions on smooth pursuit, but no additional extraocular movement abnormalities. Finger tapping, hand movement, and leg agility were slow with diminished amplitude in the OFF more than ON state, but movement always remained visible, except at the moments described when operating her chair. Bradykinesia remained fairly constant in the OFF state, whereas the apparent freezing phenomenon was transient, most often lasting about 5–15 s (though occasionally longer). There was no increase or change in dystonic posturing when she attempted to initiate hand movements to control the wheelchair, and she lacked subjective pain that frequently accompanied OFF-period dystonia. She was otherwise able to accurately maneuver the wheelchair throughout most of the day, despite obvious and painful hand dystonia. She denied subjective concerns of not knowing how to make the desired movement during freezing episodes, and she lacked constructional or ideomotor apraxia on formal testing. Freezing episodes did not depend on whether observers were present or on any apparent psychological rewards.\n\nShe has an extensive psychiatric history including the following symptoms: major depression, hallucinations, and suicidal ideation. Psychiatric treatments have included thiothixene, quetiapine, and electroconvulsive therapy with good benefit. Antipsychotics were last prescribed 10–15 years prior to her first visit at our center (except for 1–3 nightly doses of quetiapine 12.5 mg in 2014). Depression occurring concomitantly with parkinsonism was treated intermittently with nortriptyline, mirtazapine, paroxetine, nefazodone, and duloxetine. The patient has a family history of paranoid schizophrenia (brother) and alcoholism. At present, she is cognitively normal (Mini-Mental Status Exam score of 27, Montreal Cognitive Assessment score of 28) and has no evidence of changes in memory.\n\nThe patient’s current medications as of October 2016 are summarized in Table 1, categorized as “parkinsonism,” “psychiatric,” and “pain.” Her prescribed levodopa equivalent daily dose is 650 mg, and she currently takes only levodopa (i.e., no agonists or MAOB inhibitors). Frequent revision of medication schedules, particularly following DBS, was a major part of her management as the patient experienced constant debilitating pain, frequent on- and off-period dystonia, and occasional hallucinations. Motor benefit from levodopa (taken every 3 h from 6 a.m. to 6 p.m. and CR at 9 p.m.) appeared in 30 min, and lasted until 30–45 min prior to her next dose. The UPDRS was administered 53 min after a regular dose of carbidopa/levodopa during her October 2016 visit. The summary scores are as follows: Part I: 3/16, Part II: 25/52, Part III: 64.5/108, and Part IV: 4/23. For subscale III (motor), the patient has severe bradykinesia and hypokinesia, hypophonia, and cannot rise from her motorized chair without assistance. DBS settings were last adjusted in January of 2015. Neither medication nor DBS therapies currently provide sufficient relief for this patient’s apparent task-specific upper-limb freezing during navigation, though she reports worse and more frequent episodes during off-medication periods.\n\nTable 1 Current medications.\n\n\tMedication\tTotal daily dose (mg)\tComments\t\nParkinsonism\tSinemet (carbidopa–levodopa)\t150/600\t\t\nSinemet (carbidopa–levodopa)\t25/100\t1 tablet 4×/day, as needed\t\nSinemet (carbidopa–levodopa)\t50/200\t1 tablet at bedtime\t\nPsychiatric\tCymbalta (duloxetine)\t90\t\t\nDextroamphetamine Sulfate\t40\t\t\nMirtazapine\t30\t\t\nPain\tAcetaminophen\t325\tAs needed\t\nBaclofen\t50\t10 mg 3×/day, 20 mg at bedtime\t\nGabapentin\t3,600\tAdditional 300 mg as needed\t\nIbuprofen\t2,400\t\t\nDiscussion\nFreezing is a complex and poorly understood feature of PD. The pathophysiological and behavioral mechanisms associated with freezing likely involve motor, cognitive, and sensory factors (20). How these factors interact is still not fully understood and, as a result, the current array of treatment approaches for freezing do not provide sufficient long-term benefit (21). In this report, we describe a novel case of a patient who previously experienced gait freezing, and while now non-ambulatory, experiences episodes in the upper limb that appear to be freezes when navigating her wheelchair in specific situations that also commonly elicit FOG. The circumstances and sensations during these episodes as reported by the patient are similar to those experienced during previous gait freezing. To our knowledge, this is one of the first reports of apparent freezing of another part of the body during a navigation-related task (i.e., steering a wheelchair). Systematic studies of upper-limb freezing manipulated the spatiotemporal components of the task to induce freezing (12–14); however, it was not clear if these participants also experienced upper-limb freezing during other tasks or in specific environments (such as when passing through narrow spaces).\n\nWhile the motor demands differ between walking and navigating a wheelchair, sensory aspects such as optic flow are similar. One current hypothesis is that freezing is due to perceptual impairments related to visuomotor integration of one’s body within the environment (17). Evidence for this comes from patient reports as well as experiments examining how people with PD walk through spaces with varying widths, such as doorways (22, 23). The patient reported that her freezing was worse when entering/exiting elevators and when finding a seat in the dining hall. Both situations challenge spatial judgment, and navigating in the dining hall was also emotionally taxing for this particular patient. In addition, the cognitive and emotional demands associated with these scenarios are similar in both walking and using a wheelchair. Complex tasks can exacerbate freezing (24), and fear related to prior freezing events may increase anxiety and also contribute to freezing (25). This patient has a history of mood disorder that may contribute to emotion-related freezing triggers. Since cognitive-motor overload is also a plausible mechanism for freezing behavior (18), cognitive interference may play a role in this case as it does in other types of freezing. Though we saw no evidence of cognitive impairment in this individual, increasing cognitive load has been shown to trigger freezing episodes in people with PD who experience freezing, regardless of cognitive status (3, 26). As a result, cognitive-motor interference may contribute to this phenomenon. Overall, these hypotheses suggest a more general mechanism that could apply to both FOG and upper-limb freezing during navigation, even though these two tasks have very different motor demands.\n\nWe cannot rule out other explanations for the phenomenon described in this case. Dystonia is a common side effect of dopaminergic treatment, usually occurring in the off-period (27). The patient experienced previous dystonia in the lower limbs during both on- and off-medication periods. The interruption in her intended upper-limb movements could also potentially be attributed to a form of dystonia. However, this is unlikely because the patient’s previous dystonia was generalized and not associated with certain tasks or situations, whereas the current apparent freezing occurs only in the upper limb involved in wheelchair navigation and only during specific situations. More directly, dystonic posturing and pain were absent during the episodes, and finger torsion or deviation was not observed upon examination. Further, the patient did not report focal muscle tension during these episodes of suspected freezing while using the wheelchair. Recordings of muscle activity during upper-limb freezing episodes were not able to be collected for this patient. However, in future cases of suspected task-specific upper-limb freezing, this may help distinguish between dystonia, which is characterized by sustained agonist/antagonist co-contraction (28), and freezing, which is typically accompanied by inappropriate timing of agonist/antagonist muscle pairs (3). General but severe bradykinesia could feasibly contribute to the interruption of her upper-limb movements as well. On the UPDRS III, the patient scored a 4 on body bradykinesia and hypokineisa, and a 3 or 4 on finger tapping, hand movements, and leg agility. However, the duration of the episodes are too long to be purely bradykinetic in nature, and the patient is able to volitionally break the motor arrests herself in most cases, similar to what is seen in FOG.\n\nThis phenomenon of apparent upper-limb freezing is also unique from typical episodes of lower limb or gait freezing. For example, the maximal duration of the episodes reported by the patient is atypically long compared to most reports of FOG. Most FOG episodes last less than 10 s and rarely last more than 30 s before movement is regained (19). However, episodes observed within the clinic were all within the typical reported range. The lack of arm trembling concurrent with the episode is also uncharacteristic of FOG. However, there are numerous reports of upper-limb freezing episodes described as a cessation of movement in one or more hand that are not accompanied by trembling (29–32). Further, striking similarities between this phenomenon of apparent upper-limb freezing and FOG include the identifiable environmental triggers (crowded spaces, passageways) and the ability to interrupt the episodes.\n\nConclusion\nOverall, unique cases such as this highlight the need to consider freezing as a problem affecting the entire sensorimotor system and emphasize the need for clinicians and researchers to develop new treatments for non-gait freezing.\n\nEthics Statement\nThe patient gave signed consent for releasing her health information in the format of this case report. The authors consulted the Washington University Human Research Protection Office (IRB), which judged that additional ethics review was not required.\n\nAuthor Contributions\nSTN and MM wrote the manuscript. SAN and KB collected data. STN, MM, GE, SAN, and KB edited the manuscript.\n\nConflict of Interest Statement\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\nWe would like to thank the patient for agreeing to allow use of her available clinical data for scientific use and publication.\n\nFunding\nResearch reported in this publication was supported by the Greater St. Louis Chapter of the American Parkinson’s Disease Association (APDA), the APDA Advanced Center for PD Research, and by the Washington University Institute of Clinical and Translational Sciences grant UL1TR000448 sub-award TL1TR000449 from the National Center for Advancing Translational Sciences (NCATS) of the National Institutes of Health (NIH).\n==== Refs\nReferences\n1 Giladi N Nieuwboer A \nUnderstanding and treating freezing of gait in parkinsonism, proposed working definition, and setting the stage . Mov Disord (2008 ) 23 (Suppl 2 ):S423 –5 .10.1002/mds.21927 18668629 \n2 Forsaa EB Larsen JP Wentzel-Larsen T Alves G . A 12-year population-based study of freezing of gait in Parkinson’s disease . Parkinsonism Relat Disord (2015 ) 21 (3 ):254 –8 .10.1016/j.parkreldis.2014.12.020 25603767 \n3 Nutt JG Bloem BR Giladi N Hallett M Horak FB Nieuwboer A . Freezing of gait: moving forward on a mysterious clinical phenomenon . Lancet Neurol (2011 ) 10 (8 ):734 –44 .10.1016/S1474-4422(11)70143-0 21777828 \n4 Kerr GK Worringham CJ Cole MH Lacherez PF Wood JM Silburn PA \nPredictors of future falls in Parkinson disease . Neurology (2010 ) 75 (2 ):116 –24 .10.1212/WNL.0b013e3181e7b688 20574039 \n5 Paul SS Canning CG Sherrington C Lord SR Close JC Fung VS . Three simple clinical tests to accurately predict falls in people with Parkinson’s disease . Mov Disord (2013 ) 28 (5 ):655 –62 .10.1002/mds.25404 23450694 \n6 Rahman S Griffin HJ Quinn NP Jahanshahi M . Quality of life in Parkinson’s disease: the relative importance of the symptoms . Mov Disord (2008 ) 23 (10 ):1428 –34 .10.1002/mds.21667 18543333 \n7 Amboni M Cozzolino A Longo K Picillo M Barone P . Freezing of gait and executive functions in patients with Parkinson’s disease . Mov Disord (2008 ) 23 (3 ):395 –400 .10.1002/mds.21850 18067193 \n8 Cohen RG Klein KA Nomura M Fleming M Mancini M Giladi N \nInhibition, executive function, and freezing of gait . J Parkinsons Dis (2014 ) 4 (1 ):111 –22 .10.3233/jpd-130221 24496099 \n9 Giladi N . Medical treatment of freezing of gait . Mov Disord (2008 ) 23 (Suppl 2 ):S482 –8 .10.1002/mds.21914 18668620 \n10 Vercruysse S Vandenberghe W Munks L Nuttin B Devos H Nieuwboer A \nEffects of deep brain stimulation of the subthalamic nucleus on freezing of gait in Parkinson’s disease: a prospective controlled study . J Neurol Neurosurg Psychiatry (2014 ) 85 (8 ):871 –7 .10.1136/jnnp-2013-306336 24396010 \n11 Vercruysse S Gilat M Shine JM Heremans E Lewis S Nieuwboer A \nFreezing beyond gait in Parkinson’s disease: a review of current neurobehavioral evidence . Neurosci Biobehav Rev (2014 ) 43 :213 –27 .10.1016/j.neubiorev.2014.04.010 24769288 \n12 Vercruysse S Spildooren J Heremans E Vandenbossche J Wenderoth N Swinnen SP \nAbnormalities and cue dependence of rhythmical upper-limb movements in Parkinson patients with freezing of gait . Neurorehabil Neural Repair (2012 ) 26 (6 ):636 –45 .10.1177/1545968311431964 22291041 \n13 Williams AJ Peterson DS Ionno M Pickett KA Earhart GM . Upper extremity freezing and dyscoordination in Parkinson’s disease: effects of amplitude and cadence manipulations . Parkinsons Dis (2013 ) 2013 :595378 .10.1155/2013/595378 24027652 \n14 Barbe MT Amarell M Snijders AH Florin E Quatuor EL Schonau E \nGait and upper limb variability in Parkinson’s disease patients with and without freezing of gait . J Neurol (2014 ) 261 (2 ):330 –42 .10.1007/s00415-013-7199-1 24305993 \n15 Moreau C Ozsancak C Blatt JL Derambure P Destee A Defebvre L . Oral festination in Parkinson’s disease: biomechanical analysis and correlation with festination and freezing of gait . Mov Disord (2007 ) 22 (10 ):1503 –6 .10.1002/mds.21549 17516477 \n16 Vandenbossche J Deroost N Soetens E Coomans D Spildooren J Vercruysse S \nFreezing of gait in Parkinson’s disease: disturbances in automaticity and control . Front Hum Neurosci (2012 ) 6 :356 10.3389/fnhum.2012.00356 23335895 \n17 Almeida QJ Lebold CA . Freezing of gait in Parkinson’s disease: a perceptual cause for a motor impairment? \nJ Neurol Neurosurg Psychiatry (2010 ) 81 (5 ):513 –8 .10.1136/jnnp.2008.160580 19758982 \n18 Lewis SJ Barker RA . A pathophysiological model of freezing of gait in Parkinson’s disease . Parkinsonism Relat Disord (2009 ) 15 (5 ):333 –8 .10.1016/j.parkreldis.2008.08.006 18930430 \n19 Schaafsma JD Balash Y Gurevich T Bartels AL Hausdorff JM Giladi N . Characterization of freezing of gait subtypes and the response of each to levodopa in Parkinson’s disease . Eur J Neurol (2003 ) 10 (4 ):391 –8 .10.1046/j.1468-1331.2003.00611.x 12823491 \n20 Shine JM Naismith SL Lewis SJ . The pathophysiological mechanisms underlying freezing of gait in Parkinson’s disease . J Clin Neurosci (2011 ) 18 (9 ):1154 –7 .10.1016/j.jocn.2011.02.007 21724402 \n21 Walton CC Shine JM Mowszowski L Naismith SL Lewis SJG . Freezing of gait in Parkinson’s disease: current treatments and the potential role for cognitive training . Restor Neurol Neurosci (2014 ) 32 (3 ):411 –22 .10.3233/Rnn-130370 24531294 \n22 Cowie D Limousin P Peters A Day BL . Insights into the neural control of locomotion from walking through doorways in Parkinson’s disease . Neuropsychologia (2010 ) 48 (9 ):2750 –7 .10.1016/j.neuropsychologia.2010.05.022 20519135 \n23 Cohen RG Chao A Nutt JG Horak FB . Freezing of gait is associated with a mismatch between motor imagery and motor execution in narrow doorways, not with failure to judge doorway passability . Neuropsychologia (2011 ) 49 (14 ):3981 –8 .10.1016/j.neuropsychologia.2011.10.014 22027173 \n24 Spildooren J Vercruysse S Desloovere K Vandenberghe W Kerckhofs E Nieuwboer A . Freezing of gait in Parkinson’s disease: the impact of dual-tasking and turning . Mov Disord (2010 ) 25 (15 ):2563 –70 .10.1002/mds.23327 20632376 \n25 Martens KA Hall JM Gilat M Georgiades MJ Walton CC Lewis SJ . Anxiety is associated with freezing of gait and attentional set-shifting in Parkinson’s disease: a new perspective for early intervention . Gait Posture (2016 ) 49 :431 –6 .10.1016/j.gaitpost.2016.07.182 27513741 \n26 Nieuwboer A Giladi N . Characterizing freezing of gait in Parkinson’s disease: models of an episodic phenomenon . Mov Disord (2013 ) 28 (11 ):1509 –19 .10.1002/mds.25683 24132839 \n27 Krack P Pollak P Limousin P Benazzouz A Deuschl G Benabid AL . From off-period dystonia to peak-dose chorea. The clinical spectrum of varying subthalamic nucleus activity . Brain (1999 ) 122 (Pt 6 ):1133 –46 .10.1093/brain/122.6.1133 10356065 \n28 Berardelli A Rothwell JC Hallett M Thompson PD Manfredi M Marsden CD . The pathophysiology of primary dystonia . Brain (1998 ) 121 (Pt 7 ):1195 –212 .10.1093/brain/121.7.1195 9679773 \n29 Bronte-Stewart HM Ding L Alexander C Zhou Y Moore GP . Quantitative digitography (QDG): a sensitive measure of digital motor control in idiopathic Parkinson’s disease . Mov Disord (2000 ) 15 (1 ):36 –47 .10.1002/1531-8257(200001)15:1<36::AID-MDS1008>3.0.CO;2-M 10634240 \n30 Almeida QJ Wishart LR Lee TD . Bimanual coordination deficits with Parkinson’s disease: the influence of movement speed and external cueing . Mov Disord (2002 ) 17 (1 ):30 –7 .10.1002/mds.10030 11835436 \n31 Sauermann S Standhardt H Gerschlager W Lanmuller H Alesch F . Kinematic evaluation in Parkinson’s disease using a hand-held position transducer and computerized signal analysis . Acta Neurochir (Wien) (2005 ) 147 (9 ):939 –945; discussion 945 .10.1007/s00701-005-0569-4 15999229 \n32 Nieuwboer A Vercruysse S Feys P Levin O Spildooren J Swinnen S . Upper limb movement interruptions are correlated to freezing of gait in Parkinson’s disease . Eur J Neurosci (2009 ) 29 (7 ):1422 –30 .10.1111/j.1460-9568.2009.06681.x 19309319\n\n",
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] |
{
"abstract": "Breast cancer is one of the most common malignancies diagnosed in pregnancy. Although the tumor is often detected at an advanced stage, placental metastases are rare. Here, we describe the case of a woman with breast cancer recurrence during pregnancy and subsequent metastases. The focus of this study is the large amount of placenta metastases, which have been analyzed immunohistochemically. Staining with trophoblast markers (placenta alkaline phosphatase, beta human chorionic gonadotropin and human placental lactogen) showed the strict localization of metastases in the intervillous space without invasion into fetal tissue. They have a large spheroidal shape and are free of blood vessels. Staining with Ki-67 revealed an outer proliferative shell and inner necrotic core. At week 28, a healthy newborn was born by elective cesarean section. A few weeks later, after surgery and FEC60 (fluorouracil, epirubicin, cyclophosphamide) cycles, the patient died. Breast cancer metastases in the placenta are rarely described. The special immunological environment in pregnancy may influence phenotype, growth, and behavior of tumor and metastases.",
"affiliations": "Department of Obstetrics, Placenta Lab, University Hospital Jena, Jena, Germany.;Department of Oncology, Regional Centre for Excellence in Palliative Care, Oslo University Hospital, Oslo, Norway.;Department of Obstetrics, Placenta Lab, University Hospital Jena, Jena, Germany.;Department of Pathology, Center for Pediatric and Pregnancy Related Pathology, Oslo University Hospital, Oslo, Norway.",
"authors": "Froehlich|Karolin|K|;Stensheim|Hanne|H|;Markert|Udo R|UR|;Turowski|Gitta|G|",
"chemical_list": null,
"country": "Denmark",
"delete": false,
"doi": "10.1111/apm.12827",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0903-4641",
"issue": "126(5)",
"journal": "APMIS : acta pathologica, microbiologica, et immunologica Scandinavica",
"keywords": "breast cancer; metastases; placenta; pregnancy",
"medline_ta": "APMIS",
"mesh_terms": "D000328:Adult; D001943:Breast Neoplasms; D005260:Female; D006801:Humans; D010920:Placenta; D011247:Pregnancy; D011252:Pregnancy Complications, Neoplastic; D018874:Spheroids, Cellular",
"nlm_unique_id": "8803400",
"other_id": null,
"pages": "448-452",
"pmc": null,
"pmid": "29665170",
"pubdate": "2018-05",
"publication_types": "D002363:Case Reports",
"references": null,
"title": "Breast carcinoma in pregnancy with spheroid-like placental metastases-a case report.",
"title_normalized": "breast carcinoma in pregnancy with spheroid like placental metastases a case report"
} | [
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"drugdosagetext": "150 MG/M2, WEEKLY",
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"drugindication": "BREAST CANCER",
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],
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"reaction": [
{
"reactionmeddrapt": "Respiratory failure",
"reactionmeddraversionpt": "21.1",
"reactionoutcome": "5"
}
],
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},
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{
"abstract": "Acute ingestion of thyroid hormone preparations is a common intoxication, with 181 cases in children <12 yr in 2009 in the Netherlands, but generally has a mild course. However, some reports show that even low dosages may cause serious events such as seizures, thyroid storm and coma. We report a 3 yr old boy case with an acute intoxication with high dose levothyroxine (0.5 mg/kg). We describe the proper management of levothyroxine intoxication in children. A 3-year-old boy with no notable medical history ingested sixty tablets of levothyroxine 150 µg. His vital-signs were normal and the only symptom during admission was a tachycardia the following day. Laboratory data showed elevated T3, fT3 and fT4 levels; and decrease TSH levels. He was treated prophylactically and therapeutically with activated charcoal and propranolol. Despite very high levels, his clinical symptoms were relatively mild. After clinical follow-up for 3 d he was discharged. We propose that children with thyroid hormone intoxication with either a levothyroxine dose >0.1 g/kg, a short interval since ingestion, symptomatic presentation, and/or a fT4 >100 pmol/l should be monitored in the hospital during at least 48-72 h post-ingestion and on an outpatient basis for 14 d.",
"affiliations": "Rijnstate Hospital, Department of Pediatrics, Arnhem, The Netherlands.;Department of Pediatric Endocrinology, Radboud University Medical Centre, Nijmegen, The Netherlands.;Department of Clinical Pharmacy, Rijnstate Hospital, Arnhem, The Netherlands.;Rijnstate Hospital, Department of Pediatrics, Arnhem, The Netherlands.",
"authors": "Hartman|Stan|S|;Noordam|Kees|K|;Maseland|Machiel|M|;van Setten|Petra|P|",
"chemical_list": null,
"country": "Japan",
"delete": false,
"doi": "10.1297/cpe.26.171",
"fulltext": "\n==== Front\nClin Pediatr EndocrinolClin Pediatr EndocrinolCPEClinical Pediatric Endocrinology0918-57391347-7358The Japanese Society for Pediatric Endocrinology 2016-001910.1297/cpe.26.171Case ReportBenign course after acute high dose levothyroxine intoxication in a\n3-year-old boy Hartman Stan \n1\nNoordam Kees \n2\nMaseland Machiel \n3\nvan Setten Petra \n1\n1 Rijnstate Hospital, Department of Pediatrics, Arnhem, The\nNetherlands2 Department of Pediatric Endocrinology, Radboud University\nMedical Centre, Nijmegen, The Netherlands3 Department of Clinical Pharmacy, Rijnstate Hospital, Arnhem,\nThe NetherlandsCorresponding author: Petra van Setten, MD, PhD, Rijnstate Hospital Arnhem,\nWagnerlaan 55, 6800 TA Arnhem, The NetherlandsE-mail: pvansetten@rijnstate.nl27 7 2017 2017 26 3 171 175 28 7 2016 25 2 2017 2017©The Japanese Society for Pediatric\nEndocrinology2017This is an open-access article distributed under the terms of the Creative\nCommons Attribution Non-Commercial No Derivatives (by-nc-nd) License. Abstract.\nAcute ingestion of thyroid hormone preparations is a common intoxication, with 181 cases\nin children <12 yr in 2009 in the Netherlands, but generally has a mild course.\nHowever, some reports show that even low dosages may cause serious events such as\nseizures, thyroid storm and coma. We report a 3 yr old boy case with an acute intoxication\nwith high dose levothyroxine (0.5 mg/kg). We describe the proper management of\nlevothyroxine intoxication in children. A 3-year-old boy with no notable medical history\ningested sixty tablets of levothyroxine 150 µg. His vital-signs were normal and the only\nsymptom during admission was a tachycardia the following day. Laboratory data showed\nelevated T3, fT3 and fT4 levels; and decrease TSH levels. He was treated prophylactically\nand therapeutically with activated charcoal and propranolol. Despite very high levels, his\nclinical symptoms were relatively mild. After clinical follow-up for 3 d he was\ndischarged. We propose that children with thyroid hormone intoxication with either a\nlevothyroxine dose >0.1 g/kg, a short interval since ingestion, symptomatic\npresentation, and/or a fT4 >100 pmol/l should be monitored in the hospital during at\nleast 48–72 h post-ingestion and on an outpatient basis for 14 d.\n\nthyroxineintoxicationoverdoseside-effects\n==== Body\nIntroduction\nAcute ingestion of excess thyroid hormone preparations is a common intoxication reported to\npoisoning control centres. According to the 2014 American Association of Poison Control\nCentres Annual Report 9,301 exposures to thyroid hormone preparations were documented in\npoison control centres in United States of America. Of these, 4,444 (47.8%) occurred in\nchildren younger than 6 yr, 722 (7.8%) in persons aged 6–19 yr and 3,597 (38.7%) in persons\naged older than 19 yr (1). In the Netherlands 181\ncases of levothyroxine intoxications in children younger than 12 yr were reported in 2009.\nAlthough levothyroxine intoxication in children generally has a mild course (2, 3), some reports\nshow that even low dosages of levothyroxine may cause serious events such as seizures,\nthyroid storm and even coma (4). In this paper, we\ndescribe the clinical and pharmacological course of a 3 yr old boy who ingested a high dose\nlevothyroxine (total amount of 9 mg corresponding to 0.5 mg/kg, 100 times the normal dose).\nDespite high levels of fT4 and T3, he had a relatively benign clinical course.\n\nCase Report\nClinical history and past history\nA 3-yr-old boy with no notable medical history, weighing 17 kilograms presumably ingested\nup to a maximum of sixty tablets (150 µg each) of his mother’s levothyroxine prescription.\nThe mother had a prescription filled out for 90 tablets and took about 10 tablets until\nthe day of the ingestion. After ingestion of the tablets 20 remaining pills were counted.\nThe ingestion was not witnessed and the missing pills went undiscovered. Besides the\nlevothyroxine tablets, he ingested about 10 tablets of Rennie Deflatine® (each tablet\nconsists of calcium carbonate 680 mg, magnesium carbonate 80 mg, simethicone 25 mg and\nsaccharose 475 mg). His parents took him to the emergency department about three hours\nafter ingestion. He was asymptomatic with no fever or illness, alert and cooperative.\n\nPhysical examination and laboratory findings on admission\nThe child’s vital signs were as follows: respiration rate 20/min, pulse 100/min, blood\npressure 107/74 mmHg and temperature 36.9ºC. Physical and neurological examination were\nnormal. The levels of free T4, TSH and total T3 were measured for the first time\napproximately 4 h after ingestion: fT4 >100 pmol/l (ref. 11–25), TSH 7.07 mU/l (ref.\n0.30–4.0), total T3 3.8 nmol/l (ref. 1.3–2.6) as shown in Fig. 1Fig. 1. The change of the TSH, fT4, T3 and fT3 values post-ingestion. a: TSH levels\ndecreased to 0.87 mU/l on d 2, and remained < 0.3 mU/l until d 14; TSH levels\nreturned to normal afterwards. b: fT4 levels increased to > 100 pmol/l from d 1to\nd 6, and decreased thereafter, reaching normal levels on d 14. c: T3 levels\nincreased on d 1 of illness to (3.8 nmol/l), reaching its maximum on d 3 (8.7\nnmol/l); thereafter T3 levels gradually decreased to normal on d 14. d: fT3 levels\nwere increased at d 3 and gradually decreased to normal level on d 12.\n\n.\n\nClinical course\nBecause of the high amount of levothyroxine ingested (about 9000 µg, corresponding with\napproximately 0.5 mg/kg), he was admitted to the hospital and closely monitored. One dose\nof activated charcoal of 1 g/kg was administered. Prophylactic propranolol (1.8 mg/kg/day)\nwas started after an electrocardiogram showed no abnormalities.\n\nOn the second day the boy developed a tachycardia of 130/min during daytime , without\ndiarrhoea, vomiting, temperature instability, insomnia, hyperkinesia or other neurological\nsymptoms. Laboratory findings showed a suppression of TSH (0.87 mU/l) and elevated levels\nof fT4 (>100 pmol/l) , T3 (6.8 pmol/l) and fT3 (40.3 pmol/l). The dosage of propranolol\nwas raised to 3.5 mg/kg/day. Subsequently, the heart rate decreased. On the seventh day\nafter ingestion, the heart rate normalized (approximately 90/min); propranolol dosage was\nreduced to 1.8 mg/kg/day. Thyroid function tests from day 1–30 are depicted in Fig. 1A–D. The peak concentration of T3 was reached\nat day 3 (40.38 pmol/l). TSH levels were maximally depressed from day 5 to 14.\n\nThe child was discharged from the hospital on the eighth day after ingestion. Physical\nexamination on discharge showed a normal heart rate of 95/min and no further\nabnormalities. Laboratory findings showed a suppression of TSH (0.04 mU/l) and elevated\nlevels of fT4 (48 pmol/l), T3 (3.9 pmol/l) and fT3 (12.1 pmol/l). Since then he was\nmonitored in the outpatient clinic. The propranolol was stopped at day 12. Since then he\nhad normal vital signs and his thyroid function tests were completely normal at d 30\n(Fig. 1).\n\nDiscussion\nAcute ingestion of thyroid hormone preparations in the paediatric population is commonly\nreported to poison control centres. In our case a particularly high dose of levothyroxine\nwas ingested. The subsequent clinical and pharmacological time course is described.\n\nPharmacokinetics of thyroid hormones\nFrom pharmacological studies is well known that levothyroxine is a thyroxine (T4)\nanalogue, which is the predominant circulating form of thyroid hormone. In the peripheral\ntissues, T4 is partially converted to liothyronine (T3), a more biologically active\nthyroid hormone. Since T4 is pharmacologically inactive, T3 is the substance responsible\nfor development of toxicological symptoms. It is clear that if any symptoms appear, they\nare delayed in onset. Reason for this is that levothyroxine must achieve peripheral\nconversion to T3.\n\nPharmacological data also show that Tmax of levothyroxine is reached at 5-6 hours after\noral intake. Elimination half life (T1/2) is 7 d for T4 and 0.8 d for T3.\nExogenously administered thyroid hormone indirectly suppresses the thyroid gland activity,\nin our patient shown by a decreased TSH level. In our opinion his initially slightly\nelevated TSH is the result of emotional stress at admission.\n\nLewander et al. (2) specifically\nstudied the pharmacokinetics of T4 and T3 in acute T4 intoxication in 7 patients. Their\nfindings indicate a mean T1/2 for T4 of 2.8 d, which is shorter than the\nT1/2 observed in physiologic concentrations (7 d in children) and a\nT1/2 for T3 of 6 d, which is almost 5 times longer than in physiologic\nconcentrations. Furthermore the peak concentration of T3 is reached at more than 24 h\nafter the ingestion. This favours the conclusion that delay in onset of symptoms and\nduration of toxicity is due to the conversion from levothyroxine to T3 and prolonged\nelimination time of T3 in acute overdose. In our patient, the peak concentration of T3 was\non d 3 with T3 reaching normal values after 8 d. This indeed explains the occurrence of\nsymptoms on the second day after levothyroxine overdose.\n\nThe usual dose of levothyroxine in hypothyroid paediatric patients is 5–7 ug/kg/d in one\ndose. Our patient ingested 530 ug/kg, 100 times the normal dose. His fT4, T3 and fT3 blood\nlevels were increased, at least four times (respectively >100 pmol/l, 8.7 nmol/l and\n40.38 pmol/l). T3 reached a peak concentration of 8.7 nmol/l after 3 days. Despite his\nhigh dose of ingested levothyroxine and very high thyroid hormone levels, he only showed\nmild clinical symptoms, limited to a tachycardia and a relatively high blood pressure.\n\nChildren seem tolerant to large overdoses of levothyroxine when compared with adults, but\nnot immune to the development of moderate to severe toxicity following acute levothyroxine\ningestions. It is suggested that a greater production of reverse T3 (rT3) is responsible\nfor the decreased risk of a thyroid storm after a levothyroxine overdose. rT3 is an\nisomere T3 which is also derived from T4 deionisation. It binds to the thyroid hormone\nreceptors and thereby blocks the action of T3. (5)\nThe Rennie Deflatine® might have protected our patient unintentionally by\nbinding levothyroxine to cations and thereby decreasing absorption (6).\n\nComparison of the clinical course with previously reported cases\nThe majority of previously reported studies report mild symptoms in acute levothyroxine\noverdose, despite high amounts of levothyroxine taken (dosages up to 18 mg levothyroxine)\n(2,3,4,7). Symptoms\ninclude tachycardia, fever, irritability, hyperactivity, diarrhoea, abdominal pain and\nhypertension. Tunget et al. (7)\neven suggested that acute ingestions of levothyroxine less than 5 mg T4 equivalent require\nno decontamination or aggressive management, since only mild symptoms occur sporadically\nin this range. However, Tsutaoka et al. (4) reported a case of a tonic-clonic seizure in a 3.5 yr old boy on the third\nday after ingestion of a maximum of 3.6 mg levothyroxine (about 0.22 mg/kg). Rarely,\nmassive thyroid hormone overdose has led to grand mal seizures (4), thyroid storm, and even coma (8), particularly in adults. Overall, previous reports suggest that there is no\ndose-response relationship between the occurrence or severity of symptoms and amount\nlevothyroxine ingested. Even patients with a relatively low dose of levothyroxine\npotentially develop seizures and it is not possible to predict which patients will become\nsymptomatic.\n\nTreatment for the overdose of levothyroxine\nAdministration of activated charcoal and prophylactic administration of propranolol\n(potent beta-adrenergic blocker) should be recommended as the initial treatment. As such,\nwe treated our patient with activated charcoal to stimulate decontamination. Thereafter,\nwe started with propranolol to prevent possible complications of the levothyroxine\nintoxication, such as tachycardia and hypertension. Second reason for using propranolol in\nthese cases is its effect on decreasing plasma T3 and effect on increasing plasma rT3 in a\ndose-dependent manner. Other treatments such as propylthiouracil, steroids, iopanoic acid,\ncholestyramine, sodium idopate and hemoperfusion lacks in evidence (2,3,4, 7, 8). For the management of children at risk, monitoring of vital signs and\nlaboratory data is most important. Reviewing the scarce literature and national and\ninternational databases (www.toxbase.org and Poisindex (Micromedex)) we propose close\nmonitoring of clinical course during 48–72 h post ingestion in those children who ingested\n> 0.1 mg levothyroxine/kg, children with a short interval since ingestion, symptomatic\npresentation and/or a fT4 > 100 pmol/l. Monitoring of vital signs until 14 d\npost-ingestion is recommended based on elimination half-life of fT4 and the fact that two\nweeks were needed in this case to normalize levels of TSH, fT3 and fT4.\n\nWe believe that children who do not fulfil these criteria can be safely discharged after\ninforming the parents/caregivers about possible (delayed onset of) symptoms and\ncomplications. As such, we think both high and low risk children with levothyroxine\nintoxication will be safely paid attention to prevent serious symptoms.\n\nConclusion\nWe propose that children with thyroid hormone intoxication with either a levothyroxine dose\n> 0.1 g/kg, a short interval since ingestion, symptomatic presentation, and/or a fT4\n>100 pmol/l should be closely monitored in the hospital during at least 48–72 h\npost-ingestion. Based on the period needed for normalisation of thyroid hormones in our\ncase, approximately two weeks of follow-up is recommended after the episode of\noverdosing\n==== Refs\nReferences\n1 Mowry JB Spyker DA Brooks DE McMillan N Schauben JL \n2014 Annual Report of the American Association of Poison\nControl Centers National Poison Data System (NPDS): 32nd Annual Report .\nClin Toxicol (Phila) 2015 ;53 :\n962 –1147 . doi: 10.3109/15563650.2015.1102927 26624241 \n2 Lewander WJ Lacouture PG Silva JE Lovejoy FH \nAcute thyroxine ingestion in pediatric\npatients .\nPediatrics 1989 ;84 :\n262 –5 . 2748253 \n3 Litovitz TL White JD \nLevothyroxine ingestions in children: an analysis of 78\ncases . Am J Emerg\nMed 1985 ;3 : 297 –300 .\ndoi: 10.1016/0735-6757(85)90050-6 2860910 \n4 Tsutaoka BT Kim S Santucci S \nSeizure in a child after an acute ingestion of\nlevothyroxine . Pediatr Emerg\nCare 2005 ;21 : 857 –9 .\ndoi: 10.1097/01.pec.0000190240.81222.9a 16340765 \n5 Desai M Irani AJ Patil K Pandya CS \nThe importance of reverse triiodothyronine in hypothyroid\nchildren on replacement treatment . Arch Dis\nChild 1984 ;59 : 30 –5 .\ndoi: 10.1136/adc.59.1.30 6696490 \n6 Singh N Singh PN Hershman JM \nEffect of calcium carbonate on the absorption of\nlevothyroxine .\nJAMA 2000 ;283 :\n2822 –5 . doi: 10.1001/jama.283.21.2822 10838651 \n7 Tunget CL Clark RF Turchen SG Manoguerra AS \nRaising the decontamination level for thyroid hormone\ningestions . Am J Emerg\nMed 1995 ;13 : 9 –13 .\ndoi: 10.1016/0735-6757(95)90231-7 7832964 \n8 Kreisner E Lutzky M Gross JL \nCharcoal hemoperfusion in the treatment of levothyroxine\nintoxication .\nThyroid 2010 ;20 :\n209 –12 . doi: 10.1089/thy.2009.0054 20151829\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "26(3)",
"journal": "Clinical pediatric endocrinology : case reports and clinical investigations : official journal of the Japanese Society for Pediatric Endocrinology",
"keywords": "intoxication; overdose; side-effects; thyroxine",
"medline_ta": "Clin Pediatr Endocrinol",
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"other_id": null,
"pages": "171-175",
"pmc": null,
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"publication_types": "D016428:Journal Article",
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"title": "Benign course after acute high dose levothyroxine intoxication in a 3-year-old boy.",
"title_normalized": "benign course after acute high dose levothyroxine intoxication in a 3 year old boy"
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},
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{
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},
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],
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},
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"literaturereference": "HARTMAN S, NOORDAM K, MASELAND M, VAN SETTEN P. BENIGN COURSE AFTER ACUTE HIGH DOSE LEVOTHYROXINE INTOXICATION IN A 3-YEAR-OLD BOY. CLIN-PEDIATR-ENDOCRINOL 2017;26(3):171-175.",
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{
"abstract": "Dedicator-of-cytokinesis 8 (DOCK8) deficiency, a primary immunodeficiency disease, can be reversed by allogeneic hematopoietic stem cell transplantation (HSCT); however, there are few reports describing the use of alternative donor sources for HSCT in DOCK8 deficiency. We describe HSCT for patients with DOCK8 deficiency who lack a matched related or unrelated donor using bone marrow from haploidentical related donors and post-transplantation cyclophosphamide (PT/Cy) for graft-versus-host disease (GVHD) prophylaxis. Seven patients with DOCK8 deficiency (median age, 20 years; range, 7 to 25 years) received a haploidentical related donor HSCT. The conditioning regimen included 2 days of low-dose cyclophosphamide, 5 days of fludarabine, 3 days of busulfan, and 200 cGy total body irradiation. GVHD prophylaxis consisted of PT/Cy 50 mg/kg/day on days +3 and +4 and tacrolimus and mycophenolate mofetil starting at day +5. The median times to neutrophil and platelet engraftment were 15 and 19 days, respectively. All patients attained >90% donor engraftment by day +30. Four subjects developed acute GVHD (1 with maximum grade 3). No patient developed chronic GVHD. With a median follow-up time of 20.6 months (range, 9.5 to 31.7 months), 6 of 7 patients are alive and disease free. Haploidentical related donor HSCT with PT/Cy represents an effective therapeutic approach for patients with DOCK8 deficiency who lack a matched related or unrelated donor.",
"affiliations": "Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland. Electronic address: Nirali.Shah@nih.gov.;Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.;Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.;Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.;Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland.;Oral Immunity and Inflammation Unit, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland.;Division of Pediatric Allergy and Immunology, Ministry of Health, Marmara University, Training and Research Hospital, Istanbul, Turkey.;Division of Pediatric Allergy and Immunology, Ministry of Health, Marmara University, Training and Research Hospital, Istanbul, Turkey.;Clinical Center Pharmacy Department, National Institutes of Health, Bethesda, Maryland.;Dermatology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.;Laboratory of Clinical Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.;Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland.",
"authors": "Shah|Nirali N|NN|;Freeman|Alexandra F|AF|;Su|Helen|H|;Cole|Kristen|K|;Parta|Mark|M|;Moutsopoulos|Niki M|NM|;Baris|Safa|S|;Karakoc-Aydiner|Elif|E|;Hughes|Thomas E|TE|;Kong|Heidi H|HH|;Holland|Steve M|SM|;Hickstein|Dennis D|DD|",
"chemical_list": "C516591:DOCK8 protein, human; D020662:Guanine Nucleotide Exchange Factors; D003520:Cyclophosphamide",
"country": "United States",
"delete": false,
"doi": "10.1016/j.bbmt.2017.03.016",
"fulltext": null,
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"issn_linking": "1083-8791",
"issue": "23(6)",
"journal": "Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation",
"keywords": "Dedicator-of-cytokinesis-8 (DOCK8) deficiency; Haploidentical transplantation; Immune reconstitution",
"medline_ta": "Biol Blood Marrow Transplant",
"mesh_terms": "D003520:Cyclophosphamide; D006086:Graft vs Host Disease; D020662:Guanine Nucleotide Exchange Factors; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007153:Immunologic Deficiency Syndromes; D015996:Survival Rate; D019172:Transplantation Conditioning; D000075442:Transplantation, Haploidentical; D016896:Treatment Outcome",
"nlm_unique_id": "9600628",
"other_id": null,
"pages": "980-990",
"pmc": null,
"pmid": "28288951",
"pubdate": "2017-06",
"publication_types": "D016428:Journal Article",
"references": "23128504;16443512;22248482;24320824;20810158;25627830;21236388;24985403;23423745;26806585;26156584;21288495;19597425;26713094;20622910;12189531;11939602;25267759;24225641;27130861;25419693;21931011;23206845;26453586;21868572;25636378;24161820;21058221;26860634;26187864;27641484;25316679;1671578;21527516;24869942;22006977;25648539;23871780;25445639;25797423;19543331;18489989;16545731;22863841;19776401;22581261;20004785;22897717;25724123;24842530;21546070",
"title": "Haploidentical Related Donor Hematopoietic Stem Cell Transplantation for Dedicator-of-Cytokinesis 8 Deficiency Using Post-Transplantation Cyclophosphamide.",
"title_normalized": "haploidentical related donor hematopoietic stem cell transplantation for dedicator of cytokinesis 8 deficiency using post transplantation cyclophosphamide"
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] |
{
"abstract": "Gemcitabine (GCB) is a pyrimidine antimetabolite widely used in various solid tumors as a single agent or as a component of multidrug regimens. In the majority of patients, GCB is well tolerated, however life-threatening complications occasionally occur. The current report presents four cases of severe acute toxicity, which included two that were fatal, following administration of GCB alone or in combination with cisplatin. Of the four cases, in one, a Naranjo Adverse Drug Reaction Probability Score was definite, in two, probable and in one possible. To determine the potential causes of these toxicities, polymorphic variants of cytidine deaminase, the primary enzyme involved in the hepatic metabolism of GCB, were assessed. The homogeneous c.435TT variant was detected in one patient and a heterozygotic c.435CT variant in two, one of whom additionally harbored a heterozygotic c.79AC variant.",
"affiliations": "Department of Oncology, Military Institute of Medicine, 04-141 Warsaw, Poland.;Department of Oncology, Military Institute of Medicine, 04-141 Warsaw, Poland.;Department of Oncology and Radiotherapy, Medical University of Gdańsk, 80-211 Gdańsk, Poland.;Department of Oncology, Military Institute of Medicine, 04-141 Warsaw, Poland.;Department of Biology and Genetics, Medical University of Gdańsk, 80-211 Gdańsk, Poland.;Department of Pathology, Military Institute of Medicine, 04-141 Warsaw, Poland.;Department of Oncology and Radiotherapy, Medical University of Gdańsk, 80-211 Gdańsk, Poland.;Department of Oncology, Military Institute of Medicine, 04-141 Warsaw, Poland.",
"authors": "Hryciuk|Beata|B|;Szymanowski|Bartosz|B|;Romanowska|Anna|A|;Salt|Ewa|E|;Wasąg|Bartosz|B|;Grala|Bartłomiej|B|;Jassem|Jacek|J|;Duchnowska|Renata|R|",
"chemical_list": null,
"country": "Greece",
"delete": false,
"doi": "10.3892/ol.2017.7473",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1792-1074",
"issue": "15(2)",
"journal": "Oncology letters",
"keywords": "chemotherapy toxicity; cytidine deaminase; gemcitabine; polymorphism",
"medline_ta": "Oncol Lett",
"mesh_terms": null,
"nlm_unique_id": "101531236",
"other_id": null,
"pages": "1912-1916",
"pmc": null,
"pmid": "29434889",
"pubdate": "2018-02",
"publication_types": "D016428:Journal Article",
"references": "17961191;22978342;19271785;16555971;28458422;15559247;10362105;24557790;25058905;14751677;8718422;24841663;25582275;22031394;16551864;26418006;25495470;15814642;22546611;23394383;17850778;12721761;20028759;7249508;19933910;17885621;22052224;27007129;24183806;20665488;9625429;18347182;20010457;18556440;17194903;20233917;21625252;9878810;19514966;16251482;25678195",
"title": "Severe acute toxicity following gemcitabine administration: A report of four cases with cytidine deaminase polymorphisms evaluation.",
"title_normalized": "severe acute toxicity following gemcitabine administration a report of four cases with cytidine deaminase polymorphisms evaluation"
} | [
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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": "Increasingly, food allergy associated with tacrolimus after pediatric living-donor liver transplantation (LT) has been reported. Tacrolimus prevents the activation of T cells by blocking calcineurin, thus producing an immunosuppressive effect, but tacrolimus induces an imbalance in T-helper type 1 (Th1) and Th2 cells in the food allergy process. This report describes a case of tacrolimus-associated food allergy after pediatric living-donor LT. The patient was a 7-year-old Japanese girl who had undergone living-donor LT at 12 months of age, and whom we first saw in the clinic at age 18 months. She received immunosuppressive therapy by tacrolimus after transplantation. Atopic dermatitis developed in post-transplant month 18. Stridor, facial edema, lip swelling, and skin erythema after consuming tempura udon containing wheat occurred in post-transplant month 39, and she was subsequently diagnosed with anaphylactic shock. Eosinophilic leukocyte and serum immunoglobulin (Ig)E increased, and specific IgE was positive for some food allergens. Pharmacotherapy was therefore changed from tacrolimus to cyclosporine A, after which eosinophilic leukocyte and serum IgE decreased and atopic dermatitis improved.",
"affiliations": "Departments of Pediatrics, Tokyo, Japan.;Departments of Pediatrics, Tokyo, Japan.;Departments of Pediatrics, Tokyo, Japan.;Departments of Pediatrics, Tokyo, Japan.;Departments of Pediatrics, Tokyo, Japan.;Departments of Pediatrics, Tokyo, Japan.;Hepatobiliary-Pancreatic Surgery, Juntendo University Graduate School of Medicine, Tokyo, Japan.;Hepatobiliary-Pancreatic Surgery, Juntendo University Graduate School of Medicine, Tokyo, Japan.;Departments of Pediatrics, Tokyo, Japan.",
"authors": "Obayashi|Naho|N|;Suzuki|Mitsuyoshi|M|;Yokokura|Tomoaki|T|;Naritaka|Nakayuki|N|;Nakano|Satoshi|S|;Ohtsuka|Yoshikazu|Y|;Sugo|Hiroyuki|H|;Kawasaki|Seiji|S|;Shimizu|Toshiaki|T|",
"chemical_list": "D004791:Enzyme Inhibitors; D007166:Immunosuppressive Agents; D016572:Cyclosporine; D016559:Tacrolimus",
"country": "Australia",
"delete": false,
"doi": "10.1111/ped.12721",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1328-8067",
"issue": "57(6)",
"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
"keywords": "cyclosporine A; food allergy; liver transplantation; tacrolimus",
"medline_ta": "Pediatr Int",
"mesh_terms": "D016572:Cyclosporine; D004791:Enzyme Inhibitors; D005260:Female; D005512:Food Hypersensitivity; D006084:Graft Rejection; D006801:Humans; D007166:Immunosuppressive Agents; D007223:Infant; D008103:Liver Cirrhosis; D016031:Liver Transplantation; D016559:Tacrolimus",
"nlm_unique_id": "100886002",
"other_id": null,
"pages": "1205-7",
"pmc": null,
"pmid": "26541649",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Management of tacrolimus-associated food allergy after liver transplantation.",
"title_normalized": "management of tacrolimus associated food allergy after liver transplantation"
} | [
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{
"abstract": "Okinawa Prefecture, located in the subtropics, is an area of endemic adult T-cell leukemia-lymphoma (ATL) in Japan. We retrospectively analyzed 659 patients with aggressive ATL in seven institutions in Okinawa between 2002 and 2011. The median patient age was 68 years. More patients were aged ≥90 years (2.6 %), in this study, than in a nationwide survey (<1 %). The median survival time (MST) of the entire cohort was 6.5 months. Of the 217 patients who had a clinical status similar to that stated in the eligibility criteria of JCOG9801 (a randomized phase III study comparing VCAP-AMP-VECP with CHOP-14), 147 who received the CHOP regimen had a poorer MST than those in the CHOP-14 arm of JCOG9801 (8 vs 11 months). The prevalence of strongyloidiasis in the ATL patients was much higher (12.4 %) than in the historical cohort who visited the University of the Ryukyus Hospital (3.4 %). Furthermore, strongyloidiasis may be associated with ATL-related deaths. These findings suggest that, compared with other areas in Japan, in Okinawa, the proportion of patients aged ≥90 years with clinical features of aggressive ATL is higher, outcomes are poorer, and the disease is associated with a higher prevalence of strongyloidiasis.",
"affiliations": "Division of Endocrinology, Diabetes and Metabolism, Hematology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.;Laboratory of Hematoimmunology, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan. fukutaku@med.u-ryukyu.ac.jp.;Biostatistics Division, Center for Research and Administration and Support, National Cancer Center, Tokyo, Japan.;Division of Endocrinology, Diabetes and Metabolism, Hematology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.;Division of Endocrinology, Diabetes and Metabolism, Hematology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.;Division of Endocrinology, Diabetes and Metabolism, Hematology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.;Division of Endocrinology, Diabetes and Metabolism, Hematology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.;Division of Endocrinology, Diabetes and Metabolism, Hematology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.;Division of Endocrinology, Diabetes and Metabolism, Hematology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.;Department of Hematology, Heartlife Hospital, Nakagusuku, Japan.;Department of Hematology, Heartlife Hospital, Nakagusuku, Japan.;Department of Hematology, Heartlife Hospital, Nakagusuku, Japan.;Department of Hematology, Heartlife Hospital, Nakagusuku, Japan.;Department of Hematology, Heartlife Hospital, Nakagusuku, Japan.;Department of Hematology, Okinawa Prefectural Chubu Hospital, Uruma, Japan.;Department of Hematology, Nakagami Hospital, Okinawa, Japan.;Department of Hematology, Naha City Hospital, Naha, Japan.;Department of Hematology, Naha City Hospital, Naha, Japan.;Department of Hematology, Okinawa Prefectural Nambu Medical Center and Children's Medical Center, Haebaru, Japan.;Department of Hematology, Okinawa Red Cross Hospital, Naha, Japan.;Laboratory of Hematoimmunology, School of Health Sciences, Faculty of Medicine, University of the Ryukyus, 207 Uehara, Nishihara, Okinawa, 903-0215, Japan.;Department of Pathology and Cell Biology, Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.;Division of Endocrinology, Diabetes and Metabolism, Hematology (Second Department of Internal Medicine), Graduate School of Medicine, University of the Ryukyus, Nishihara, Japan.",
"authors": "Nishi|Yukiko|Y|;Fukushima|Takuya|T|;Nomura|Shogo|S|;Tomoyose|Takeaki|T|;Nakachi|Sawako|S|;Morichika|Kazuho|K|;Tedokon|Iori|I|;Tamaki|Keita|K|;Shimabukuro|Natsuki|N|;Taira|Naoya|N|;Miyagi|Takashi|T|;Karimata|Kaori|K|;Ohama|Masayo|M|;Yamanoha|Atsushi|A|;Tamaki|Kazumitsu|K|;Hayashi|Masaki|M|;Arakaki|Hitoshi|H|;Uchihara|Jun-Nosuke|JN|;Ohshiro|Kazuiku|K|;Asakura|Yoshitaka|Y|;Kuba-Miyara|Megumi|M|;Karube|Kennosuke|K|;Masuzaki|Hiroaki|H|",
"chemical_list": "D014750:Vincristine; D004317:Doxorubicin; D003520:Cyclophosphamide; D011241:Prednisone",
"country": "Japan",
"delete": false,
"doi": "10.1007/s12185-016-2042-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0925-5710",
"issue": "104(4)",
"journal": "International journal of hematology",
"keywords": "Adult T-cell leukemia–lymphoma; Okinawa; Retrospective analysis; Strongyloidiasis; Subtropics",
"medline_ta": "Int J Hematol",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D015331:Cohort Studies; D003520:Cyclophosphamide; D004317:Doxorubicin; D006801:Humans; D007564:Japan; D015459:Leukemia-Lymphoma, Adult T-Cell; D011241:Prednisone; D012189:Retrospective Studies; D013322:Strongyloidiasis; D014750:Vincristine",
"nlm_unique_id": "9111627",
"other_id": null,
"pages": "468-75",
"pmc": null,
"pmid": "27329124",
"pubdate": "2016-10",
"publication_types": "D016428:Journal Article",
"references": "25209605;8475941;11380402;1543206;2886441;12627852;6979048;6261256;2303290;2016910;9988339;25733162;2891797;17717704;6143175;6275274;20479287;7031654;301762;22234682;22185799;1751370;17968021;22689862",
"title": "Characterization of patients with aggressive adult T-cell leukemia-lymphoma in Okinawa, Japan: a retrospective analysis of a large cohort.",
"title_normalized": "characterization of patients with aggressive adult t cell leukemia lymphoma in okinawa japan a retrospective analysis of a large cohort"
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"literaturereference": "NISHI Y, FUKUSHIMA T, NOMURA S, TOMOYOSE T, NAKACHI S, MORICHIKA K, ET AL. CHARACTERIZATION OF PATIENTS WITH AGGRESSIVE ADULT T-CELL LEUKEMIA-LYMPHOMA IN OKINAWA, JAPAN: A RETROSPECTIVE ANALYSIS OF A LARGE COHORT. INTERNATIONAL JOURNAL OF HEMATOLOGY 2016;104 (4):468-75.",
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{
"abstract": "All-trans retinoic acid (ATRA) is the mainstay of treatment in patients with acute promyelocytic leukemia. Despite being effective, it can lead to cardiac complications either as a component of ATRA syndrome or an isolated form denominated as ATRA-induced isolated perimyocarditis. We present a case of this complication and review the literature. (Level of Difficulty: Intermediate.).",
"affiliations": "Hacettepe University School of Medicine Department of Cardiology, Ankara, Turkey.;Hacettepe University School of Medicine Department of Hematology, Ankara, Turkey.;Hacettepe University School of Medicine Department of Radiology, Ankara, Turkey.;Hacettepe University School of Medicine Department of Cardiology, Ankara, Turkey.;Hacettepe University School of Medicine Department of Hematology, Ankara, Turkey.;Hacettepe University School of Medicine Department of Hematology, Ankara, Turkey.",
"authors": "Karakulak|Ugur Nadir|UN|;Aladag|Elifcan|E|;Hazirolan|Tuncay|T|;Ozer|Necla|N|;Demiroglu|Haluk|H|;Goker|Hakan|H|",
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"doi": "10.1016/j.jaccas.2020.09.050",
"fulltext": "\n==== Front\nJACC Case Rep\nJACC Case Rep\nJACC Case Reports\n2666-0849\nElsevier\n\nS2666-0849(20)31217-1\n10.1016/j.jaccas.2020.09.050\nMini-Focus Issue: Cardiomyopathies and Myocarditis\nCase Report: Clinical Case\nAll-trans Retinoic Acid–Induced Isolated Myocarditis\nA Case Report and Review of the Literature\nKarakulak Ugur Nadir MD ugurnadir.karakulak@hacettepe.edu.tr\na∗\nAladag Elifcan MD b\nHazirolan Tuncay MD c\nOzer Necla MD a\nDemiroglu Haluk MD b\nGoker Hakan MD b\na Hacettepe University School of Medicine Department of Cardiology, Ankara, Turkey\nb Hacettepe University School of Medicine Department of Hematology, Ankara, Turkey\nc Hacettepe University School of Medicine Department of Radiology, Ankara, Turkey\n∗ Address for correspondence: Dr. Ugur Nadir Karakulak, Hacettepe University School of Medicine Department of Cardiology, Ankara 06100, Turkey. ugurnadir.karakulak@hacettepe.edu.tr\n18 11 2020\n11 2020\n18 11 2020\n2 13 21012106\n22 5 2020\n8 9 2020\n22 9 2020\n© 2020 The Authors\n2020\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).\nAll-trans retinoic acid (ATRA) is the mainstay of treatment in patients with acute promyelocytic leukemia. Despite being effective, it can lead to cardiac complications either as a component of ATRA syndrome or an isolated form denominated as ATRA-induced isolated perimyocarditis. We present a case of this complication and review the literature. (Level of Difficulty: Intermediate.)\n\nGraphical abstract\n\nKey Words\n\ndrug toxicity\nimaging\nmyocarditis\nAbbreviations and Acronyms\n\nAPL, acute promyelocytic leukemia\nATRA, all-trans retinoic acid\nCRP, C-reactive protein\nCT, computed tomography\nLVEF, left ventricle ejection fraction\nMRI, magnetic resonance imaging\nTTE, transthoracic echocardiography\n==== Body\nA 23-year-old woman diagnosed with acute promyelocytic leukemia (APL) was admitted to the hematology unit. Induction therapy consisting of idarubicin 20 mg/day (on the second, fourth, sixth, and eighth days) and all-trans retinoic acid (ATRA) at a dose of 45 mg/m2/day was initiated. The patient had been well until 18th day from the initiation of therapy. However, she experienced a typical chest pain in the left-retrosternal region without radiating; thus, she was referred to the cardiology clinic for evaluation of chest pain on the 18th day of induction therapy. Her temperature was 36.8°C, blood pressure was 120/70 mm Hg, the heart rate was 86 beats/min, respiratory rate was 12 breaths/min, and the oxygen saturation was 98%. The patient looked anxious.Learning Objectives\n\n• To recognize ATRA-related cardiac complications.\n\n• To understand the clinical course of ATRA-induced perimyocarditis.\n\n• To take action against this complication.\n\nMedical History\n\nThe patient had no medical history or family history of cardiovascular diseases or risk factors. She did not report history of smoking, medication, or drug abuse. Findings on a screening electrocardiogram were normal (Figure 1A). Transthoracic echocardiography (TTE) before the induction therapy revealed no wall motion abnormality and a normal left ventricle ejection fraction (LVEF).Figure 1 The Electrocardiographic Records of the Patient\n\n(A) Baseline electrocardiography before all-trans retinoic acid treatment. (B) Electrocardiography shows ST-segment elevation, mainly in the anterior and lateral derivations during chest pain. (C) Electrocardiography shows resolution of ST-segment elevation after the discontinuation of all-trans retinoic acid.\n\nDifferential Diagnosis\n\nThe differential diagnosis for chest pain in this patient included acute coronary syndrome, viral myocarditis and/or pericarditis, stress cardiomyopathy, and endocarditis.\n\nInvestigations\n\nElectrocardiography revealed ST-segment elevation, mainly in the anterior and lateral derivations (Figure 1B). TTE revealed globally reduced LV systolic function with an EF of 43% (Videos 1, 2, and 3). Speckle tracking echocardiography in the apical 3-chamber view also showed reduced global longitudinal myocardial deformation of –14.0% (Video 4). Laboratory test findings indicated a white blood cell count of 3.9 × 103/μl, troponin I of 2,341.6 ng/l (range: 14 to 42.9 ng/l), C-reactive protein (CRP) of 22.2 mg/dl (range: 0 to 0.8 mg/dl), and procalcitonin of 0.21 ng/ml (range: 0 to 0.14 ng/ml). There were no signs or symptoms suggestive of infection. Coronary computed tomography (CT) was performed promptly and revealed that there was no obstructive lesion in a given coronary artery (Figure 2). In the view of the possibility of ATRA-related toxicity, we ceased to give the ATRA as the troponin level peaked (6,936.3 ng/l) on the 21st day of treatment. Three days later, we reinitiated the drug as troponin values started to decrease below 400 ng/l. Nonetheless, because chest pain was exacerbated and troponin (5,911 ng/l) and CRP (29.4 mg/dl) levels peaked again, the drug was discontinued, and cardiac magnetic resonance imaging (MRI) was performed on the same day. T1 (Figure 3A) and T2 (Figure 3B) mapping showed prolongation in relaxation time in the basal inferolateral region and all segments in the septum, consistent with interstitial edema. In addition, the post-gadolinium T1 mapping showed late enhancement in the inferolateral wall with an extracellular volume fraction of 59% (Figure 3C). LVEF determined by cardiac MRI was 45% and similar to that measured by TTE.Figure 2 The Cardiac Computed Tomography of the Patient\n\nCardiac computed tomography reveals no coronary obstructive lesion in the (A) left and (B) right system. Arrows indicate the crux segment of the right coronary artery.\n\nFigure 3 Cardiac Magnetic Resonance Imaging Findings of the Patient\n\nCardiac magnetic resonance imaging reveals prolonged native myocardial relaxation times in T1-weighted mapping.\n\nA region of interest placed in the septum and the inferolateral wall shows an increase in T1 relaxation times. (A) T1 signal is 1,309 ms for the septum and 1,235 ms for the inferolateral wall, consistent with interstitial edema. (For normal myocardium, the mean/2SD value is 950/42 ms). (B) In the T2 mapping, the area of interstitial edema in the inferior wall has an increased relaxation time of 66 ms (for normal myocardium, mean/2 standard deviations is 50/4 ms). (C) The post-gadolinium T1 mapping shows late enhancement in the inferolateral wall (yellow arrowhead) with an extracellular volume fraction of 59%. max = maximum; min = minimum; SD = standard deviation.\n\nManagement\n\nA beta-blocker and angiotensin-converting enzyme inhibitor were initiated as soon as systolic dysfunction was detected. Because of low platelet count (20,000 × 103/μl), neither an antiplatelet nor an anticoagulant agent could be given. No additional medical treatment was given.\n\nDiscussion\n\nATRA syndrome is characterized by fever, hypotension, pulmonary infiltration, and pericardial effusion; it is seen in one-fourth of the patients receiving ATRA. Cardiac involvement can be seen both as a component of ATRA syndrome and as an isolated perimyocarditis. The clinical picture may resemble acute coronary syndrome and viral myocarditis. It can be difficult to ascertain whether the perimyocarditis is a component of the ATRA syndrome or is a purely drug-related toxic phenomenon. However, it occurs, the pathological mechanism is thought to be caused by ATRA-induced promyelocyte maturation, cytokine release causing increased capillary permeability and endothelial damage, and subsequent extravasation and tissue infiltration of APL cells (1). In our case, the patient did not express other findings suggestive of ATRA syndrome, such as fever, hypotension, respiratory distress, and weight gain due to generalized edema and pleural effusion. Although increase in troponin level, typical chest pain, and changes in electrocardiography and echocardiography findings suggested acute coronary syndrome, the patient’s characteristics and the absence of cardiovascular risk factors raised the suspicion of a drug-related complication. Hence, we performed coronary CT to exclude coronary artery occlusion. Mitigating symptoms with the cessation of the drug and peaking troponin levels after re-initiation of the drug indicated that this clinical picture was ATRA-induced perimyocarditis (Figure 4A). Concomitant increase in CRP (Figure 4B) and procalcitonin levels also suggested the inflammatory nature of the underlying event. Eventually, the diagnosis was confirmed with cardiac MRI findings.Figure 4 The laboratory Findings of the Patient\n\nGraph of (A) troponin I and (B) C-reactive protein levels according to treatment days of the ATRA. ATRA = all-trans retinoic acid.\n\nThus far, there are limited numbers of studies reporting the cases of ATRA-induced isolated perimyocarditis in the literature (Table 1). In these cases, almost all patients were young (9 to 58 years) and experienced the disease within 3 weeks following the initiation of the induction therapy. Our patient’s age (23 years) and the emergence of the disease (18th day) are consistent with the previous cases. Different electrocardiographic changes and different myocardial segment involvements on echocardiography reported in the literature indicate that ATRA does not exhibit a specific involvement pattern. We did not consider anti-inflammatory therapy. In many of the previous case reports, nevertheless, anti-inflammatory therapy such as dexamethasone and prednisone, along with conventional heart failure therapy, was initiated to alleviate myocardial and pericardial inflammation.Table 1 All-trans Retinoic Acid–Induced Isolated Perimyocarditis Cases in the Literature\n\nFirst Author (Ref. #)\tYear\tAge (yrs), Sex\tDay of Occurrence∗\tEjection Fraction, %\tWall Motion Abnormalities\tTreatment\tChanges on Electrocardiography\t\nChoi et al. (2)\t2011\t39, female\t18\t38\tBasal and midanterior\tDexamethasone and diuretic\tNo change\t\nBen El Makki et al. (3)\t2019\t27, male\t10\t33\tDiffuse\tVasopressors, diuretic,\nACE inhibitor, beta blocker\tDiffuse ST-segment elevation\t\nKlein et al. (4)\t2007\t34, female\t19\tNo data\tNo data\tNo specific treatment\tDiffuse ST-segment elevation\t\nKlein et al. (4)\t2007\t46, male\t23\tNo data\tDiffuse\tNo specific treatment\tDiffuse ST-segment elevation\t\nFabbiano et al. (5)\t2005\t45, male\t23\tNo data\tPosterolateral\tNo specific treatment\tLateral ST-segment elevation\nV1 to V2 ST-segment depression\t\nVan Rijssel et al. (6)\t2010\t58, male\t21\tNo data\tNo data\tThe patient died 2 days later\tNo data\t\nCarcelero et al. (7)\t2018\t35, male\t16\t35\tDiffuse\tAnti-inflammatory agents, diuretics, ACE inhibitor, and dobutamine\tDiffuse ST-segment elevation\t\nIsik et al. (8)\t2010\t9, female\tWithin first week\t40\tDiffuse\tPrednisolone, inotropics, and diuretics\tDiffuse voltage depression\t\nACE = angiotensin-converting enzyme.\n\n∗ Day of occurrence indicates how many days the event occurred after induction therapy.\n\nFollow-Up\n\nThe patient was completely asymptomatic and the troponin level (4.2 ng/l) was within normal limits 3 days after the discontinuation. CRP (0.503 mg/dl) and procalcitonin (0.016 ng/ml) also returned to their normal levels 10 days after the discontinuation. Electrocardiogram showed resolution of ST-segment elevation (Figure 1C). TTE revealed normal LV systolic function with an EF of 56% (Videos 5, 6, and 7). Speckle tracking echocardiography in the apical 3-chamber view indicated normal global longitudinal myocardial deformation of –27.7% (Video 8). Arsenic trioxide has been initiated for leukemia treatment.\n\nConclusions\n\nATRA-induced isolated perimyocarditis should be kept in mind in patients with APL. Although rare, it warrants high suspicion and early detection because it can cause devastating complications. In the present case, we demonstrated the ATRA-induced isolated perimyocarditis by using a variety of imaging modalities including 2- and 3-dimensional echocardiography, coronary CT, and cardiac MRI. In our case, the complete recovery of myocardial function was achieved by discontinuation of ATRA and conventional heart failure therapy.\n\nAuthor Disclosures\n\nThe authors have reported that they have no relationships relevant to the contents of this paper to disclose.\n\nAppendix\n\nSupplemental Video 1\n\nSupplemental Video 2\n\nSupplemental Video 3\n\nSupplemental Video 4\n\nSupplemental Video 5\n\nSupplemental Video 6\n\nSupplemental Video 7\n\nSupplemental Video 8\n\nThe authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the JACC: Case Reportsauthor instructions page.\n\nAppendix\n\nFor supplemental videos, please see the online version of this paper.\n==== Refs\nReferences\n\n1 Fenaux P. De Botton S. Retinoic acid syndrome. Recognition, prevention and management Drug Safety 18 1998 273 279 9565738\n2 Choi S. Kim H.S. Jung C.S. Reversible symptomatic myocarditis induced by all-trans retinoic acid administration during induction treatment of acute promyelocytic leukemia: rare cardiac manifestation as a retinoic acid syndrome J Cardiovasc Ultrasound 19 2011 95 98 21860725\n3 Ben El Makki A. Mahtat E.M. Kheyi J. Bouzelmat H. Chaib A. A rare case of perimyocarditis induced by all-trans retinoic acid administration during induction treatment of acute promyelocytic leukemia Med Pharm Rep 92 2019 418 420 31750445\n4 Klein S.K. Biemond B.J. van Oers M.H. Two cases of isolated symptomatic myocarditis induced by all-trans retinoic acid (ATRA) Ann Hematol 86 2007 917 918 17619879\n5 Fabbiano F. Magrin S. Cangialosi C. Felice R. Mirto S. Pitrolo F. All-trans retinoic acid induced cardiac and skeletal myositis in induction therapy of acute promyelocytic leukaemia Br J Haematol 129 2005 444 445 15842672\n6 van Rijssel R.H. Wegman J. Oud M.E. Pals S.T. van Oers M.H. A case of ATRA-induced isolated myocarditis in the absence of circulating malignant cells: demonstration of the t(15;17) translocation in the inflammatory infiltrate by in situ hybridisation Leuk Res 34 2010 e142 e144 20060166\n7 Carcelero San Martin E. Riu Viladoms G. Creus Baro N. Severe myopericarditis following induction therapy with idarubicin and transretinoic acid in a patient with acute promyelocytic leukemia Med Clin (Barc) 150 2018 492 493 29196036\n8 Isik P. Cetin I. Tavil B. All-transretinoic acid (ATRA) treatment-related pancarditis and severe pulmonary edema in a child with acute promyelocytic leukemia J Pediatr Hematol Oncol 32 2010 e346 e348 20881874\n\n",
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"abstract": "We present a 58-year-old man with recurrent multiple myeloma treated with 2 autologous stem cell transplantations. He was admitted for dyspnea and found to have severe type B lactic acidosis with serum lactate level of 193.6 mg/dL. This case reviews malignancy-associated type B lactic acidosis and discusses its etiology, pathogenesis, and management.",
"affiliations": "University of Nebraska Medical Center, Omaha, NE 68198-3040, USA.",
"authors": "Sia|Patrick|P|;Plumb|Troy J|TJ|;Fillaus|Jennifer A|JA|",
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"abstract": "Lidocaine is the most common medication used for local anesthesia in cardiac procedures. Sometimes, a higher dose of lidocaine is used to improve the patient's comfort, especially in device implantation or complex interventional procedures requiring several sheath insertions for access. We describe a patient with idiopathic cardiomyopathy who underwent implantable cardioverter defibrillator implantation for primary prevention and developed local anesthetic systemic toxicity (LAST) associated with lidocaine use. Multiple susceptible factors leading to lidocaine toxicity found in this case are common in patients with advanced heart failure. This case emphasizes the importance of dose adjustment of local anesthetic agents in individual patients, especially those with advanced heart failure who undergo cardiovascular procedures. The risk factors, preventive measures, and therapeutic approaches to manage this type of complication are discussed in detail.",
"affiliations": "Cardiac Arrhythmia Service, 1295 NW 14th Street, Suite 4062, Miami, FL 33136 USA. j.vilesgonzalez@med.miami.edu.",
"authors": "Tanawuttiwat|Tanyanan|T|;Thisayakorn|Piyapon|P|;Viles-Gonzalez|Juan F|JF|",
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"title": "LAST (local anesthetic systemic toxicity) but not least: systemic lidocaine toxicity during cardiac intervention.",
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} | [
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Discomfort",
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"reactionoutcome": null
},
{
"reactionmeddrapt": "Generalised tonic-clonic seizure",
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"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Respiratory acidosis",
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"reactionoutcome": "6"
},
{
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},
{
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},
{
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}
],
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},
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},
"reporttype": "1",
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"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20150326"
},
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"medicinalproduct": "LIDOCAINE HYDROCHLORIDE (WATSON LABORATORIES)"
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"medicinalproduct": "CARVEDILOL."
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"actiondrug": "5",
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"activesubstancename": "CANDESARTAN"
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},
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"drugstructuredosageunit": "003",
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"medicinalproduct": "ISOSORBIDE DINITRATE."
}
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"patientonsetageunit": "801",
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"reaction": [
{
"reactionmeddrapt": "Overdose",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Pulseless electrical activity",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Generalised tonic-clonic seizure",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Acidosis",
"reactionmeddraversionpt": "18.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TANAWUTTIWAT T, THISAYAKORN P, VILES-GONZALEZ JF. LAST (LOCAL ANESTHETIC SYSTEMIC TOXICITY) BUT NOT LEAST: SYSTEMIC LIDOCAINE TOXICITY DURING CARDIAC INTERVENTION. J INVASIVE CARDIOL. 2014;26(1):E13-5.",
"literaturereference_normalized": "last local anesthetic systemic toxicity but not least systemic lidocaine toxicity during cardiac intervention",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20141002",
"receivedate": "20141002",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 10492811,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
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"seriousnesshospitalization": null,
"seriousnesslifethreatening": null,
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}
] |
{
"abstract": "To estimate the incidence of immune checkpoint inhibitor-related myositis (ICI-myositis) in cancer patients receiving ICIs, and to report associated clinical manifestations, patterns of care, and outcomes.\n\n\n\nWe identified a retrospective cohort of patients receiving ICIs between 2016 and 2019 seen at the University of Texas MD Anderson Cancer Center. Cases of ICI-myositis were identified using International Classification of Disease codes and confirmed by reviewing medical records and pathology, as available.\n\n\n\nA total of 9,088 patients received an ICI. Thirty-six patients (0.40%) were identified as having ICI-myositis: 17 patients (47%) with ICI-myositis alone and 19 (53%) with overlap manifestations (5 patients with myocarditis, 5 with myasthenia gravis, and 9 with both). The incidence of ICI-myositis was 0.31% in those receiving ICI monotherapy and 0.94% in those receiving combination ICI therapy (relative risk 3.1 [95% confidence interval 1.5-6.1]). Twenty-five patients (69%) received ≥1 treatment in addition to glucocorticoids: plasmapheresis in 17 patients (47%), intravenous immunoglobulin in 12 (33%), and biologics in 11 (31%). Patients with overlap conditions had worse outcomes than those with myositis alone, and 79% of them developed respiratory failure. Eight patients died as a result of ICI-myositis, and all had overlap syndrome with myasthenia gravis or myocarditis (P < 0.05); 75% of these patients had a concomitant infection.\n\n\n\nICI-myositis is a rare but severe adverse event. More than half of the patients presented with overlap manifestations and had deleterious outcomes, including respiratory failure and death. None of the patients with ICI-myositis alone died as a result of adverse events. Optimal treatment strategies have yet to be determined.",
"affiliations": "University of Texas MD Anderson Cancer Center, Houston.;University of Texas MD Anderson Cancer Center, Houston.;University of Texas MD Anderson Cancer Center, Houston.;University of Texas MD Anderson Cancer Center, Houston.;University of Texas MD Anderson Cancer Center, Houston.;University of Texas MD Anderson Cancer Center, Houston.;University of Texas MD Anderson Cancer Center, Houston, and Assiut University Hospitals, Assiut, Egypt.;University of Texas MD Anderson Cancer Center, Houston.;University of Texas MD Anderson Cancer Center, Houston.",
"authors": "Aldrich|Jeffrey|J|0000-0002-8896-1222;Pundole|Xerxes|X|;Tummala|Sudhakar|S|;Palaskas|Nicolas|N|;Andersen|Clark R|CR|;Shoukier|Mahran|M|;Abdel-Wahab|Noha|N|;Deswal|Anita|A|;Suarez-Almazor|Maria E|ME|0000-0001-5381-5797",
"chemical_list": "D000082082:Immune Checkpoint Inhibitors",
"country": "United States",
"delete": false,
"doi": "10.1002/art.41604",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2326-5191",
"issue": "73(5)",
"journal": "Arthritis & rheumatology (Hoboken, N.J.)",
"keywords": null,
"medline_ta": "Arthritis Rheumatol",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D005260:Female; D006801:Humans; D000082082:Immune Checkpoint Inhibitors; D007239:Infections; D008297:Male; D008875:Middle Aged; D009157:Myasthenia Gravis; D009205:Myocarditis; D009220:Myositis; D009369:Neoplasms; D012131:Respiratory Insufficiency; D012189:Retrospective Studies",
"nlm_unique_id": "101623795",
"other_id": null,
"pages": "866-874",
"pmc": null,
"pmid": "33258544",
"pubdate": "2021-05",
"publication_types": "D016428:Journal Article; D052061:Research Support, N.I.H., Extramural",
"references": null,
"title": "Inflammatory Myositis in Cancer Patients Receiving Immune Checkpoint Inhibitors.",
"title_normalized": "inflammatory myositis in cancer patients receiving immune checkpoint inhibitors"
} | [
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},
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"medicinalproduct": "MYCOPHENOLATE MOFETIL."
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"activesubstancename": "METHYLPREDNISOLONE"
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"medicinalproduct": "METHYLPREDNISOLONE."
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},
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"drugauthorizationnumb": "103705",
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"medicinalproduct": "RITUXIMAB."
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"actiondrug": "6",
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"activesubstancename": "INFLIXIMAB"
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"medicinalproduct": "INFLIXIMAB"
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"reactionmeddraversionpt": "24.0",
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},
{
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{
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{
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},
{
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"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Candida infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Enterobacter infection",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Myocarditis",
"reactionmeddraversionpt": "24.0",
"reactionoutcome": "5"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "ALDRICH J, PUNDOLE X, TUMMALA S, PALASKAS N, ANDERSEN, SHOUKIER M, ABDEL?WAHAB N, DESWAL A AND SUAREZ?ALMAZOR M. INFLAMMATORY MYOSITIS IN CANCER PATIENTS RECEIVING IMMUNE CHECKPOINT INHIBITORS. ARTHRITIS AND RHEUMATOLOGY 2021 MAY?73 (5):866?74.",
"literaturereference_normalized": "inflammatory myositis in cancer patients receiving immune checkpoint inhibitors",
"qualification": "1",
"reportercountry": "US"
},
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"receiptdate": "20210827",
"receivedate": "20210827",
"receiver": {
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},
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},
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"transmissiondate": "20211014"
}
] |
{
"abstract": "BACKGROUND\nAcute pancreatitis is an uncommon complication of anti-myeloma agents. Ixazomib is a first-in-class oral proteasome inhibitor to receive regulatory approval for the treatment of multiple myeloma. This case report describes the first case of ixazomib-associated pancreatitis.\n\n\nMETHODS\nAn 80-year-old female with relapsed multiple myeloma presented with severe diarrhea, nausea, vomiting, abdominal pain, and acute renal failure 3 weeks after starting ixazomib and dexamethasone for disease progression. An extensive workup revealed acute pancreatitis without a definitive cause. Her condition improved with supportive measures and the discontinutation of ixazomib. The latter was suspected as the probable etiology of the patient's acute pancreatitis, given no clear alternative causes and the temporal relationship between initiating ixazomib and the development of her symptoms.\n\n\nCONCLUSIONS\nPractitioners should include acute pancreatitis as part of their differential diagnosis in patients on ixazomib treatment who present with gastrointestinal symptoms.",
"affiliations": null,
"authors": "Steiner|Raphael E|RE|;Orlowski|Robert Z|RZ|;Lee|Hans C|HC|",
"chemical_list": "D000970:Antineoplastic Agents; D001896:Boron Compounds; C548400:ixazomib; D005998:Glycine",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000484655",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0001-5792",
"issue": "139(1)",
"journal": "Acta haematologica",
"keywords": "Acute pancreatitis; Ixazomib; Myeloma; Proteasome inhibitors",
"medline_ta": "Acta Haematol",
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"abstract": "Symptomatic hyponatremia is considered a rare complication of oral bowel preparation for colonoscopy. The pathophysiology underlying this phenomenon has been widely regarded as a mere sequela of excessive arginine vasopressin (AVP) release.\n\n\n\nThis case describes a 61-year old woman who developed acute hyponatremic encephalopathy when preparing for elective outpatient lower endoscopy. She had had negligible oral solute intake for two days and ingested four liters of clear fluid within two hours. On admission, the patient was agitated and had slurred speech. Treatment with hypertonic saline lead to full recovery. A brisk aquaresis confirmed acute dilutional hyponatremia.\n\n\n\nApart from elevated AVP-levels, the amount and speed of fluid intake and concomitant low-solute intake constitute important risk factors in the development of clinically relevant hyponatremias in patients undergoing colonoscopies. Understanding that the cause of sodium imbalance in this scenario is multifactorial and complex is pivotal to recognizing and ideally preventing this complication, for which we propose the term \"bowel prep hyponatremia\".",
"affiliations": "Fourth Department of Medicine, Section of Nephrology, Klinikum Wels-Grieskirchen, Grieskirchnerstraße 42, 4600, Wels, Austria. martin.windpessl@klinikum-wegr.at.;First Department of Medicine, Landeskrankenhaus Steyr, Steyr, Austria.;Fourth Department of Medicine, Section of Nephrology, Klinikum Wels-Grieskirchen, Grieskirchnerstraße 42, 4600, Wels, Austria.",
"authors": "Windpessl|Martin|M|0000-0002-6273-7513;Schwarz|Christoph|C|;Wallner|Manfred|M|",
"chemical_list": "D012462:Saline Solution, Hypertonic",
"country": "England",
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"doi": "10.1186/s12882-017-0464-2",
"fulltext": "\n==== Front\nBMC NephrolBMC NephrolBMC Nephrology1471-2369BioMed Central London 46410.1186/s12882-017-0464-2Case Report“Bowel prep hyponatremia“ – a state of acute water intoxication facilitated by low dietary solute intake: case report and literature review http://orcid.org/0000-0002-6273-7513Windpessl Martin +43 (0)724241592194martin.windpessl@klinikum-wegr.at 1Schwarz Christoph christoph.schwarz@gespag.at 2Wallner Manfred manfred.wallner@klinikum-wegr.at 11 0000 0004 0522 7001grid.459707.8Fourth Department of Medicine, Section of Nephrology, Klinikum Wels-Grieskirchen, Grieskirchnerstraße 42, 4600 Wels, Austria 2 First Department of Medicine, Landeskrankenhaus Steyr, Steyr, Austria 7 2 2017 7 2 2017 2017 18 5421 6 2016 26 1 2017 © The Author(s). 2017\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.Background\nSymptomatic hyponatremia is considered a rare complication of oral bowel preparation for colonoscopy. The pathophysiology underlying this phenomenon has been widely regarded as a mere sequela of excessive arginine vasopressin (AVP) release.\n\nCase presentation\nThis case describes a 61-year old woman who developed acute hyponatremic encephalopathy when preparing for elective outpatient lower endoscopy. She had had negligible oral solute intake for two days and ingested four liters of clear fluid within two hours. On admission, the patient was agitated and had slurred speech. Treatment with hypertonic saline lead to full recovery. A brisk aquaresis confirmed acute dilutional hyponatremia.\n\nConclusion\nApart from elevated AVP-levels, the amount and speed of fluid intake and concomitant low-solute intake constitute important risk factors in the development of clinically relevant hyponatremias in patients undergoing colonoscopies. Understanding that the cause of sodium imbalance in this scenario is multifactorial and complex is pivotal to recognizing and ideally preventing this complication, for which we propose the term “bowel prep hyponatremia”.\n\nKeywords\nBowel preparationColonoscopyHyponatremiaWater intoxicationLow-solute hyponatremiaCase reportissue-copyright-statement© The Author(s) 2017\n==== Body\nBackground\nColonoscopy is the gold standard method for colorectal cancer screening with millions being performed each year [1, 2]. A prerequisite for high quality examinations, oral bowel-cleansing preparations have been demonstrated to be safe for use in individuals without significant comorbidities. On rare occasions, however, profound electrolyte abnormalities can ensue [2]. While the role of the various purgatives and the effect of non-osmotic arginine vasopressin (AVP) release as a trigger for hyponatremia in this clinical setting have been extensively discussed, the importance of two other contributory factors, namely preceding low dietary solute intake and the amount and speed of concomitant water intake, has not been appreciated to date. Free water clearance is significantly impaired if solute intake is markedly decreased and electrolyte-free water intake is high, predisposing individuals to dilutional hyponatremia, as exemplified by our case. In all, this scenario is reminiscent of acute hyponatremia in marathon runners. When preparing for colonoscopy, the inevitably restricted diet plays a crucial role in the development of what we propose to call “bowel prep hyponatremia“.\n\nCase presentation\nA 61-year-old woman was admitted because of sudden onset of confusion and slurred speech. In preparation for an elective outpatient colonoscopy she had commenced bowel preparation four hours earlier with sodium picosulfate/magnesium citrate (PICOLAX ®). As instructed, she had ingested two liters of water and two liters of tea, albeit within two hours. Shortly thereafter, she felt nauseous, dizzy and vomited repeatedly. Her husband found her confused with unintelligible speech and unsteady gait and called the ambulance.\n\nOn physical examination, the patient appeared agitated and her speech was incomprehensible. She weighed 56 kg and her height was 168 cm (BMI 19.9 kg/m2). Vital signs were as follows: Afebrile, blood pressure 132/66 mmHg, pulse 82 beats/min. The patient was clinically euvolemic and could follow verbal commands. No lateralizing signs were found on neurological examination but generalized tremor was present. Acute CT scanning of the brain did not reveal any abnormalities.\n\nHer medical records showed a history of hypothyroidism for which she took levothyroxine. She was a non-smoker and did not drink alcohol. Family history was unremarkable and there was no history of diuretic use or anorexia, as corroborated by her husband.\n\nIn the emergency department, biochemistry results were as follows: Serum sodium 122 mmol/l, potassium 3.1 mmol/l, chloride 87 mmol/l, BUN 14.8 mg/dl, creatinine 1.1 mg/dl, uric acid 4.1 mg/dl, glucose 108 mg/dl. Serum osmolality was 251 mOsm/kg. In view of the patient’s symptoms and the clear time of onset, acute hyponatremia was deemed likely and treatment with hypertonic saline (3%) at a rate of 50 ml/h was commenced. Urine osmolality was not done on admission but was 232 mOsm/kg with a urinary sodium of 39 mmol/l when tested two hours later. Thyroid-stimulating hormone was suppressed under replacement therapy. The sodium level increased to 128 mmol/l within the ensuing four hours. In parallel, the patient’s symptoms abated. Twelve hours after admission, she had voided 2600 ml of urine and her mentation and electrolytes had normalized.\n\nOn further questioning, it transpired that the patient had had very limited food intake prior to the scheduled procedure. On the day before admission (two days before the endoscopy appointment), her diet consisted of carrot-ginger soup with white bread for lunch and rusk with tea for dinner. The next day, a breakfast consisting of two slices of plain toast and a cup of coffee, followed by a broth at lunchtime, was all she had to eat. No additional salt had been added to her meals. Furthermore, the patient had been taking a nonsteroidal anti-inflammatory drug (NSAID) for the last five days because of shoulder pain (Diclofenac 50 mg bid). A diagnosis of hyponatremic encephalopathy due to acute water intoxication facilitated by poor dietary solute intake was made. On follow-up appointment 1 week later, the patient was well and electrolytes were normal. Adrenal function was tested and found to be intact.\n\nDiscussion and conclusions\nEssentially a disorder of water balance, hyponatremia is the most prevalent electrolyte abnormality in clinical practice [3]. Acute hyponatremia is frequently associated with major neurologic manifestations including seizures, coma, permanent brain damage, and death [3, 4]. It is often encountered in hospitalized patients, typically in the postoperative state in the context of pain and nausea, both well-known triggers of non-osmotic AVP-release, and concomitant treatment with electrolyte free water solutions such as 5% dextrose. The development of hyponatremia in the extra-hospital setting is less well recognized. Exercise-induced hyponatremia, for instance following marathon runs, constitutes a prime example; in this setting, high fluid intake and non-osmotic AVP-release are main contributors to acute water intoxication, too [5]. In a chart review involving more than thousand hyponatremic patients presenting to an emergency department, only eleven patients (0.8%) were identified with acute hyponatremia [4].\n\nColonoscopy remains the method of choice for evaluation of the large intestine [6]. Adequate colonic cleansing is crucial for the quality of the examination and various purgative regimens are available to this end. While polyethylene glycole (PEG) is still considered the prototypical agent, picosulfate/magnesium citrate (PICOLAX ®) was found to be equally effective and is regularly used in Europe [7]. Although generally safe in the healthy population, significant adverse effects have been reported following bowel preparation and encompass pulmonary aspiration, anaphylaxis and electrolyte disturbances, amongst others [8, 9].\n\nAcute water intoxication in preparation for colonoscopy was first reported by Schröppel et al. [9]. Their patient was a 59-year old woman who had ingested 7 liters of fluid over a 7-h period. Her sodium was 122 mmol/l on admission and her clinical course was strikingly similar to our patient’s.\n\nIn 2003, Ayus and colleagues reported the clinical course of three patients who developed profound dysnatremias as a complication of elective colonoscopy [10]. While two male patients exhibited significant comorbidities and proceeded to undergo endoscopy, ultimately with a fatal outcome, the index patient was a comparatively healthy woman of 62 years who developed status epilepticus after bowel preparation and was found to have severe hyponatremia (116 mmol/l).\n\nSince then, more than a dozen additional cases of symptomatic “bowel prep hyponatremia” have been reported in the medical literature [11–20]. In these cases, the median patient age was 69.5 years with only two patients younger than 50 years; 17 of 18 patients were female. The role of the various purgatives is discussed extensively in these reports and the principal pathophysiological focus is placed on the risk of volume depletion following bowel preparation triggering AVP-stimulation [19, 21]. Accordingly, patients are generally encouraged to drink fluids liberally [16, 21].\n\nHowever, information is scarce on two other crucial aspects of renal water handling, namely the amount of dietary solute intake before endoscopy and the characteristics of concomitant fluid ingestion. Specifically, none of the previous reports specified the particular dietary components prior to endoscopy in detail and only limited information is given with regard to the amount and speed of fluid intake (Table 1).Table 1 Characteristics and presentation of patients with symptomatic hyponatremia related to bowel preparation reported in the literature\n\nReference\tAge\tGender\tNa Nadir\tPresentation\tPrep\tTime\tDiet\tUosm\n\tUNa\n\tUK\n\t\n4\t54\tf\t119\tBizarre behavior\t4.5 l PEG\t-\t-\t-\t-\t-\t\n9\t59\tf\t120\tSeizure\t3 l PEG-ELS + 4 l tea\t7\t-\t185\t22\t5\t\n10\t62\tf\t116\tSeizure\t4 l PEG-ELS + water\t-\t-\t-\t-\t-\t\n11\t75\tf\t116\tSeizure\tSP\t-\t-\t-\t-\t-\t\n11\t64\tf\t111\tSeizure\tSPS/MC\t-\t-\t-\t-\t-\t\n11\t24\tf\t132\tSeizure\tSP\t-\t-\t-\t-\t-\t\n12\t79\tf\t108\tComa\t“cathartics”\t-\t-\t-\t-\t-\t\n13\t73\tf\t117\tSeizure\tPEG + 64 ounces of Gatorade\t-\t-\t390\t146\t35.7\t\n14\t80\tf\t110\tSeizure\tSPS/MC\t-\t-\t-\t-\t-\t\n15\t70\tf\t110\tSeizure\t4 l PEG + 3 l water\t-\t-\t-\t-\t-\t\n15\t65\tf\t127\tSeizure\t4 l PEG\t-\t-\t-\t-\t-\t\n16\t34\tm\t117\tEncephalopathy\tBis + Man + > 6 l water\t-\tsmall breakfast, broth\t-\t-\t-\t\n17\t57\tf\t120\tRhabdomyolysis\tSPS/MC + Bis\t-\tliquid diet for 3 days\t-\t67\t24\t\n18\t69\tf\t113\tSeizure\t4 l PEG\t-\t-\t344\t122\t28.5\t\n19\t76\tf\t112\tSeizure\tSPS/MC\t-\t-\t370\t-\t-\t\nPresent case\t61\tf\t122\tEncephalopathy\t2 l SPS/MC + 2 l tea\t2\tbroth, rusk for 2 days\t232\t39\t-\t\n\nAbbreviations: Na-Nadir lowest serum sodium concentration recorded (mmol/l), Prep type of bowel preparation used and amount of fluid ingested in preparation for endoscopy (l), time speed of fluid ingestion (hours), U osm urine osmolality (mosm/l), U\nNa urine sodium (mmol/l) U\nk urine potassium (mmol/l), PEG polyethylene glycol, PEG-ELS PEG/electrolyte lavage solution, SP sodium phosphate, SPS/MC sodium picosulfate/magnesium citrate, Bis/Man bisacodyl/mannitol\n\n\n\n\nRenal water excretion is largely guided by AVP release. While its main determinant is plasma osmolality, several non-osmotic stimuli such as nausea and anxiety exist. In a case series involving 40 patients, raised AVP concentration after bowel cleansing but prior to endoscopy was found in 25% [20]. Therefore hyponatremia in this context has been traditionally regarded as a mere form of excessive AVP release [18, 20].\n\nThe importance of dietary solute intake is a lesser known facet of renal water excretion. A normal kidney can excrete urine with a concentration in the range of 50 mOsm/kg to 1200 mOsm/kg. Although the diluting capacity decreases with age, it generally allows for a broad range of water intake without the development of dilutional hyponatremia [22]. Up to 20 liters of water may be ingested over a 24-h period before serum sodium concentration begins to fall [23]. However, this assumes consumption of a normal diet containing adequate salt and protein. The average western diet yields approximately 800 mOsm of solutes per day, mainly derived from urea generation through protein metabolism, in addition to dietary electrolytes (mainly sodium and potassium) [24].\n\nAs demonstrated elegantly by Berl, urine excretion is dependent on solutes in urine that act as osmoles [22]. The maximum volume of urine excretion per day can be estimated by dividing the total daily solute excretion (roughly equal to the amount of solute intake) by the minimum urine osmolality in a given patient. If the minimum urine osmolality is 50 mosm/l (i.e. maximally dilute urine), then the daily urine volume will be 16 liters maximally (800 mOsm/day/50 mosm/kg = 16 l/day); in other words, the maximum water excretion per hour is approximately 700 ml. However, if sodium and overall food intake is limited, daily solute load can fall to 250 mOsm [23]. Under such circumstances, the maximum urine volume per day is only 5 liters (250/50), or about 200 ml per hour. If more fluid is ingested, particulary in a short period of time, dilutional hyponatremia will ensue. Consequently, restricted diets, when accompanied by copious water intake, can culminate in hyponatremia, with beer potomania constituting the prototypical example. Other forms of poor nutritional intake have been associated with hyponatremia, such as ovolactovegetarism, “tea and toast“diet“ of the elderly and “crash diets“ [25–27]. The underlying pathophysiological phenomenon has been dubbed “low solute hyponatremia“ [23]. Obviously, temporary food restriction is part of the preparation for colonoscopy; dietary regimens for colonic cleansing incorporate clear liquids and low-residue foods “during one to four days” [6].\n\nOur patient’s diet on the two days preceeding her scheduled examination was virtually devoid of protein and sodium. Although we cannot specify exactly the amount of solutes ingested within the two days before admission in this case, it seems to be within the range of a previous case report [27].\n\nThe quantity and speed of water intake is another factor which merits emphasis. Although the manufacturer of PICOLAX ® recommends drinking “approximately 250 ml per hour of water or other clear fluid while the washout persists”, this advice was neither heeded by our patient nor was the recommended speed of fluid intake specified in the information leaflet [28]. Furthermore, leaflets occasionally instruct patients to “disregard the manufacturer’s instructions” [16]. Symptomatic hyponatremia can be induced by an acute water load in various scenarios, for instance prior to a sonographic examination or urine drug testing [29, 30]. As our patient ingested four liters of water within just two hours (about 70 ml/kg), her renal capacities for water elimination were obviously overwhelmed. Again, only one previous case report specifies the speed of fluid intake [9].\n\nIn theory, agents that induce an osmotic diarrhea should not allow relevant intestinal water absorption. However, there is anecdotal evidence of sodium and water retention after bowel preparation with PEG [31]. Furthermore, PICOLAX® is a combined formulation, one sachet containing magnesium oxide, sodium picosulfate and citric acid. While magnesium citrate is an osmotic laxative, sodium picosulfate is a pro-drug that is hydrolyzed by colonic bacteria to the active metabolite, which acts as a stimulant laxative [32]. Physiologically, most intestinal fluid is absorbed in the small bowel, consequently, rapid transit of the agent into the colon could allow subsequent water ingestion to be absorbed efficiently.\n\nThe patient presented was water intoxicated, but her urine was not maximally dilute, although urine osmolality was less than serum osmolality. Notably, low urine osmolality is not consistently found in low solute hyponatremia, as shown in a review involving 22 cases of beer potomania [24]. In our case, urine osmolality on admission is not known but a value of 232 mOsm/kg a few hours later is in keeping with ongoing AVP secretion, with various causes described above [20].\n\nThe brisk aquaresis after treatment with hypertonic saline renders support to our hypothesis that low solute intake contributed to the development of the hyponatremia. As described in cases of beer potomania or psychogenic polydipsia, the supplementation of osmotic agents (such as protein or salt) swiftly increases urine production, because the ratio of solute intake or excretion to urine osmolality determines urinary volume.\n\nLastly, NSAID are known to augment AVP effects and our patient’s diclofenac intake may have increased her vulnerability for water intoxication [5].\n\nTo avoid potentially devastating complications, we suggest to instruct patients at risk, in particular women above 50 years of age, to ensure liberal salt intake and sufficient protein intake on the days before endoscopy and to refrain from overdrinking, manifested in weight gain. Split-dose bowel-prep regimens, as opposed to day-before regimens, may be superior in this regard [33].\n\nHyponatremia has been dubbed “a forgotten consequence of bowel preparation for colonoscopy” [34]. When too much fluid is ingested in too little time, concomitant low dietary solute intake is a fundamental factor predisposing patients to “bowel prep hyponatremia”, particulary in the context of ongoing AVP secretion. Understanding that the cause of sodium imbalance is multifactorial is pivotal to recognizing and ideally preventing this complication.\n\nAbbreviations\nAVPArginine vasopressin\n\nBMIBody mass index\n\nCTComputed tomography\n\nNSAIDNonsteroidal anti-inflammatory drug\n\nAcknowledgement\nThe authors thank Dr. Roland Nömeyer for critical reading of the manuscript.\n\nFunding\nNone.\n\nAvailability of data and materials\nData regarding the case report belongs to clinical and laboratory charts stored in the hospital repository and cannot be shared.\n\nAuthors’ contributions\nMW drafted the manuscript. CS and MW expanded the discussion and revised the manuscript. All authors read and approved the final manuscript.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nConsent for publication\nThe patient gave informed consent on the publication of data. A copy of the written consent is available for review by the Editor of this journal.\n\nEthics approval and consent to participate\nNot applicable.\n\nDeclarations\nThe authors confirm that CARE guidelines/methodology were adhered to.\n==== Refs\nReferences\n1. Seeff LC Richards TB Shapiro JA How many endoscopies are performed for colorectal cancer screening? Results from CDC’s survey of endoscopic capacity Gastroenterology 2004 127 1670 1677 10.1053/j.gastro.2004.09.051 15578503 \n2. Connor A Tolan D Hughes S Carr N Tomson C Consensus guidelines for the safe prescription and administration of oral bowel-cleansing agents Gut 2012 61 1525 1532 10.1136/gutjnl-2011-300861 22842619 \n3. 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Spengos K Vassilopoulou S Tsivgoulis G Dimitrakopoulos A Toulas P Vassilapoulos D Hyponatraemia and central pontine myelinolysis after elective colonoscopy Eur J Neurol 2005 12 322 323 10.1111/j.1468-1331.2004.00991.x 15804252 \n13. Nagler J Poppers D Turetz M Severe hyponatremia and seizure following a polyethylene glycol-based bowel preparation for colonoscopy J Clin Gastroenterol 2006 40 558 559 10.1097/00004836-200607000-00017 16825941 \n14. Dillon CE Laher MS The rapid development of hyponatraemia and seizures in an elderly patient following sodium picosulfate/magnesium citrate (Picolax) Age Ageing 2009 38 487 10.1093/ageing/afp054 19406975 \n15. Baeg MK, Park JM, Ko SH, et al. Seizures due to hyponatremia following polyethylene glycol preparation; a report of two cases. Endoscopy. 2013; 45 Suppl 2 UCTN:E269-270.\n16. Veitenhansl M Reisch N Schmauss S Wörnle M Gärtner R Hyponatraemic encephalopathy and rhabdomyolysis. Complications after preparation for colonoscopy with mannitol Internist (Berl) 2007 48 625 629 10.1007/s00108-007-1815-z 17333050 \n17. Más A Chillarón JJ Esteve E Navalpotro I Supervía A Severe rhabdomyolysis and hyponatremia induced by picosulfate and bisacodyl during the preparation of colonoscopy Rev Esp Enferm Dig 2013 105 180 181 10.4321/S1130-01082013000300016 23735032 \n18. Ko SH Lim CH Kim JY Kang SH Baeg MK Oh HJ Case of inappropriate ADH syndrome: hyponatremia due to polyethylene glycol bowel preparation World J Gastroenterol 2014 20 12350 12354 10.3748/wjg.v20.i34.12350 25232272 \n19. Cho YS Nam KM Park JH Byun SH Ryu JS Kim HJ Acute hyponatremia with seizure and mental change after oral sodium picosulfate/magnesium citrate bowel preparation Ann Coloproctol 2014 30 290 293 10.3393/ac.2014.30.6.290 25580417 \n20. Cohen CD Keuneke C Schiemann U Hyponatraemia as a complication of colonoscopy Lancet 2001 357 282 283 10.1016/S0140-6736(00)03619-9 11214135 \n21. Lichtenstein G Bowel preparations for colonoscopy: a review Am J Health Syst Pharm 2009 66 27 37 10.2146/ajhp080084 19106342 \n22. Berl T Impact of solute intake on urine flow and water excretion J Am Soc Nephrol 2008 19 1076 1078 10.1681/ASN.2007091042 18337482 \n23. Fenves AZ Thomas S Knochel JP Beer potomania: two cases and review of the literature Clin Nephrol 1996 45 61 64 8616959 \n24. Sanghvi SR Kellerman PS Nanovic L Beer potomania: an unusual cause of hyponatremia at high risk of complications from rapid correction Am J Kidney Dis 2007 50 673 680 10.1053/j.ajkd.2007.07.015 17900468 \n25. Thaler SM Teitelbaum I Berl T “Beer potomania” in non-beer drinkers: effect of low dietary solute intake Am J Kidney Dis 1998 31 1028 1031 10.1053/ajkd.1998.v31.pm9631849 9631849 \n26. Yeates KE Singer M Morton AR Salt and water: a simple approach to hyponatremia. Review CMAJ 2004 170 365 369 10.1503/cmaj.1040502 14757675 \n27. Fox BD Crash diet potomania Lancet 2002 359 942 10.1016/S0140-6736(02)08027-3 11918914 \n28. Ferring Pharmaceutical Limited (2016) PICOLAX ® package leaflet. Drayton Hall, United Kingdom.\n29. Tilley MA Cotant CL Acute water intoxication during military urine drug screening Mil Med 2011 176 451 453 10.7205/MILMED-D-10-00228 21539169 \n30. Klonoff DC Jurow AH Acute water intoxication as a complication of urine drug testing in the workplace JAMA 1991 265 84 85 10.1001/jama.1991.03460010084036 1984128 \n31. Granberry MC White LM Gardner SF Exacerbation of congestive heart failure after administration of polyethylene glycol-electrolyte lavage solution Ann Pharmacother 1995 29 1232 1235 10.1177/106002809502901208 8672827 \n32. Adamcewicz M Bearelly D Porat G Friedenberg FK Mechanism of action and toxicities of purgatives used for colonoscopy preparation Expert Opin Drug Metab Toxicol 2011 7 89 101 10.1517/17425255.2011.542411 21162694 \n33. Martel M Barkun AN Menard C Restellini S Kherad O Vanasse A Split-Dose Preparations Are Superior to Day-Before Bowel Cleansing Regimens: A Meta-analysis Gastroenterology 2015 149 79 88 10.1053/j.gastro.2015.04.004 25863216 \n34. Scarpignato C Blandizzi C Editorial: hyponatremia - a possible but forgotten consequence of bowel preparation for colonoscopy Aliment Pharmacol Ther 2014 40 1110 1112 10.1111/apt.12917 25280254\n\n",
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"issn_linking": "1471-2369",
"issue": "18(1)",
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"keywords": "Bowel preparation; Case report; Colonoscopy; Hyponatremia; Low-solute hyponatremia; Water intoxication",
"medline_ta": "BMC Nephrol",
"mesh_terms": "D001927:Brain Diseases; D003113:Colonoscopy; D005260:Female; D006801:Humans; D007010:Hyponatremia; D008875:Middle Aged; D011300:Preoperative Care; D012462:Saline Solution, Hypertonic; D014869:Water Intoxication; D014883:Water-Electrolyte Imbalance",
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"medicinalproduct": "LEVOTHYROXINE SODIUM."
}
],
"patientagegroup": null,
"patientonsetage": "61",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Blood chloride decreased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Blood thyroid stimulating hormone decreased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Hyponatraemic encephalopathy",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Water intoxication",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "1"
},
{
"reactionmeddrapt": "Blood osmolarity decreased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Hypophagia",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Blood potassium decreased",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": null
}
],
"summary": null
},
"primarysource": {
"literaturereference": "WINDPESSL M, SCHWARZ C, WALLNER M. ^BOWEL PREP HYPONATREMIA^ - A STATE OF ACUTE WATER INTOXICATION FACILITATED BY LOW DIETARY SOLUTE INTAKE: CASE REPORT AND LITERATURE REVIEW. [REVIEW]. BMC-NEPHROL 2017?18(1):54.",
"literaturereference_normalized": "bowel prep hyponatremia a state of acute water intoxication facilitated by low dietary solute intake case report and literature review",
"qualification": "3",
"reportercountry": "AT"
},
"primarysourcecountry": "AT",
"receiptdate": "20180327",
"receivedate": "20170324",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportid": 13370113,
"safetyreportversion": 2,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20180508"
}
] |
{
"abstract": "Neurologists are worried about bleeding and complications from lumbar punctures in patients who use antiplatelet agents, such as aspirin and clopidogrel. We evaluated the bleeding risks of performing lumbar punctures in patients who are using or have recently used antiplatelet agents by retrospective review of lumbar punctures performed at the Johns Hopkins Hospital between 2004 and 2018 in patients who were actively using or recently used aspirin or clopidogrel, or both. Patients were stratified into time groups based on when the lumbar puncture was done relative to the time the antiplatelet drug was discontinued: <1 week, 1-4 weeks, >4 weeks. We recorded red blood cell counts for the earliest and latest spinal fluid collections to determine the risk of traumatic bleeding; we also noted any complications. Antiplatelet medication use within 1 week of lumbar puncture was associated with a 3% incidence of bloody tap and 4% incidence of traumatic tap that cleared. In the group of patients who waited for a lumbar puncture at least 4 weeks after discontinuation of antiplatelet drug, there was a 5% incidence of bloody or traumatic tap. There was no difference in rates of bleeding between aspirin versus aspirin plus clopidogrel. The rate of hematoma complications was highest in the group of patients on aspirin at the time of the procedure (0.7%). Aspirin or clopidogrel, or both, did not meaningfully increase hemorrhagic complications in patients undergoing lumbar punctures, regardless of when the antiplatelet drug was discontinued relative to the time of the procedure.",
"affiliations": "Department of Neurology, Johns Hopkins University, Baltimore, MD.;Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA. Electronic address: mlevy11@mgh.harvard.edu.",
"authors": "Lee|Paul W|PW|;Levy|Michael|M|",
"chemical_list": "D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D001241:Aspirin",
"country": "England",
"delete": false,
"doi": "10.1016/j.mayocp.2019.05.018",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0025-6196",
"issue": "94(8)",
"journal": "Mayo Clinic proceedings",
"keywords": null,
"medline_ta": "Mayo Clin Proc",
"mesh_terms": "D000046:Academic Medical Centers; D000284:Administration, Oral; D000368:Aged; D001241:Aspirin; D015142:Baltimore; D000077144:Clopidogrel; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006406:Hematoma; D006801:Humans; D015994:Incidence; D008297:Male; D061214:Patient Safety; D010975:Platelet Aggregation Inhibitors; D011300:Preoperative Care; D012189:Retrospective Studies; D018570:Risk Assessment; D013129:Spinal Puncture; D013997:Time Factors; D016896:Treatment Outcome; D028761:Withholding Treatment",
"nlm_unique_id": "0405543",
"other_id": null,
"pages": "1552-1555",
"pmc": null,
"pmid": "31378231",
"pubdate": "2019-08",
"publication_types": "D003160:Comparative Study; D016428:Journal Article",
"references": null,
"title": "Risk of Hematoma From Aspirin or Clopidogrel Owing to Lumbar Puncture.",
"title_normalized": "risk of hematoma from aspirin or clopidogrel owing to lumbar puncture"
} | [
{
"companynumb": "US-BAYER-2019-149448",
"fulfillexpeditecriteria": "1",
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"patient": {
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{
"actiondrug": null,
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"activesubstancename": "ASPIRIN"
},
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"drugauthorizationnumb": "999999",
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"drugdosagetext": "UNK",
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"drugindication": "ANTIPLATELET THERAPY",
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"medicinalproduct": "ASPIRIN."
},
{
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"activesubstancename": "CLOPIDOGREL BISULFATE"
},
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"medicinalproduct": "CLOPIDOGREL"
}
],
"patientagegroup": "6",
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"patientonsetageunit": "801",
"patientsex": null,
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"reaction": [
{
"reactionmeddrapt": "Spinal cord haematoma",
"reactionmeddraversionpt": "22.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Labelled drug-drug interaction medication error",
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"reactionoutcome": null
}
],
"summary": null
},
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"literaturereference": "LEE PW, LEVY M. RISK OF HEMATOMA FROM ASPIRIN OR CLOPIDOGREL OWING TO LUMBAR PUNCTURE. MAYO CLINIC PROCEEDINGS. 2019?94:8:1552-1555",
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},
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},
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{
"companynumb": "US-TEVA-2020-US-1178889",
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"medicinalproduct": "ASPIRIN."
},
{
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},
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"medicinalproduct": "CLOPIDOGREL"
}
],
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"reaction": [
{
"reactionmeddrapt": "Spinal cord haematoma",
"reactionmeddraversionpt": "22.1",
"reactionoutcome": "6"
}
],
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},
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"literaturereference": "LEE PW, LEVY M. RISK OF HEMATOMA FROM ASPIRIN OR CLOPIDOGREL OWING TO LUMBAR PUNCTURE. MAYO-CLIN-PROC 2019?94(8):1552-1555.",
"literaturereference_normalized": "risk of hematoma from aspirin or clopidogrel owing to lumbar puncture",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20200203",
"receivedate": "20200203",
"receiver": {
"receiverorganization": "FDA",
"receivertype": "6"
},
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"safetyreportid": 17359750,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
"seriousnesshospitalization": 1,
"seriousnesslifethreatening": null,
"seriousnessother": null,
"transmissiondate": "20200409"
},
{
"companynumb": "US-BAYER-2019-149440",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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{
"actiondrug": null,
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"activesubstancename": "ASPIRIN"
},
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"medicinalproduct": "ASPIRIN."
}
],
"patientagegroup": "6",
"patientonsetage": "79",
"patientonsetageunit": "801",
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{
"reactionmeddrapt": "Spinal cord haematoma",
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"reactionoutcome": null
}
],
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},
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"literaturereference": "LEE PW, LEVY M. RISK OF HEMATOMA FROM ASPIRIN OR CLOPIDOGREL OWING TO LUMBAR PUNCTURE. MAYO CLINIC PROCEEDINGS. 2019?94:8:1552-1555",
"literaturereference_normalized": "risk of hematoma from aspirin or clopidogrel owing to lumbar puncture",
"qualification": "1",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20190819",
"receivedate": "20190819",
"receiver": {
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},
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"safetyreportid": 16716400,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
"seriousnessdeath": null,
"seriousnessdisabling": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20191005"
}
] |
{
"abstract": "BACKGROUND\nIn 2006, the American Association of Poison Control Centers (AAPCC) published an out of hospital guideline for diphenhydramine overdoses in children. This guideline has not been validated.\n\n\nOBJECTIVE\nOur objective was to determine the incidence of serious clinical effects or use of medical treatments after unintentional diphenhydramine ingestions in children. We sought to determine if patients with less than 7.5 mg/kg ingestions developed medical complications of diphenhydramine toxicity.\n\n\nMETHODS\nIn our observational case series, we searched 7 years of data (2000-2006) in the Texas Poison Center Network for diphenhydramine using the AAPCC generic codes. We included only acute, single ingestions of diphenhydramine in children under 6 years old. We included only patients with a recorded weight, known amount of ingestant, and known follow-up. We defined \"serious clinical effects\" as hallucinations, seizure, wide QRS on electrocardiogram, wide complex dysrhythmia, any conduction block, hypotension, hypertension, rhabdomyolysis, pyrexia, dystonia, coma, respiratory depression, or death. One trained abstractor reviewed the data and entered it into an electronic data collection form. Twenty percent of the charts were audited for abstractor agreement.\n\n\nRESULTS\nOur search resulted in 928 cases. Of these, 305 were included in our study. Of the patients who ingested doses less than 7.5 mg/kg, 99.7% (299/300) did not require critical treatments or were without serious clinical effects. One child was admitted. Five children ingested doses of more than 7.5 mg/kg. All five were observed in the emergency department and discharged home. Two patients had serious clinical effects of hallucinations, one of which ingested more than 7.5 mg/kg. No child required critical treatments. Our agreement on chart review for 20% of the cases was very good for \"serious clinical effects\" (kappa, 0.79; 95% CI, 0.39-1.0) and excellent for \"critical treatments\" (kappa, 1.0).\n\n\nCONCLUSIONS\nBased on our observational case series, 99.6% of patients who reportedly ingested doses less than 7.5 mg/kg did not develop serious clinical effects or require admission. Pediatric ingestions over 7.5 mg/kg were uncommon in our study population. Serious clinical effects, critical treatments, and admission from diphenhydramine were rare in children under 6 years old.",
"affiliations": "Department of Emergency Medicine, Wilford Hall Medical Center, US Air Force, San Antonio, TX 78261, USA. vikbebarta@yahoo.com",
"authors": "Bebarta|Vikhyat Sugyani|VS|;Blair|Holly W|HW|;Morgan|David L|DL|;Maddry|Joseph|J|;Borys|Douglas J|DJ|",
"chemical_list": "D004155:Diphenhydramine",
"country": "England",
"delete": false,
"doi": "10.3109/15563650.2010.497149",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1556-3650",
"issue": "48(6)",
"journal": "Clinical toxicology (Philadelphia, Pa.)",
"keywords": null,
"medline_ta": "Clin Toxicol (Phila)",
"mesh_terms": "D002648:Child; D002675:Child, Preschool; D004155:Diphenhydramine; D005260:Female; D006801:Humans; D007223:Infant; D008297:Male; D011039:Poison Control Centers; D017410:Practice Guidelines as Topic; D012189:Retrospective Studies; D014481:United States",
"nlm_unique_id": "101241654",
"other_id": null,
"pages": "559-62",
"pmc": null,
"pmid": "20569075",
"pubdate": "2010-07",
"publication_types": "D016428:Journal Article; D023361:Validation Study",
"references": null,
"title": "Validation of the American Association of Poison Control Centers out of hospital guideline for pediatric diphenhydramine ingestions.",
"title_normalized": "validation of the american association of poison control centers out of hospital guideline for pediatric diphenhydramine ingestions"
} | [
{
"companynumb": "US-JNJFOC-2011003938",
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"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "DIPHENHYDRAMINE"
},
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"drugdosageform": "UNSPECIFIED",
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"medicinalproduct": "DIPHENHYDRAMINE."
},
{
"actiondrug": "5",
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"activesubstancename": "DIPHENHYDRAMINE"
},
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"drugdosagetext": "DAILY DOSE TEXT: 8.05 MG/KG",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ACCIDENTAL EXPOSURE TO PRODUCT",
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"medicinalproduct": "DIPHENHYDRAMINE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Accidental exposure to product by child",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BEBARTA V., BLAIR H., MORGAN D., MADDRY J., BORYS D. VALIDATION OF THE AMERICAN ASSOCIATION OF POISON CONTROL CENTERS OUT OF HOSPITAL GUIDELINE FOR PEDIATRIC DIPHENHYDRAMINE INGESTIONS. CLINICAL TOXICOLOGY 01-JAN-2010;48:559 - 562",
"literaturereference_normalized": "validation of the american association of poison control centers out of hospital guideline for pediatric diphenhydramine ingestions",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170414",
"receivedate": "20170414",
"receiver": {
"receiverorganization": "FDA",
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},
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"safetyreportid": 13443844,
"safetyreportversion": 1,
"sender": {
"senderorganization": "FDA-Public Use",
"sendertype": "2"
},
"serious": 1,
"seriousnesscongenitalanomali": null,
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"seriousnesslifethreatening": null,
"seriousnessother": 1,
"transmissiondate": "20170830"
},
{
"companynumb": "US-JNJFOC-2011003936",
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"patient": {
"drug": [
{
"actiondrug": "5",
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"activesubstancename": "DIPHENHYDRAMINE"
},
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"drugcharacterization": "1",
"drugcumulativedosagenumb": null,
"drugcumulativedosageunit": null,
"drugdosageform": "UNSPECIFIED",
"drugdosagetext": "DAILY DOSE TEXT: 7.84 MG/KG",
"drugenddate": null,
"drugenddateformat": null,
"drugindication": "ACCIDENTAL EXPOSURE TO PRODUCT",
"drugintervaldosagedefinition": null,
"drugintervaldosageunitnumb": null,
"drugrecurreadministration": "3",
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"medicinalproduct": "DIPHENHYDRAMINE."
},
{
"actiondrug": "5",
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"activesubstancename": "DIPHENHYDRAMINE"
},
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"drugtreatmentdurationunit": null,
"medicinalproduct": "DIPHENHYDRAMINE."
}
],
"patientagegroup": "3",
"patientonsetage": "3",
"patientonsetageunit": "801",
"patientsex": "2",
"patientweight": null,
"reaction": [
{
"reactionmeddrapt": "Accidental exposure to product by child",
"reactionmeddraversionpt": "20.0",
"reactionoutcome": "1"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "BEBARTA V., BLAIR H., MORGAN D., MADDRY J., BORYS D. VALIDATION OF THE AMERICAN ASSOCIATION OF POISON CONTROL CENTERS OUT OF HOSPITAL GUIDELINE FOR PEDIATRIC DIPHENHYDRAMINE INGESTIONS. CLINICAL TOXICOLOGY 01-JAN-2010;48:559 - 562",
"literaturereference_normalized": "validation of the american association of poison control centers out of hospital guideline for pediatric diphenhydramine ingestions",
"qualification": "3",
"reportercountry": "US"
},
"primarysourcecountry": "US",
"receiptdate": "20170415",
"receivedate": "20170415",
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{
"abstract": "An 85-year-old male patient receiving hormone therapy for prostate cancer and secondary open-angle pseudoexfoliation glaucoma developed peripheral choroidal detachment in both eyes. The patient had been admitted to the eye hospital for clarification of a vascular occlusion in the left eye. Cerebral magnetic resonance imaging could exclude metastases and a cerebral space-occupying lesion as the cause of the ocular findings. The local antiglaucomatous treatment was interrupted and as a result the intraocular pressure normalized and the choroidal detachment receded completely. Patients with prostate cancer who receive hormone therapy should also undergo regular ophthalmological screening including funduscopy and measurment of intraocular pressure.",
"affiliations": "Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Halle (Saale), Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle, Deutschland. gesine.lehmann@uk-halle.de.;Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Halle (Saale), Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle, Deutschland.;Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Halle (Saale), Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle, Deutschland.;Klinik und Poliklinik für Augenheilkunde, Universitätsklinikum Halle (Saale), Martin-Luther-Universität Halle-Wittenberg, Ernst-Grube-Str. 40, 06120, Halle, Deutschland.",
"authors": "Lehmann|G|G|;Wienrich|R|R|;Fiorentzis|M|M|;Viestenz|A|A|",
"chemical_list": null,
"country": "Germany",
"delete": false,
"doi": "10.1007/s00347-019-00956-y",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0941-293X",
"issue": "117(5)",
"journal": "Der Ophthalmologe : Zeitschrift der Deutschen Ophthalmologischen Gesellschaft",
"keywords": "GnRH analogues; Hormone therapy; Hypotonia; Intraocular pressure; Retinal and choroidal detachment",
"medline_ta": "Ophthalmologe",
"mesh_terms": "D000369:Aged, 80 and over; D000080324:Choroidal Effusions; D005902:Glaucoma, Open-Angle; D020249:Hormone Replacement Therapy; D006801:Humans; D007429:Intraocular Pressure; D008297:Male; D011471:Prostatic Neoplasms; D012008:Recurrence; D012163:Retinal Detachment; D014065:Tonometry, Ocular",
"nlm_unique_id": "9206148",
"other_id": null,
"pages": "456-460",
"pmc": null,
"pmid": "31455973",
"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrent choroidal detachment in a patient undergoing hormone therapy for prostate cancer.",
"title_normalized": "recurrent choroidal detachment in a patient undergoing hormone therapy for prostate cancer"
} | [
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},
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{
"abstract": "A 26-year-old man was admitted to our hospital with dyspnea, fever, and weight loss. A chest X-ray showed multiple tumor shadows, and a computed tomography (CT) scan showed swelling of the mediastinal and hilar lymph nodes, a mass in the retroperitoneum, and an embolus in the inferior vena cava. A biopsy from the left cervical lymph node revealeda poorly differentiated adenocarcinoma. Metastatic lung cancer was suspected, but in spite of the examinations, its primary site was unknown. Serum alfa-fetoprotein(AFP)was slightly elevated, but an AFP stain of the tumor was negative. The patient's respiratory failure rapidly worsened, and therefore, additional examinations could not be performed. The patient received chemotherapy with carboplatin and paclitaxel. His condition improved, but the tumor increased in size after 5 courses of chemotherapy. He received chemotherapy with docetaxel as second-line treatment, but it was not effective. The third-line chemotherapy regimen with carboplatin and gemcitabine was effective. In total, he received 7 lines of chemotherapy, and he lived for approximately 12 months since receiving the first chemotherapy regimen. After he died, we were able to perform OCT-4 immunohistochemistry on a tumor biopsy specimen from the lymph node, which came back positive for OCT-4. Therefore, we made a final diagnosis of extragonadal germ cell cancer syndrome.",
"affiliations": "Dept. of Internal Medicine,Osaka Koseinenkin Hospital.",
"authors": "Tanaka|Yoko|Y|;Tago|Kentaro|K|;Narabayashi|Tomoko|T|;Sasaki|Yoshiaki|Y|;Iwahashi|Eriko|E|;Hibino|Chihiro|C|;Iwasaki|Teruo|T|;Watanabe|Takahiro|T|;Kasugai|Tsutomu|T|;Kohama|Joji|J|;Ohno|Kiyoshi|K|",
"chemical_list": null,
"country": "Japan",
"delete": false,
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"issn_linking": "0385-0684",
"issue": "41(5)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000230:Adenocarcinoma; D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D003937:Diagnosis, Differential; D017809:Fatal Outcome; D006801:Humans; D008175:Lung Neoplasms; D008207:Lymphatic Metastasis; D008297:Male; D009373:Neoplasms, Germ Cell and Embryonal; D009382:Neoplasms, Unknown Primary",
"nlm_unique_id": "7810034",
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"pages": "627-31",
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"pmid": "24917010",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "A case of primary unknown cancer difficult to distinguish from lung cancer.",
"title_normalized": "a case of primary unknown cancer difficult to distinguish from lung cancer"
} | [
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}
],
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"reaction": [
{
"reactionmeddrapt": "Malignant neoplasm progression",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "5"
},
{
"reactionmeddrapt": "General physical health deterioration",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
},
{
"reactionmeddrapt": "Drug ineffective",
"reactionmeddraversionpt": "21.0",
"reactionoutcome": "6"
}
],
"summary": null
},
"primarysource": {
"literaturereference": "TANAKA Y, TAGO K, NARABAYASHI T, SASAKI Y, IWAHASHI E, HIBINO C ET AL.,. A CASE OF PRIMARY UNKNOWN CANCER DIFFICULT TO DISTINGUISH FROM LUNG CANCER. JAPANESE JOURNAL OF CANCER AND CHEMOTHERAPY. 2014?41 (5):627 TO 631",
"literaturereference_normalized": "a case of primary unknown cancer difficult to distinguish from lung cancer",
"qualification": "3",
"reportercountry": "JP"
},
"primarysourcecountry": "JP",
"receiptdate": "20180303",
"receivedate": "20180303",
"receiver": {
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"receivertype": "6"
},
"reporttype": "1",
"safetyreportid": 14595817,
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"sendertype": "2"
},
"serious": 1,
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] |
{
"abstract": "OBJECTIVE\nWe describe the case of a 9-year-old boy who developed Wernicke's encephalopathy while receiving chemotherapy for acute lymphoblastic leukemia (ALL).\n\n\nMETHODS\nAfter suffering anorexia for 4 weeks following chemotherapy, he exhibited nystagmus and ataxia. Symptoms rapidly worsened following an increased glucose load, and included a depressed consciousness, irregular respiration, and ophthalmoplegia. The serum thiamine level was 9 ng/ml (normal: 20-50). Cranial computed tomography (CT) revealed a low density area bilaterally at the neostriatum. Thiamine 100 mg/day was administered intravenously.\n\n\nRESULTS\nThe patient's neurological signs improved dramatically. However, he subsequently developed pancytopenia and died of pneumonia.\n\n\nCONCLUSIONS\nThe possibility of Wernicke's encephalopathy should be considered in children who are receiving chemotherapy for malignant disease when a persistent loss of appetite is followed by such neurological symptoms as nystagmus and ataxia.",
"affiliations": "Division of Hematology/Oncology, Children's Medical Center, Japanese Red Cross Nagoya First Hospital, Japan.",
"authors": "Miyajima|Y|Y|;Fukuda|M|M|;Kojima|S|S|;Matsuyama|T|T|;Shylaja|N|N|;Aso|K|K|",
"chemical_list": "D013831:Thiamine",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0192-8562",
"issue": "15(3)",
"journal": "The American journal of pediatric hematology/oncology",
"keywords": null,
"medline_ta": "Am J Pediatr Hematol Oncol",
"mesh_terms": "D000855:Anorexia; D002648:Child; D006801:Humans; D008297:Male; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D013831:Thiamine; D013832:Thiamine Deficiency; D014057:Tomography, X-Ray Computed; D014899:Wernicke Encephalopathy",
"nlm_unique_id": "7908071",
"other_id": null,
"pages": "331-4",
"pmc": null,
"pmid": "8328648",
"pubdate": "1993-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Wernicke's encephalopathy in a child with acute lymphoblastic leukemia.",
"title_normalized": "wernicke s encephalopathy in a child with acute lymphoblastic leukemia"
} | [
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"literaturereference": "KIZILOCAK, H.. WERNICKE^S ENCEPHALOPATHY IN A CHILD WITH ACUTE LYMPHOBLASTIC LEUKEMIA. TURKISH JOURNAL OF HEMATOLOGY. 2017;34(1):99-100",
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"reactionmeddraversionpt": "20.0",
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},
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"literaturereference": "KIZILOCAK H, OZDEMIR GN, DIKME G, HASILOGLU ZI, CELKAN T. WERNICKE^S ENCEPHALOPATHY IN A CHILD WITH ACUTE LYMPHOBLASTIC LEUKEMIA. TURKISH JOURNAL OF HEMATOLOGY. 2017;34(1):99-100",
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"qualification": "1",
"reportercountry": "TR"
},
"primarysourcecountry": "TR",
"receiptdate": "20170406",
"receivedate": "20170406",
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},
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{
"abstract": "BACKGROUND\nExtramedullary plasmacytoma (EMP) is a plasma cell neoplasm that presents as a solitary tumor. EMP in the gastrointestinal organs are extremely uncommon.\n\n\nMETHODS\nA 36-year-old man was admitted to our hospital with advanced anemia. He had no specific medical history. Gastroendoscopic findings showed an 8.0-cm submucosal tumor with ulcer on the greater curvature of the gastric body. Fine-needle aspiration was performed, and the pathologic diagnosis of the submucosal tumor was a plasmacytoma. Therefore, the patient was diagnosed with gastric plasmacytoma. A total gastrectomy was performed with lymphadenectomy. The result of intraoperative peritoneal lavage cytology was positive. Histological examination revealed serosa-exposed plasmacytoma of the stomach with lymph nodes metastasis. Additionaly the patient received a three-drug chemotherapy regimen (bortezomib, cyclophosphamide, and dexamethasone [VCD]) from 3 weeks after the operation. After 4 cycles of chemotherapy, the patient received autologous peripheral blood stem-cell transplantation (auto-PBSCT). Eighteen months after diagnosis, the patient is in complete remission with no evidence of local relapse or evolution to multiple myeloma.\n\n\nCONCLUSIONS\nThis is the first reported case of advanced gastric plasmacytoma using adjuvant chemotherapy involving bortezomib and auto-PBSCT after the resection, and the patient has maintained a good course over a year. This protocol could be a new way to treat these tumors.",
"affiliations": "Department of Surgery, Chugoku Rosai Hospital, 1-5-1, Tagaya, Hiro, Kure City, Hiroshima 737-0193, Japan.;Department of Surgery, Chugoku Rosai Hospital, 1-5-1, Tagaya, Hiro, Kure City, Hiroshima 737-0193, Japan. Electronic address: thiroes@gmail.com.;Department of Internal Medicine, Chugoku Rosai Hospital, 1-5-1, Tagaya, Hiro, Kure City, Hiroshima 737-0193, Japan.;Department of Hematology, National Hospital Organization Kure Medical Center, 3-1, Aoyamatyo, Kure City, Hiroshima 737-0023, Japan.;Department of Hematology, National Hospital Organization Kure Medical Center, 3-1, Aoyamatyo, Kure City, Hiroshima 737-0023, Japan.;Department of Hematology, National Hospital Organization Kure Medical Center, 3-1, Aoyamatyo, Kure City, Hiroshima 737-0023, Japan.;Department of Diagnostic Pathology, Chugoku Rosai Hospital, 1-5-1, Tagaya, Hiro, Kure City, Hiroshima 737-0193, Japan.;Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan.;Department of Surgery, Chugoku Rosai Hospital, 1-5-1, Tagaya, Hiro, Kure City, Hiroshima 737-0193, Japan; Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan.",
"authors": "Fukuhara|Sotaro|S|;Tazawa|Hirofumi|H|;Okanobu|Hideharu|H|;Kida|Michiko|M|;Kido|Miki|M|;Takafuta|Toshiro|T|;Nishida|Toshihiro|T|;Ohdan|Hideki|H|;Sakimoto|Hideto|H|",
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"doi": "10.1016/j.ijscr.2016.08.041",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(16)30337-610.1016/j.ijscr.2016.08.041Case ReportSuccessful treatment of primary advanced gastric plasmacytoma using a combination of surgical resection and chemotherapy with bortezomib: A case report Fukuhara Sotaro aTazawa Hirofumi thiroes@gmail.coma⁎Okanobu Hideharu bKida Michiko cKido Miki cTakafuta Toshiro cNishida Toshihiro dOhdan Hideki eSakimoto Hideto aea Department of Surgery, Chugoku Rosai Hospital, 1-5-1, Tagaya, Hiro, Kure City, Hiroshima 737-0193, Japanb Department of Internal Medicine, Chugoku Rosai Hospital, 1-5-1, Tagaya, Hiro, Kure City, Hiroshima 737-0193, Japanc Department of Hematology, National Hospital Organization Kure Medical Center, 3-1, Aoyamatyo, Kure City, Hiroshima 737-0023, Japand Department of Diagnostic Pathology, Chugoku Rosai Hospital, 1-5-1, Tagaya, Hiro, Kure City, Hiroshima 737-0193, Japane Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8551, Japan⁎ Corresponding author. thiroes@gmail.com03 9 2016 2016 03 9 2016 27 133 136 14 6 2016 25 8 2016 27 8 2016 © 2016 The Authors2016This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• No general treatment guidelines have been established for gastricplasmacytoma.\n\n• Combination therapy with chemotherapy involving bortezomib and autologous peripheral blood stem-cell transplantation after the resection could be one of the useful options for the advanced gastricplasmacytoma.\n\n\n\nIntroduction\nExtramedullary plasmacytoma (EMP) is a plasma cell neoplasm that presents as a solitary tumor. EMP in the gastrointestinal organs are extremely uncommon.\n\nPresentation of case\nA 36-year-old man was admitted to our hospital with advanced anemia. He had no specific medical history. Gastroendoscopic findings showed an 8.0-cm submucosal tumor with ulcer on the greater curvature of the gastric body. Fine-needle aspiration was performed, and the pathologic diagnosis of the submucosal tumor was a plasmacytoma. Therefore, the patient was diagnosed with gastric plasmacytoma. A total gastrectomy was performed with lymphadenectomy. The result of intraoperative peritoneal lavage cytology was positive. Histological examination revealed serosa-exposed plasmacytoma of the stomach with lymph nodes metastasis. Additionaly the patient received a three-drug chemotherapy regimen (bortezomib, cyclophosphamide, and dexamethasone [VCD]) from 3 weeks after the operation. After 4 cycles of chemotherapy, the patient received autologous peripheral blood stem-cell transplantation (auto-PBSCT). Eighteen months after diagnosis, the patient is in complete remission with no evidence of local relapse or evolution to multiple myeloma.\n\nConclusions\nThis is the first reported case of advanced gastric plasmacytoma using adjuvant chemotherapy involving bortezomib and auto-PBSCT after the resection, and the patient has maintained a good course over a year. This protocol could be a new way to treat these tumors.\n\nAbbreviations\nAuto-PBSCT, autologous peripheral blood stem-cell transplantationCT, computed tomographyEMP, extramedullary plasmacytomaESD, endoscopic submucosal dissectionFDG, fludeoxyglucose (18F)PET-CT, positron emission tomography-CTVCD, bortezomib, cyclophosphamide, and dexamethasoneVD, bortezomib and dexamethasoneKeywords\nPlasmacytomaStomachSurgical resectionChemotherapy\n==== Body\n1 Introduction\nExtramedullary plasmacytoma (EMP) is a rare disease and is histopathologically characterized by infiltrates of plasma cells of diverse maturity and by their monoclonal immunoglobulin products [1]. The disease occurs almost exclusively in the head, neck, and upper respiratory tract. EMPs in the gastrointestinal organs are uncommon [2]. The next most frequent site of lesion occurrence is the stomach; however, this is also extremely rare, accounting for less than 5% of all EMPs [3]. Although plasmacytoma is rare and few cases have been reported before, the adjuvant treatment lacks definitive guidelines. In such a situation we attempted with this unique combination therapy and have achieved satisfactory result. This is the first reported case of gastric plasmacytoma treated by combination chemotherapy (bortezomib, cyclophosphamide, and dexamethasone [VCD]), and autologous peripheral blood stem-cell transplantation (auto-PBSCT). Therefore we are presenting this case highlighting a new way to treat these tumors.\n\n2 Presentation of case\nA 36-year-old man with dyspnea and general fatigue visited a local doctor. Blood examination revealed advanced anemia, and he was referred to our hospital for a detailed examination. The results of laboratory examinations were as follows: white blood cell count, 5150/mm3 (normal range 4500–9000); red blood cell count, 234 × 104/mm3 (normal range 435–555); hemoglobin level, 5.7 g/dL (normal range 13.6–17.0); hematocrit, 20.6% (normal range 40.7–50.1); platelet count, 26.8 × 104/mm3 (normal range 14.0–36.0); serum blood urea nitrogen level, 25.0 mg/dL (normal range 8–20); serum creatinine level, 0.73 mg/dL (normal range 0.5–1.2); serum alkaline phosphatase level, 123 U/L (normal range 100–340); serum calcium level, 9.2 mg/dL (normal range 8.2–10.2); and serum Fe level, 14.2 μg/dL (normal range 54–181). The levels of tumor markers were within the normal ranges (carcinoembryonic antigen 1.0 ng/mL and CA 19–9 2.0 U/mL). The patient had no history of serious illness, operations, or hospitalizations. Gastrointestinal endoscopy showed an 8.0-cm submucosal tumor with ulcer on the greater curvature of the gastric body (Fig. 1a). Magnifying narrow-band imaging endoscopy revealed the abnormal mucosal microstructure in the discolored protrusion (Fig. 1b). Examination by color Doppler endoscopic ultrasonography showed the hypoechoic mass with hypervascularity arising from the submucosal layer (Fig. 1c). Fine-needle aspiration was performed, and the pathologic diagnosis of the submucosal tumor was a possible plasmacytoma of the stomach. Abdominal computed tomography (CT) revealed focal wall thickening with hyperenhancement on the greater curvature and no sign of any lymph node swelling (Fig. 2a, b). We did not observe any accumulation of fludeoxyglucose uptake in positron emission tomography (PET)-CT, even at the lesion site of the main stomach tumor. Bone marrow puncture and M protein identification for the evaluation of multiple myeloma were normal. Testing for urinary Bence Jones protein was negative. The patient was diagnosed with primary gastric plasmacytoma, and we performed a total gastrectomy with extended removal of regional lymph nodes (D2) specified in the Japanese classification of gastric cancer [4]. The result of intraoperative peritoneal lavage cytology was positive. Histological examination revealed serosa-exposed plasmacytoma of the stomach with 4 out of 15 lymph nodes metastasis. (Fig. 3a, b). The immunohistological findings showed that the tumor cells were negative for CD20, CD79a, CD3, and cyclin D1, and positive for CD138 (Fig. 4a, b). The Ki-67 labeling index was high. The surface immunoglobulin was the IgA-κ type. The patient received combination therapy with a three-drug chemotherapy (VCD) 3 weeks after the operation. Bortezomib (1.3 mg/m2; days 1, 4, 8, and 11), cyclophosphamide (1.5 g/m2; days 1–14), and dexamethasone (40 mg/day; days 1, 4, 8, and 11) were given in each cycle. After 4 cycles of the three-drug chemotherapy, the patient received high-dose melphalan (140 mg/m2) followed by auto-PBSCT. Eighteen months after diagnosis, the patient is in complete remission with no evidence of local relapse or evolution to multiple myeloma.\n\n3 Discussion\nPlasma cell neoplasms are categorized into four groups; multiple myeloma, plasma cell leukemias, solitary plasmacytomas of the bone, and EMP [3]. The diagnosis of EMP requires demonstration of a histologically evidence of tumor in the bone marrow. In this case, the patient had a biopsy-proven extramedullary plasma cell tumor with lymph node involvement and a monoclonal band on serum protein electrophoresis of IgA. Bone marrow biopsy revealed less than 5% of plasma cells. No bone lesions were found. Therefore, the diagnosis was EMP of the stomach.\n\nAll segments of the gastrointestinal tract may be involved by EMPs, with the small intestine being the most common, followed by the stomach, colon, and esophagus. Gastric plasmacytomas are a very rare form of EMP. Gastric tumors account for 2–5% of all EMPs, and tend to be identified at a late stage if an endoscopic examination is not performed [5]. Almost all patients with EMPs are treated with radiation therapy, surgery, or combination therapy. However, no general treatment guidelines have been established for gastric EMPs. Additionally, the invasiveness of these initial therapeutic approaches precludes their recommendation for EMPs of the head and neck [6].\n\nIn this case, we performed a total gastrectomy with D2 lymphadenectomy under the diagnosis of primary solid plasmacytoma of the stomach. The pathological diagnosis was serosa-exposed plasmacytoma (8.0 × 6.5 cm) of the stomach with multiple lymph nodes metastasis. The tumor was large, with lymph nodes metastasis and presence of a serosa component, accompanying a positive cytodiagnosis of ascites. In solitary plasmacytomas treated with radiation therapy, large tumor bulk (≥50 mm) indicates a more progressive course and suggests a poor prognosis [7]. To our knowledge, there is no report in English about the relation between tumor progression and overall survival rate. However, one report in Japanese from Kawata et al. [8] summarized 71 cases of primary solid plasmacytoma of the stomach in Japan. The report detailed disease progression in 43 patients, 15 of whom had died by the time of publication. The invasion depth of the 15 cases had been pT4 (SE), indicating that patients with gastric plasmacytoma with invasion to the serosa have a markedly poorer prognosis than the others. Most of the cases reported in the literature are early stage of gastric plasmacytom, and these cases have been treated with endscopic submucosal dissection [9], [10], [11]. Until now, there has been few evidence that additional chemotherapy is beneficial. Wiltshaw et al. [12], [13] reported on the effectiveness of additional chemotherapy with melphalan, prednisone, cyclophosphamide, or vincristine alone or in combination with complete remission rates of 50–88%. Preud'Homme et al. reported that 20-year-old female of huge gastric plasmacytoma had been treated with chemotherapy (Rubidazone, procarbazine, and vinblastine) for two years [14]. The patient had been free of metastasis for three years after the finishing chemotherapy. Katodritou et al. reported that 68-year-old male with 5-cm gastric plasmacytoma had been treated with 4 cycle of chemotherapy (Bortezomib and dexamethasone) [15]. Thirteen months after the diagnosis the patient had been in complete remission with no evidence of local relapse or evolution to multiple myeloma. Zhao et al. reported that 79-year-old male with 16-cm gastric plasmacytoma infiltrating the lamina propria received surgery consisted of total gastrectomy with a subtotal pancreatectomy, splenectomy, and oesophageal and jejunum Roux-en-Y anastomosis [16]. There was no indication of recurrence or metastasis at eight momths after the operation. Some EMP cases are known to develop multiple myeloma. After treatment of EMP in non-upper aerodigestive regions, 21.2% of patients had recurrence and 14.1% of them converted to multiple myeloma [3]. High-dose chemotherapy (bortezomib) with auto-PBSCT is a standard treatment for young patients with multiple myeloma. The condition typically follows a relapsing course, and many patients require multiple lines of therapy. In this case, this patient was so young and the tumor was large, with lymph nodes metastasis and presence of a serosa component, accompanying a positive cytodiagnosis of ascites which indicated high risk to develop multiple myeloma. From the above reasons, we attempted with high-dose chemotherapy including bortezomib and auto-PBSCT after the resection. The combination of bortezomib and dexamethasone (VD), alone or with cyclophosphamide (VCD), has shown good efficacy and tolerability in patients with relapsed or refractory multiple myeloma in non-randomized trials [17], [18]. We performed combination therapy with VCD and auto-PBSCT after the operation because of the advanced pathological results. This combination was well tolerated and induced complete and sustained remission. The only documented side effect was transient mild neutropenia and thrombocytopenia. The use of bortezomib, with or without dexamethasone, could be a reliable, safe, and effective alternative for treating extramedullary plasmacytomas. Sixteen months after diagnosis, the patient is in complete remission with no evidence of local relapse or evolution to multiple myeloma. This is the first reported case of successful management of advanced EMP of the stomach with the combination of surgical resection and chemotherapy (VCD and auto-PBSCT).\n\n4 Conclusion\nNo general treatment guidelines have been established for primary gastric plasmacytoma. We performed combination therapy for the advanced gastric plasmacytoma using adjuvant chemotherapy involving bortezomib and auto-PBSCT after the resection, and the patient has maintained a good course over a year. This protocol could be a new way to treat these tumors.\n\nConflicts of interest\nNone of the authors has anything to disclose.\n\nFunding\nNone of the authors has anything to disclose.\n\nEthical approval\nAll procedures used in this research were approved by the Ethical Committee of Chugoku Rosai Hospital.\n\nConsent\nWritten informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy of the written consent form is available for review by the Editor-in-Chief of this journal.\n\nAuthor contribution\nFukuhara, Tazawa, Sakimoto and Ohdan wrote the manuscript. Okanobu diagnosed this case. Tazawa and Sakimoto performed the operation. Kida, Kido, and Takafuta performed the chemotherapy. Nishida diagnosed this disease pathologically. All authors conceived of the study and participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript.\n\nGuarantor\nHirofumi Tazawa has accepted full responsibility for this work and the decision to publish it.\n\nAcknowledgment\nNone.\n\nFig. 1 (a) Endoscopy showed an 8.0-cm protuberant lesion with ulcer on the greater curvature of the gastric body. (b) Magnifying narrow-band imaging endoscopy revealed the abnormal mucosal microstructure in the discolored protrusion (white arrows). (c) Endoscopic ultrasonography showed a hypoechoic mass deriving from the submucosal layer.\n\nFig. 1Fig. 2 (a, b) Axial and coronal images of CT showed focal wall thickening with hyperenhancement on the greater curvature of the stomach (white arrows).\n\nFig. 2Fig. 3 (a, b) The resected tumor was 8.0 × 6.5 cm in size. The tumor was ash white and elastic hard with the presence of a seroma component.\n\nFig. 3Fig. 4 (a) Microscopic examination (hematoxylin-eosin staining, original magnification × 400) revealed numerous plasma cells infiltrating the serosa of the stomach. (b) Immunohistochemical staining of the tumor cells for CD138 showed positive results.\n\nFig. 4\n==== Refs\nReferences\n1 Grogan T.M. Spier C.M. B-Cell Immunoproliferative Disorders, Including Myeloma and Amyloidosis, Neoplastic Hematopathology 1st edition 2001 Lippincott Wilkins & Wilkins 1557 1587 \n2 Weber D.M. Solitary bone and extramedullary plasmacytoma Hematol. Am. Soc. Hematol. Educ. Program 1 2005 373 376 \n3 Alexiou C. Kau R.J. Dietzfelbinger H. Kremer M. Extramedullary plasmacytoma: tumor occurrence and therapeutic concepts Cancer 85 1999 2305 2314 10357398 \n4 Japanese Gastric Cancer Association Japanese classification of gastric carcinoma: 3rd english edition Gastric Cancer 14 2011 101 112 21573743 \n5 Nolan K.D. Mone M.C. Nelson E.W. Plasma cell neoplasms. Review of disease progression and report of a new variant Surg. Oncol. 14 2005 85 90 15993050 \n6 Dimopoulos M.A. Hamilos G. Solitary bone plasmacytoma and extramedullary plasmacytoma Curr. Treat. Options Oncol. 3 2002 255 259 12057071 \n7 Tsang R.W. Gospodarowicz M.K. Pintilie M. Bezjak A. Wells W. Solitary plasmacytoma treated with radiotherapy: impact of tumor size on outcome Int. J. Radiat. Oncol. Biol. Phys. 50 2001 113 120 11316553 \n8 Kawata K. Ikeya T. Tanahashi Y. Aiba S. Shiozaki H. Plasmacytoma of the stomach: a case report Gan No Rinsho 42 1996 1706 1710 \n9 Park C.H. Lee S.M. Kim T.O. Kim D.U. Jung W.J. Treatment of solitary extramedullary plasmacytoma of the stomach with endoscopic submucosal dissection Gut Liver 3 2009 334 337 20431772 \n10 Harada S. Fukunishi S. Takeuchi T. Ota K. Kazunori S. Magnifying narrow-band imaging endoscopy for the diagnosis of gastric primary extramedullary plasmacytoma: a first case report Endoscopy 46 2014 E435 E436 25314181 \n11 Park S.Y. Moon H.S. Seong J.K. Jeong H.Y. Yoon B.Y. Successful treatment of a gastric plasmacytoma using a combination of endoscopic submucosal dissection and oral thalidomide Clin. Endosc. 47 2014 564 567 25505724 \n12 Witshaw E. Chemotherapy in the management of extramedullary plasmacytoma Cancer Chemother. Phamacol. 1 1978 167 175 \n13 Soesan M. Paccagnella A. Chiarion-Sileni V. Salvagno L. Fornasiero A. Extramedullary plasmacytoma: clinical behavior and response to treatment Ann. Oncol. 3 1992 51 57 1606070 \n14 Preud'Homme J.L. Galian A. Danon F. Marti R. Rambaud J.C. Extramedullary plasmacytoma with gastric and lymph node involvement: an immunological study Cancer 46 1980 1753 1758 6775799 \n15 Katodritou E. Kartsios C. Gastari V. Verrou E. Mihou D. Successful treatment of extramedullary gastric plasmacytoma with the combination of bortezomib and dexamethasone: first reported case Leuk. Res. 32 2008 339 341 17560647 \n16 Zhao Z.H. Yang J.F. Wang J.D. Wei J.G. Liu F. Imaging finding of primary gastric plasmacytoma: a case report World J. Gastroenterol. 20 2014 10202 10207 25110449 \n17 Mikhael J.R. Belch A.R. Prince H.M. Lucio M.N. Maiolino A. High response rate to bortezomib with or without dexamethasone in patients with relapsed or refractory multiple myeloma: results of a global phase 3b expanded access program Br. J. Haematol. 144 2009 169 175 19036114 \n18 Kropff M. Bisping G. Schuck E. Liebisch P. Lang N. Bortezomib in combination with intermediate-dose dexamethasone and continuous low-dose oral cyclophosphamide for relapsed multiple myeloma Br. J. Haematol. 138 2007 330 337 17614819\n\n",
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"title": "Successful treatment of primary advanced gastric plasmacytoma using a combination of surgical resection and chemotherapy with bortezomib: A case report.",
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{
"abstract": "Hepatocellular carcinoma (HCC) is becoming a rapidly prevalent hepatic tumor throughout the world. Initially, liver transplantation and resection were the only available options. But there is a recent advent of new treatment modalities like ablative embolization techniques and chemotherapy. Guidelines are available regarding the use of these techniques according to the stage of the tumor. Sorafenib is a chemotherapeutic agent approved for the management of advanced HCC. It works by inhibiting different tyrosine kinases, which halt the progression of the tumor. The common side effects associated with it are diarrhea, hand-foot skin reaction, and alopecia. Acute on chronic liver failure (ACLF), defined as the development of acute liver failure, in the setting of chronic liver disease, is a rare adverse event associated with sorafenib. Here, we present a case of a 65-year-old male presented to Nishtar Hospital Multan, Pakistan, who developed advanced-stage HCC due to underlying liver cirrhosis. There was no metastasis or vascular involvement. After discussing the options, he selected microwave ablation (MWA). There was a recurrence of the tumor after the procedure so he was started on sorafenib. A week after the initiation of a low dose drug (200 mg twice daily), he developed signs and symptoms of ACLF, which included hyperbilirubinemia, prolonged prothrombin time (PT), and flapping tremors. He was admitted to the intensive care unit (ICU) and was successfully managed. He was discharged with a follow-up scheduled after two weeks. This is a unique and rare adverse event of sorafenib.",
"affiliations": "Internal Medicine / Gastroenterology, Nishtar Medical University & Hospital, Multan, PAK.;Internal Medicine, Rawalpindi Medical University, Rawalpindi, PAK.;Gastroenterology, Nishtar Medical University & Hospital, Multan, PAK.;Internal Medicine / Gastroenterology, Nishtar Medical University & Hospital, Multan, PAK.;Internal Medicine, NewYork-Presbyterian Queens, Flushing, USA.",
"authors": "Malik|Anam Naveed|AN|;Tameez Ud Din|Asim|A|;Chaudhary|Farooq Mohyud Din|FMD|;Quratulain|Fnu|F|;Siddiqui|Khaleeq H|KH|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.7759/cureus.5176",
"fulltext": "\n==== Front\nCureusCureus2168-8184Cureus2168-8184Cureus Palo Alto (CA) 10.7759/cureus.5176Internal MedicineGastroenterologySorafenib-induced Acute on Chronic Liver Failure in a Patient with Hepatocellular Carcinoma After Microwave Ablation Muacevic Alexander Adler John R Malik Anam Naveed 1Tameez Ud Din Asim 2Chaudhary Farooq Mohyud Din 3Quratulain FNU 1Siddiqui Khaleeq H 4\n1 \nInternal Medicine / Gastroenterology, Nishtar Medical University & Hospital, Multan, PAK \n2 \nInternal Medicine, Rawalpindi Medical University, Rawalpindi, PAK \n3 \nGastroenterology, Nishtar Medical University & Hospital, Multan, PAK \n4 \nInternal Medicine, NewYork-Presbyterian Queens, Flushing, USA \nFarooq Mohyud Din Chaudhary farooqmdc@gmail.com19 7 2019 7 2019 11 7 e517612 7 2019 19 7 2019 Copyright © 2019, Malik et al.2019Malik 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 https://www.cureus.com/articles/21634-sorafenib-induced-acute-on-chronic-liver-failure-in-a-patient-with-hepatocellular-carcinoma-after-microwave-ablationHepatocellular carcinoma (HCC) is becoming a rapidly prevalent hepatic tumor throughout the world. Initially, liver transplantation and resection were the only available options. But there is a recent advent of new treatment modalities like ablative embolization techniques and chemotherapy. Guidelines are available regarding the use of these techniques according to the stage of the tumor. Sorafenib is a chemotherapeutic agent approved for the management of advanced HCC. It works by inhibiting different tyrosine kinases, which halt the progression of the tumor. The common side effects associated with it are diarrhea, hand-foot skin reaction, and alopecia. Acute on chronic liver failure (ACLF), defined as the development of acute liver failure, in the setting of chronic liver disease, is a rare adverse event associated with sorafenib. Here, we present a case of a 65-year-old male presented to Nishtar Hospital Multan, Pakistan, who developed advanced-stage HCC due to underlying liver cirrhosis. There was no metastasis or vascular involvement. After discussing the options, he selected microwave ablation (MWA). There was a recurrence of the tumor after the procedure so he was started on sorafenib. A week after the initiation of a low dose drug (200 mg twice daily), he developed signs and symptoms of ACLF, which included hyperbilirubinemia, prolonged prothrombin time (PT), and flapping tremors. He was admitted to the intensive care unit (ICU) and was successfully managed. He was discharged with a follow-up scheduled after two weeks. This is a unique and rare adverse event of sorafenib.\n\nsorafenibacute on chronic liver failuremicrowave ablationThe 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\nThe prevalence of hepatocellular carcinoma (HCC) is rising all around the world. A study reported about 14 million cases in 2012, which is expected to rise in the coming years, making it one of the most common primary hepatic tumors [1]. Multiple treatment options are available, depending upon the stage of the tumor. Liver transplantation, although one of the curative options, is not feasible in many patients because of the late presentation of HCC. Currently, ablative techniques, including radiofrequency ablation (RFA) and microwave ablation (MWA), are also being used. Other options include surgical resection, embolization techniques, and systemic chemotherapy. Sorafenib is an approved chemotherapeutic agent for HCC. It works by inhibiting certain tyrosine kinases that are involved in HCC tumor progression and vascular growth [2-3]. A phase III trial done to assess the efficacy and safety of sorafenib demonstrated liver dysfunction in <1% of the patients in the treatment group [4].\n\nAcute on chronic failure (ACLF), as implied by its name, is defined as the acute development of liver dysfunction in the setting of chronic liver disease [5]. Here, we report the case of an HCC patient who was diagnosed with ACLF after initiating sorafenib following MWA.\n\nCase presentation\nA 65-year-old male presented to Nishtar Hospital Multan, Pakistan, in 2016, with the complaint of multiple episodes of hematemesis. There was no history of viral hepatitis, alcohol intake, diabetes, or any other co-morbid illness. There was no significant family history of similar illness or liver disease. Examination showed pallor, vitiligo, and palmar erythema. Flapping tremors were absent. Abdominal examination showed an enlarged spleen. Further workup revealed hemoglobin 7.3 g/dl (normal 13-18 g/dl), platelet count 120,000/mm3 (normal 150,000-400,000 /mm3), albumin 3.1 g/dl (normal, 3.5-5.5 g/dl), total bilirubin 1.5 mg/dl (normal up to 1.2 mg/dl), aspartate aminotransferase (AST) 51 U/l (normal range, 10-40 U/l), and alanine aminotransferase (ALT) 68 U/l (normal range, 7-56 U/l). Prothrombin time was 15 sec (control 12 sec). Hepatitis B surface antigen (HBsAg) and antibodies to hepatitis C virus (anti-HCV) were negative. Ultrasound showed coarse echotexture of the liver with irregular margins. However, no lesion was seen. Mild ascites was noted, and the spleen was enlarged. A Child-Pugh score of 7 (Class B) was calculated based on the above parameters. The patient was resuscitated with vasopressors (octreotide) and packed red blood cells (RBCs). After hemodynamic stability, esophagogastroduodenoscopy (EGD) was performed, which showed esophageal varices with stigmata of a recent bleed. Band ligation was performed. A final diagnosis of decompensated chronic liver disease complicated by variceal bleed was established, and the patient was discharged upon beta-blockers, spironolactone, and lactulose.\n\nAfterward, the patient did not get proper follow-up for an evaluation of the cause of his liver disease. He later developed an episode of portosystemic encephalopathy (PSE) and worsening of ascites in 2017. He was on beta-blockers and diuretics, with poor compliance.\n\nIn 2019, he complained of fatigue and started losing weight, which prompted him to consult a physician in a private hospital of Multan. An ultrasound abdomen in March 2019 revealed a hypoechoic mass of about 3.5 x 2.6 cm. Subsequently, triphasic computed tomography (CT) abdomen revealed a single 3.5 x 4.2 cm lesion in segment VIII of his liver, which showed arterial hyper-enhancement with washout in the venous phase. Mild ascites was noted. There was no metastasis, and the portal and hepatic veins were patent. Labs revealed Hb 11.5 g/dl, albumin 2.9 g/dl, bilirubin 2.8 mg/dl, PT 18 sec (control 13 sec), HBsAg negative, and anti-HCV negative. At that time, his Child-Pugh score was B9. His Barcelona Clinic Liver Cancer (BCLC) stage was advanced (stage C) due to deranged liver function. He was advised a live donor liver transplant (LDLT). However, he was not willing for LDLT and inquired about alternative management options. He underwent microwave ablation (MWA) in April 2019. A post-procedure scan showed successful ablation of the lesion. He tolerated the procedure well and was discharged. Follow-up was planned after four weeks. On follow-up, triphasic CT abdomen in May 2019 showed a hypodense lesion 2.5 x 2.5 cm in segment VIII, consistent with previous successful MWA as well as a new arterialized lesion in segment VI of size 2.7 x 2.3 cm showing washout of contrast on venous phases (see Figure 1). No evidence of thrombosis in the portal vein or extrahepatic metastasis was seen. Gross ascites was also evident at that time.\n\nFigure 1 Triphasic CT abdomen\nShowing one lesion in segment VIII (A) and another in segment VI (B) of the liver in successive plain (A1/B1), arterial (A2/B2), and venous (A3/B3) phases of the study. A hypodense lesion (A1) in segment VIII was consistent with previous successful microwave ablation. This lesion is neither showing arterial hyperenhancement (A2) nor any washout (A3). A new arterialized lesion (B2) is seen in segment VI of the liver, showing washout of contrast on the venous phase (B3). No evidence of thrombosis in the portal vein or extrahepatic metastasis seen. Gross ascites is also evident.\n\nCT: computed tomography\n\nFollowing the diagnosis of advanced recurrent HCC, the patient was then started on tab sorafenib 200 mg twice daily in June 2019. A week after starting the new drug, the patient developed nausea, vomiting, loose motions, and yellow discoloration of the eyes. He was admitted to the intensive care unit of Nishtar Hospital Multan. Upon admission, the patient had fever 100°F, jaundice, clubbing, vitiligo, and palmar erythema. He was slightly confused. Flapping tremors were present. Abdominal examination showed a mildly tender distended abdomen with reduced liver span and ascites. Labs were as follows: hemoglobin 11.9 g/dl with a hematocrit of 32.5 and mean corpuscular volume (MCV) of 100 fL, total leukocyte count (TLC) 8000/mm3, platelets 71000/mm3. He had hypoalbuminemia (3.2 g/dl, normal 3.5-5), PT 30 sec (control 12 sec), and international normalized ratio (INR) 2.5. Total bilirubin on the day of admission was 3.5 mg/dl, which rapidly increased to 17.8 mg/dl after two days, with ALT 17.4 and AST 79.4, urea 29 mg/dl, creatinine 0.55 mg/dl, sodium 132 mEq/l, potassium 4.03 mEq/l, alpha-fetoprotein 132 ng/ml (normal 0-10 ng/ml). His Child-Pugh score was 13, model end-stage liver disease (MELD) 17, and MELD sodium (MELD-Na) 31. Ascitic fluid examination showed a high serum ascites albumin gradient (SAAG) ascites without evidence of spontaneous bacterial peritonitis (SBP). HBsAg and Anti-HCV were negative. Antibodies to hepatitis A and E of the immunoglobulin M (IgM) variety were negative. Hepatitis B core IgM was also negative. There was no history of illicit or indigenous drug usage as well as any alcohol intake.\n\nThese results were consistent with the diagnoses of ACLF. After ruling out the typical causes, the etiology of acute insult was determined to be the newly started drug sorafenib. The patient was managed in the intensive care unit with intravenous dextrose, containing fluids, antibiotics, and lactulose. After a few days, his condition started improving. His jaundice and coagulopathy started improving gradually. Eventually, he was discharged with a plan to follow-up in two weeks' time to assess recovery and discuss future treatment options.\n\nDiscussion\nMultiple modalities are available for the management of HCC, including liver transplant, resection, embolization, ablation, chemotherapy, and supportive care. The treatment mainly depends on the grade and stage of the tumor. Liver transplantation is a curative treatment for early-stage liver tumors [6]. Although our patient had advanced liver disease (stage C), he was advised LDLT, as there was no metastasis or vascular invasion visible on triphasic CT scan. Our patient agreed to MWA but there was a recurrence of the tumor.\n\nSorafenib is approved for the treatment of advanced HCC [7]. Based on these findings, our patient was started on sorafenib 200 mg twice daily. Although the recommended dose is 800 mg/day (400 mg twice daily), studies have found that there is no difference in the two regimens in terms of efficacy. It is recommended to start with a low dose in patients who are prone to develop complications, which was the case with our patient [8].\n\nThe most common adverse effects associated with sorafenib are loose stools, hand-foot skin reaction, and alopecia. Our patient also showed some of these symptoms. Liver failure was not reported as a major adverse event in clinical trials [4,7]. Wang QL et al. reported a case of ACLF induced by sorafenib after trans-arterial chemoembolization (TACE) and RFA, and the dose of the drug was 400 mg twice daily [9]. Van Hootegem A et al. also reported a similar case [10]. In contrast to these two cases, our patient underwent MWA, and the dosing schedule was 200 mg twice daily.\n\nACLF is defined in multiple ways in different studies. The common points include the manifestation of acute signs of liver failure in a patient with a chronic liver disease, most often preceded by a precipitating event. The acute signs of failure mentioned in the literature are raised bilirubin, deranged liver function tests, and prothrombin time (PT) [11-13]. In this case, the total bilirubin was 3.5 mg/dl on admission, which raised to 17.8 mg/dl in two days and PT was 30 seconds.\n\nThe management of ACLF is mainly supportive. Other specific symptoms like hepatic encephalopathy, raised intracranial pressure, and coagulopathy should be treated according to guidelines. In the present case, the patient was managed similarly and was discharged after an improvement in symptoms [14].\n\nConclusions\nACLF is a rare but serious adverse event associated with sorafenib in a patient with advanced HCC. It is diagnosed primarily by the clinical presentation and laboratory values. Jaundice and prolonged PT are common manifestations. The management is mainly supportive. In this report, we present a case of HCC, which was unsuccessfully ablated by microwave ablation. Sorafenib was started due to its advanced stage but signs of acute liver failure were developed within a week of initiation of therapy. This is a very rare adverse effect of 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 Review of hepatocellular carcinoma: epidemiology, etiology, and carcinogenesis J Carcinog Ghouri YA Mian I Rowe JH 1 16 2017 28694740 \n2 Hepatocellular carcinoma review: current treatment, and evidence-based medicine World J Gastroenterol Raza A Sood GK 4115 4127 20 2014 24764650 \n3 Microwave ablation of hepatocellular carcinoma World J Hepatol Poggi G Tosoratti N Montagna B Picchi C 2578 2589 7 2015 26557950 \n4 Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial Lancet Oncol Cheng AL Kang YK Chen Z 25 34 10 2009 19095497 \n5 Acute-on-chronic liver failure: an update Gut Hernaez R Solà E Moreau R Ginès P 541 553 66 2017 28053053 \n6 EASL clinical practice guidelines: management of hepatocellular carcinoma J Hepatol Galle PR Forner A Llovet JM 182 236 69 2018 29628281 \n7 Sorafenib in advanced hepatocellular carcinoma N Engl J Med Llovet JM Ricci S Mazzaferro V 378 390 359 2008 18650514 \n8 Advanced hepatocellular carcinoma and sorafenib: diagnosis, indications, clinical and radiological follow-up World J Hepatol Colagrande S Regini F Taliani GG Nardi C Inghilesi AL 1041 1053 7 2015 26052393 \n9 Sorafenib-induced acute-on-chronic liver failure in a patient with hepatocellular carcinoma after transarterial chemoembolization and radiofrequency ablation: a case report Mol Clin Oncol Wang QL Li XJ Yao ZC Zhang P Xu SL Huang H Hu KP 693 695 7 2017 28856003 \n10 Sorafenib-induced liver failure: a case report and review of the literature Case Reports Hepatol Van Hootegem A Verslype C Van Steenbergen W 941395 2011 2011 25954549 \n11 Decreasing serum alpha-fetoprotein levels in predicting poor prognosis of acute hepatic failure in patients with chronic hepatitis B J Gastroenterol Yang SS Cheng KS Lai YC Wu CH Chen TK Lee CL Chen DS 626 632 37 2002 12203078 \n12 Acute-on-chronic liver failure: pathophysiological basis of therapeutic options Blood Purif Jalan R Williams R 252 261 20 2002 11867872 \n13 Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study Liver Transpl Sen S Davies NA Mookerjee RP Cheshire LM Hodges SJ Williams R Jalan R 1109 1119 10 2004 15350001 \n14 AASLD position paper: the management of acute liver failure Hepatology Polson J Lee WM 1179 1197 41 2005 15841455\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2168-8184",
"issue": "11(7)",
"journal": "Cureus",
"keywords": "acute on chronic liver failure; microwave ablation; sorafenib",
"medline_ta": "Cureus",
"mesh_terms": null,
"nlm_unique_id": "101596737",
"other_id": null,
"pages": "e5176",
"pmc": null,
"pmid": "31565587",
"pubdate": "2019-07-19",
"publication_types": "D002363:Case Reports",
"references": "28856003;18650514;12203078;24764650;26557950;19095497;28053053;11867872;29628281;26052393;28694740;15841455;15350001;25954549",
"title": "Sorafenib-induced Acute on Chronic Liver Failure in a Patient with Hepatocellular Carcinoma After Microwave Ablation.",
"title_normalized": "sorafenib induced acute on chronic liver failure in a patient with hepatocellular carcinoma after microwave ablation"
} | [
{
"companynumb": "PK-BAYER-2022A071303",
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{
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{
"reactionmeddrapt": "Acute on chronic liver failure",
"reactionmeddraversionpt": "25.0",
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},
{
"reactionmeddrapt": "Hepatitis acute",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Drug reaction with eosinophilia and systemic symptoms",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Ischaemic hepatitis",
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"reactionoutcome": null
},
{
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},
{
"reactionmeddrapt": "Biopsy liver",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Portal vein flow decreased",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Hypersensitivity",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Vasoconstriction",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": null
},
{
"reactionmeddrapt": "Off label use",
"reactionmeddraversionpt": "25.0",
"reactionoutcome": null
}
],
"summary": null
},
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"literaturereference": "Malik AN; Tameez Ud Din A; Chaudhary FMD; Quratulain F; Siddiqui KH. Sorafenib-induced Acute on Chronic Liver Failure in a Patient with Hepatocellular Carcinoma After Microwave Ablation. Cureus. 2022;11 (7):e5176",
"literaturereference_normalized": "sorafenib induced acute on chronic liver failure in a patient with hepatocellular carcinoma after microwave ablation",
"qualification": "3",
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},
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] |
{
"abstract": "Monoclonal gammopathy is increasingly recognized as a cause of kidney injury. These renal conditions behave differently than ones without monoclonal gammopathy and require specific treatment. To avoid misdiagnosis, testing for paraprotein should be performed in addition to vasculitis and autoimmune diseases serologies in adults with unexplained AKI or proteinuria. Because the prevalence of monoclonal gammopathy is much more common than glomerular diseases, the nephrotoxicity of the monoclonal protein must be confirmed before cytotoxic therapy is initiated. This can only be done by a kidney biopsy. After a monoclonal gammopathy of renal significant is verified, the evaluation should then focus on the identification of the pathologic clone, because therapy is clone specific. We present this patient to illustrate the clinical presentation of a patient with renal dysfunction and a monoclonal gammopathy. This patient is also used to discuss the diagnostic process in detail when monoclonal gammopathy-associated renal disease is suspected.",
"affiliations": "Divisions of Nephrology and Hypertension and Hematology and Leung.nelson@mayo.edu.;Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.",
"authors": "Leung|Nelson|N|;Nasr|Samih H|SH|",
"chemical_list": "D007147:Immunoglobulin Light Chains",
"country": "United States",
"delete": false,
"doi": "10.2215/CJN.10641015",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1555-9041",
"issue": "11(6)",
"journal": "Clinical journal of the American Society of Nephrology : CJASN",
"keywords": "Acute Kidney Injury; Adult; Humans; MGRS; Paraproteins; glomerular disease; kidney biopsy; multiple myeloma; proteinuria; renal failure",
"medline_ta": "Clin J Am Soc Nephrol",
"mesh_terms": "D015432:Glomerulonephritis, Membranoproliferative; D006801:Humans; D007147:Immunoglobulin Light Chains; D008297:Male; D008875:Middle Aged; D010265:Paraproteinemias",
"nlm_unique_id": "101271570",
"other_id": null,
"pages": "1073-82",
"pmc": null,
"pmid": "26992418",
"pubdate": "2016-06-06",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "21543655;20139393;19520758;7878478;1904132;25373138;14578323;12493586;20870327;20090778;23091105;19037251;2117910;23123401;24108460;8849389;18808676;8041241;22156754;11901068;14655186;21784830;26176826;23302715;22417785;10528660;14712438;15010372;25939936;20410922;23623956;19470674;23922059;7634552;21511832;22872726;23729727;17699249;12830460;26154922;23704299;7816264;13807843;21220603;14717936;22045243;12371978;26371138;10844934;20061318;23024162;11423577;24172683;25949411;25387837;20876681;22067518;23233639;16728700;16044444;16794250;16855634;12176905;25607108;15774572;25439696;23508840;22997259;16571879;8306508;21569004;20130531;25860232;20705965;23047823;15685519",
"title": "A Patient with Abnormal Kidney Function and a Monoclonal Light Chain in the Urine.",
"title_normalized": "a patient with abnormal kidney function and a monoclonal light chain in the urine"
} | [
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{
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"reactionoutcome": "2"
}
],
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},
"primarysource": {
"literaturereference": "LEUNG N, NASR SH. A PATIENT WITH ABNORMAL KIDNEY FUNCTION AND A MONOCLONAL LIGHT CHAIN IN THE URINE. C-J-AM-SOC-NEPHROL 2016;11(6):1073-1082.",
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"qualification": "1",
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},
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},
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"transmissiondate": "20171127"
},
{
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"actiondrug": "5",
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"activesubstancename": "AMLODIPINE BESYLATE"
},
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"drugauthorizationnumb": "076692",
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"medicinalproduct": "AMLODIPINE BESYLATE."
}
],
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"reaction": [
{
"reactionmeddrapt": "Oedema peripheral",
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"reactionoutcome": "6"
}
],
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},
"primarysource": {
"literaturereference": "LEUNG N, NASR S. A PATIENT WITH ABNORMAL KIDNEY FUNCTION AND A MONOCLONAL LIGHT CHAIN IN THE URINE. CLIN J AM SOC NEPHROL. 2016?11(6):1073?82.",
"literaturereference_normalized": "a patient with abnormal kidney function and a monoclonal light chain in the urine",
"qualification": "3",
"reportercountry": "COUNTRY NOT SPECIFIED"
},
"primarysourcecountry": "US",
"receiptdate": "20180904",
"receivedate": "20180904",
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"seriousnessother": null,
"transmissiondate": "20181010"
}
] |
{
"abstract": "OBJECTIVE\nInfarct core can expand rapidly in acute stroke patients receiving intravenous tissue plasminogen activator (IV t-PA). We investigated changes in the extent of infarct core during IV t-PA treatment, and explored the associative factors of this infarct core expansion in patients with proximal artery occlusion.\n\n\nMETHODS\nWe included patients who were considered for sequential intra-arterial therapy (IAT) due to occlusion of intracranial proximal artery after IV t-PA. Patients who had a baseline Alberta Stroke Program Early Computed Tomography (CT) Score (ASPECTS) ≥6 and who underwent two consecutive CT scans before and shortly after IV t-PA infusion were enrolled. Patients were classified into no, moderate, and marked expansion groups based on decreases in ASPECTS (0-1, 2-3, and ≥4, respectively) on follow-up CT. Collateral status was graded using CT angiography.\n\n\nRESULTS\nOf the 104 patients, 16 (15.4%) patients showed moderate and 13 (12.5%) patients showed marked infarct core expansion on follow-up CT scans obtained at 71.1±19.1 min after baseline CT scan. Sixteen (15.4%) patients had an ASPECTS value <6 on the follow-up CT. None of the patients with marked expansion were independent at 3 months. Univariate analysis and ordinal logistic regression analysis demonstrated that the infarct core expansion was significantly associated with collateral status (p<0.001).\n\n\nCONCLUSIONS\nAmong patients who were considered for IAT after IV t-PA treatment, one out of every seven patients exhibited marked expansion of infarct core on follow-up CT before IAT. These patients tend to have poor collaterals and poor outcomes despite rescue IAT.",
"affiliations": "Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.;Department of Biostatistics, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.;Department of Neurology, Yonsei University College of Medicine, Seoul, Korea. jhheo@yuhs.ac.",
"authors": "Song|Dongbeom|D|https://orcid.org/0000-0002-7175-4948;Yoo|Joonsang|J|;Baek|Jang Hyun|JH|;Kim|Jinkwon|J|;Lee|Hye Sun|HS|;Kim|Young Dae|YD|;Nam|Hyo Suk|HS|;Heo|Ji Hoe|JH|https://orcid.org/0000-0001-9898-3321",
"chemical_list": "D005343:Fibrinolytic Agents",
"country": "Korea (South)",
"delete": false,
"doi": "10.3349/ymj.2018.59.2.310",
"fulltext": "\n==== Front\nYonsei Med JYonsei Med. JYMJYonsei Medical Journal0513-57961976-2437Yonsei University College of Medicine 2943620110.3349/ymj.2018.59.2.310Original ArticleNeurology & NeurosciencesInfarct Core Expansion on Computed Tomography before and after Intravenous Thrombolysis https://orcid.org/0000-0002-7175-4948Song Dongbeom 1Yoo Joonsang 1Baek Jang-Hyun 1Kim Jinkwon 12Lee Hye Sun 3Kim Young Dae 1Nam Hyo Suk 1https://orcid.org/0000-0001-9898-3321Heo Ji Hoe 11 Department of Neurology, Yonsei University College of Medicine, Seoul, Korea.2 Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam, Korea.3 Department of Biostatistics, Yonsei University College of Medicine, Seoul, Korea.\nCorresponding author: Dr. Ji Hoe Heo, Department of Neurology, Yonsei University College of Medicine, 50-1 Yonsei-ro, Seodaemun-gu, Seoul 03722, Korea. Tel: 82-2-2228-1605, Fax: 82-2-393-0705, jhheo@yuhs.ac01 3 2018 05 2 2017 59 2 310 316 14 8 2017 11 12 2017 22 12 2017 © Copyright: Yonsei University College of Medicine 20182018Yonsei University College of MedicineThis 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.Purpose\nInfarct core can expand rapidly in acute stroke patients receiving intravenous tissue plasminogen activator (IV t-PA). We investigated changes in the extent of infarct core during IV t-PA treatment, and explored the associative factors of this infarct core expansion in patients with proximal artery occlusion.\n\nMaterials and Methods\nWe included patients who were considered for sequential intra-arterial therapy (IAT) due to occlusion of intracranial proximal artery after IV t-PA. Patients who had a baseline Alberta Stroke Program Early Computed Tomography (CT) Score (ASPECTS) ≥6 and who underwent two consecutive CT scans before and shortly after IV t-PA infusion were enrolled. Patients were classified into no, moderate, and marked expansion groups based on decreases in ASPECTS (0–1, 2–3, and ≥4, respectively) on follow-up CT. Collateral status was graded using CT angiography.\n\nResults\nOf the 104 patients, 16 (15.4%) patients showed moderate and 13 (12.5%) patients showed marked infarct core expansion on follow-up CT scans obtained at 71.1±19.1 min after baseline CT scan. Sixteen (15.4%) patients had an ASPECTS value <6 on the follow-up CT. None of the patients with marked expansion were independent at 3 months. Univariate analysis and ordinal logistic regression analysis demonstrated that the infarct core expansion was significantly associated with collateral status (p<0.001).\n\nConclusion\nAmong patients who were considered for IAT after IV t-PA treatment, one out of every seven patients exhibited marked expansion of infarct core on follow-up CT before IAT. These patients tend to have poor collaterals and poor outcomes despite rescue IAT.\n\nAcute stroke therapyischemic strokeCT scancollateral circulationtissue plasminogen activatorMinistry of Health and Welfarehttp://dx.doi.org/10.13039/501100003625HI15C2814HI15C1056\n==== Body\nINTRODUCTION\nIntra-arterial therapy (IAT) using a stent retriever is safe and effective in acute stroke with intracranial proximal artery occlusion.12345678 However, despite successful reperfusion by IAT, some patients do not show clinical improvement. One of the plausible explanations for this futile reperfusion is rapid conversion of ischemic penumbra into irreversible infarct core.910 While patients who already have extensive areas of irreversible damage are usually excluded from reperfusion therapy,811 some salvageable areas can be converted to irreversible infarct core during the reperfusion treatment. However, there are few reports on infarct core progression in the hyperacute stage in patients with proximal artery occlusion, and its prevalence, related factors, and clinical significance are largely unknown.\n\nBefore the efficacy of IAT was proven, IAT was sometimes performed as a rescue treatment to patients who do not respond to intravenous tissue plasminogen activator (IV t-PA) after follow-up imaging study. By analyzing two consecutive computed tomography (CT) scans acquired before and shortly after IV t-PA, we investigated the change in the extent of the infarct core during IV t-PA treatment, its associative factors, and clinical significance.\n\nMATERIALS AND METHODS\nStudy population\nWe included patients who were potential candidate for IAT due to persistent occlusion of intracranial proximal artery after IV t-PA (Actilyse, Boehringer-Ingelheim, Ingelheim, Germany) and who had two consecutive CT scans before and shortly after IV t-PA. This group was derived from a cohort that was developed to investigate the factors associated with thrombus resolution after IV t-PA.1213 In the cohort, two consecutive noncontrast CT (NCCT) scans were acquired before and shortly after IV t-PA infusion in the same scanner (LightSpeed Plus, GE Healthcare, Milwaukee, WI, USA or SOMATOM Sensation 64, Siemens Healthcare, Erlangen, Germany) (Supplementary Material, only online), and CT angiography (CTA) was taken with follow-up NCCT. For this study, we included patients who had unilateral intracranial proximal artery [internal carotid artery (ICA), middle cerebral artery (MCA) M1, or M2] occlusion on CTA between January 2009 and December 2014. We excluded patients who already had a large infarct core in the initial NCCT, indicated by an Alberta Stroke Program Early CT Score (ASPECTS) <6. Patients received IV infusion of t-PA within 3 hours of symptom onset until December 2012 and within 4.5 hours thereafter. Additional IAT was considered if patients did not show a satisfactory clinical response [<50% improvement as measured by the National Institutes of Health Stroke Scale (NIHSS) score] to IV t-PA infusion.\n\nImage analysis\nIn this study, infarct core was defined as low-density area on NCCT and calculated based on the ASPECTS scoring system. ASPECTS was measured with NCCT using revised methodology, which does not account for isolated cortical swelling.14 Patients were classified into three groups: no, moderate, and marked expansion groups, defined based on a decrease of 0??, 2??, and ≥4, respectively, in ASPECTS between the two scans. The CTA-collateral score (CTA-CS) was measured with reconstructed maximum intensity projection CTA images as follows: 0=absence of collateral supply to the occluded vascular territory; 1=collateral supply filling <50%, but >0% of the occluded vascular territory; 2=collateral supply filling >50%, but <100% of the occluded vascular territory; and 3=collateral supply filling 100% of the occluded vascular territory.15 Two stroke neurologists, who were blinded to all clinical information, other than the side of the infarction, independently reviewed the CT scans and measured ASPECTS and CTA-CS. Disagreements between the two readers were resolved by consensus. Good collateral status was defined as CTA-CS ≥2.\n\nClinical variables and outcomes\nStroke mechanisms were determined based on the Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification. The initial stroke severity was assessed using the NIHSS, and the functional outcome was measured using the modified Rankin Scale (mRS) score at 90 days. The degree of reperfusion was graded by the Thrombolysis in Cerebral Infarction (TICI) scale in the final run of IAT. TICI scales of the patients who did not undergo IAT were graded with 24-hour follow-up MR angiography. We obtained outcome data and clinical variables, such as vascular risk factors, laboratory results, and time metrics, from the aforementioned prospective cohort. Successful reperfusion was defined as TICI ≥2b, and a favorable outcome was defined as mRS ≤2. Symptomatic intracranial hemorrhage (ICH) was defined as any hemorrhage associated with neurological deterioration, as indicated by a decrease of 4 points on the NIHSS within 7 days (European Cooperative Acute Stroke Study III definition).16 This study was approved by the Institutional Review Board of Severance Hospital (IRB No. 4-2013-0828), Yonsei University Health System, with a waiver of written informed consent from the patients or their qualified next-of-kin because of the retrospective nature of the study.\n\nStatistical analysis\nValues are presented as a number (%), mean±standard deviation (SD), or median [interquartile range (IQR)], as appropriate. We compared the baseline characteristics, treatment modalities, time parameters, and imaging characteristics between the mild, moderate, and severe infarct expansion groups. Analysis of variance or Kruskal-Wallis test, χ2 test, and Fisher's exact test were used, as appropriate. The Spearman's rank correlation coefficient was computed between the ASPECTS difference and the CTA-CS. Variables achieving p-values less than 0.1 in the univariate analyses with an ordinal association and clinically important time variables were adjusted for using multivariate analyses (ordinal logistic regression analysis). Univariate analyses (independent sample t-test or Wilcoxon rank sum test for continuous variables, and χ2 test or Fisher's exact test for categorical variables) were also performed to compare the baseline characteristics, treatment modalities, time parameters, and imaging characteristics between the favorable and unfavorable outcome groups. Variables achieving p-values less than 0.1 in the univariate analyses for favorable outcomes were entered for multivariate analyses (binomial logistic regression analysis). Inter-rater agreements were assessed using linear weighted κ statistics. Statistical analyses were performed using the R Statistical Software. Results with a two-sided p-value <0.05 were considered statistically significant.\n\nRESULTS\nBaseline characteristics\nDuring the study period, 176 patients in the CT-based thrombus imaging cohort received IV t-PA treatment for an anterior circulation stroke with serial CT scans acquired before and after the IV t-PA treatment. After excluding 65 patients without proximal artery occlusion on CTA and seven patients with ASPECTS ≤6 on initial CT, 104 patients were included for this study. The mean age of the study patients was 67.3±10.4 years, and 60 (57.7%) of the patients were men. The median NIHSS score at admission was 16 (IQR, 13??9). Ninety (86.5%) patients were treated with combined IV t-PA and IAT, while 14 (13.5%) patients were treated with IV t-PA alone. The reasons for not performing IAT despite the presence of occlusion on CTA were rapid improvement of clinical symptom in eight patients, early ischemic change in more than one third of MCA territory in four patients, presence of hemorrhage on follow-up CT in one patient, and active tuberculosis in one patient. The primary modality used in the IAT was the stent retriever in 52 (57.8%) patients, intra-arterial urokinase infusion in 31 (34.4%) patients, modified thrombus suction using a Penumbra catheter in four (4.4%) patients, and carotid stent placement in three (3.3%) patients. Baseline characteristics of the study group appear in Table 1.\n\nInfarct core expansion\nFollow-up CT scans were obtained at 71.1±19.1 minutes after baseline CT scan. On the follow-up CT scan, 75 (72.1%) patients showed almost no infarct core expansion. However, 16 (15.4%) patients showed moderate and 13 (12.5%) patients showed marked infarct core expansion (Table 1). Although we excluded patients with a baseline ASPECTS <6, there were 16 (15.4%) patients who had ASPECTS <6 in the follow-up scan (Fig. 1). Inter-rater agreements for the expansion of the infarct core [linear weighted κ, 0.641; 95% confidence interval (CI), 0.485–0.797], ASPECTS (linear weighted κ, 0.666; 95% CI, 0.609–0.723), and CTA-CS (linear weighted κ, 0.625; 95% CI, 0.530–0.721) were all good.\n\nFactors associated with infarct core expansion\nUnivariate analyses revealed an association of the infarct core expansion with ICA occlusion, poor collateral status, and severe initial neurological deficits, but not with the time interval between the two consecutive CT scans. The proportion of patients with hypercholesterolemia was significantly higher in the moderate expansion group; however, there was no ordinal association between the history of hypercholesterolemia and infarct core expansion. In the ordinal logistic regression analysis, the infarct core expansion was significantly associated with collateral status (odds ratio, 9.232; 95% CI, 4.484–22.209; p<0.001) (Table 2). A significant correlation between the difference in ASPECTS on the consecutive CT scans, and CTA-CS (Fig. 2) (Spearman's rank correlation coefficient ρ=−0.733; p<0.001) was also noted.\n\nInfarct core expansion and clinical outcomes\nFifty eight (55.8%) patients showed a favorable clinical outcome at 3 months. Infarct core expansion was associated with unfavorable clinical outcomes in the univariate (Supplementary Table 1, only online) and multivariate analyses after adjusting for confounding variables, such as sex, age, prothrombin time, time from onset to IV t-PA, initial NIHSS score, initial occlusion site, and successful reperfusion. None of the 13 patients with a marked expansion (≥4 point decrease in ASPECTS) of the ischemic core were independent at 3 months. In addition, only two out of the 16 patients with ASPECTS <6 on the follow-up CT showed a favorable clinical outcome. Although we could not perform multivariate analyses given the low numbers of symptomatic ICH and death events within 3 months, a significant association between infarct core expansion and symptomatic ICH and death within 3 months was observed in the univariate analyses (Table 1).\n\nDISCUSSION\nThis study investigated the expansion of infarct core during IV t-PA treatment in patients with proximal artery occlusion. The study showed that 1) infarct core markedly expanded in about 12% of the patients with proximal artery occlusion at the end of IV t-PA infusion, 2) these patients had poor functional outcomes when they were treated with IAT after the infusion of IV t-PA, and 3) poor collaterals were predictive of a marked expansion of the infarct core.\n\nIAT using a stent retriever is the treatment of choice in patients with intracranial proximal artery occlusion even if they already received IV t-PA treatment based on the recent results from randomized controlled trials.234,567,8 This study simulated the situation in which additional IAT is required after IV t-PA treatment, as we included patients who had proximal artery occlusion after IV t-PA. Indeed, the majority of the patients in this study population was treated with IAT. In patients who receive IAT on top of IV t-PA, IAT is sometimes performed after the infusion of IV t-PA is completed. However, our study demonstrated that infarct core could expand significantly during this time interval in some patients. In this study, 12% of the patients who did not have a large infarct core on the initial scan showed marked infarct core progression (decrease of ASPECTS ≥4). Despite a rescue IAT, none of these patients recovered to an independent life at 3 months. Although we do not know what the prognosis of these patients would be if they were to receive IAT as a combined therapy without waiting for completion of IV t-PA infusion or follow-up imaging, our results indirectly suggest that combined IAT with infusion of IV t-PA should be initiated as soon as possible and that patients who are expected to have infarct core expansion within an hour may not be an ideal candidates for combined IAT. While the poor outcomes in patients with infarct core expansion could be due to the higher failure of reperfusion in this group, the prognostic effect of infarct core progression was still significant after adjusting the successful reperfusion in the multivariate analysis.\n\nWe sought to identify factors associated with infarct core expansion and found that collateral status was one of its main associative factors. Collaterals are virtually the only source of blood supply in the presence of a proximal artery occlusion.1718 Collaterals help the tissues at risk to maintain their viability until final reperfusion is achieved. Previous studies have shown that the rate of infarct growth is determined by collateral status192021 and that better collateral status in the hyper-acute stage is associated with more favorable clinical outcomes.222324 The results of this study are in line with those of previous studies. Although the elapsed time would be another factor determining the infarct core expansion,192526 no definite association was observed between time between the two CT scans and the infarct core expansion in our study. This might be accounted for, in part, by the relatively constant time interval between the CTs, with a mean of ~70 minutes and an SD of ~14 minutes in this study. Nevertheless, our findings suggest that collateral blood supply might be more important than mere time.\n\nWe excluded patients who already have considerable infarct core in the initial imaging study (ASPECTS<6) based on recent clinical trial results811 because the primary aim of this study was to evaluate the infarct core expansion after the initial imaging. However, it should be acknowledged that the lack of evidence for clinical efficacy of IAT in patients with low ASPECTS does not necessarily mean that IAT should not be indicated in this group of patients. It is also difficult to provide specific suggestions regarding the use of collateral score in selecting an IAT candidate with this study because the patients in this study received IAT as a rescue therapy after waiting for IV t-PA response and that about 40% of the patients were not treated with a stent retriever, a currently standard modality of choice for IAT.8\n\nThere are several limitations to this study. First, occlusion sites and collateral scores were evaluated not in the initial imaging studies but in the follow-up studies after t-PA infusion because this study population was derived from the cohort for CT-based thrombus imaging. Since there is a slight chance of clot resolution and dynamic change of collateral status over the period of t-PA infusion, this should be considered as a limitation of our study. Second, patients who did not have proximal artery occlusion after IV t-PA treatment were not included in this study. Thus, the findings of this study cannot be applied to patients with successful recanalization after IV t-PA or those with distal artery occlusions. Third, while about 30% of patients had a history of previous stroke, data on pre-stroke mRS were not available. Therefore, this should be considered in the interpretation of outcome results. Finally, this study has a moderate sample size and a retrospective single-center design. Therefore, generalization of our results must be performed with caution.\n\nIn conclusion, our study revealed that some patients who received IV t-PA showed a rapid expansion of the infarct core during IV t-PA infusion, and they showed poor functional outcomes after rescue IAT. These patients with a rapid expansion of infarct core had poor collateral circulations. Our findings support the important role of collateral status for maintaining tissue viability and suggest that IAT should be started as soon as possible without waiting for completion of t-PA infusion.\n\nACKNOWLEDGEMENTS\nThis study was supported by a grant by Korea Healthcare Technology Research and Development Project, funded by the Ministry for Health and Welfare, Republic of Korea (HI15C2814, HI15C1056).\n\nThe authors have no financial conflicts of interest.\n\nSUPPLEMENTARY MATERIALS\nSupplementary Imaging Protocol\n Supplementary Table 1\nFactors Associated with Favorable Outcomes\n\n Fig. 1 Distribution of ASPECTS on initial and follow-up CT images. ASPECTS, Alberta Stroke Program Early Computed Tomography Score; CT, computed tomography.\nFig. 2 Difference in ASPECTS on consecutive CT scans according to collateral status. ASPECTS, Alberta Stroke Program Early Computed Tomography Score; CT, computed tomography; CTA, CT angiography.\nTable 1 Baseline Characteristics and Outcomes According to Infarct Core Expansion\nVariables\tTotal (n=104)\tNo expansion (n=75)\tModerate expansion (n=16)\tMarked expansion (n=13)\tp value\t\nSex, male\t60 (57.7)\t44 (58.7)\t7 (43.8)\t9 (69.2)\t0.366\t\nAge (yr)\t67.3±10.4\t66.1±11.1\t71.4±4.62\t69.2±10.2\t0.137\t\nHypertension\t70 (67.3)\t47 (62.7)\t13 (81.2)\t10 (76.9)\t0.314\t\nDiabetes mellitus\t26 (25.0)\t18 (23.1)\t6 (35.3)\t3 (23.1)\t0.822\t\nHypercholesterolemia*\t9 (8.7)\t4 (5.3)\t4 (25.0)\t1 (7.7)\t0.036\t\nCurrent smoker\t19 (18.3)\t15 (20.0)\t1 (6.3)\t3 (23.1)\t0.361\t\nOld cerebrovascular accident\t32 (30.8)\t23 (30.7)\t5 (31.2)\t4 (30.8)\t1.000\t\nAtrial fibrillation\t53 (51.0)\t34 (45.3)\t10 (62.5)\t9 (69.2)\t0.170\t\nTOAST classification\t\t\t\t\t0.137\t\n Negative evaluation\t11 (10.7)\t4 (5.41)\t4 (25.0)\t3 (23.1)\t\t\n Large-artery atherosclerosis\t21 (20.4)\t19 (25.7)\t1 (6.25)\t1 (7.69)\t\t\n Cardiac embolism\t54 (52.4)\t37 (50.0)\t9 (56.2)\t8 (61.5)\t\t\n More than two causes\t14 (13.6)\t11 (14.9)\t2 (12.5)\t1 (7.69)\t\t\n Other determined\t3 (2.91)\t3 (4.05)\t0 (0.00)\t0 (0.00)\t\t\nOcclusion site\t\t\t\t\t0.004\t\n ICA\t37 (35.6)\t19 (25.3)\t8 (50.0)\t10 (76.9)\t\t\n M1\t46 (44.2)\t37 (49.3)\t7 (43.8)\t2 (15.4)\t\t\n M2\t21 (20.2)\t19 (25.3)\t1 (6.25)\t1 (7.69)\t\t\nSystolic blood pressure (mm Hg)\t148.0±27.4\t148.5±27.4\t148.1±32.1\t144.5±22.7\t0.891\t\nHemoglobin (g/dL)\t13.8±1.5\t13.8±1.6\t13.4±1.6\t14.3±1.4\t0.313\t\nPlatelet count (×109/L)\t225.8±61.1\t228.4±61.4\t209.8±73.5\t230.9±40.5\t0.522\t\nProthrombin time, international normalized ratio\t0.99±0.10\t0.98±0.10\t1.00±0.12\t1.02±0.10\t0.359\t\nPartial thrombin time (sec)\t30.1 (6.0)\t29.6 (5.2)\t32.4 (8.1)\t30.3 (6.7)\t0.240\t\nBlood sugar level (mg/dL)\t137.3±50.8\t138.8±54.1\t134.4±48.9\t131.9±33.5\t0.877\t\nTotal cholesterol (mg/dL)\t167.5±36.8\t168±36.5\t162±41.3\t169±35.7\t0.830\t\nLow density lipoprotein (mg/dL)\t99.4±32.8\t101.2±35.1\t91.7±28.5\t97.8±24.0\t0.622\t\nNIHSS\t15.5 [13.0–19.0]\t15.0 [11.0–19.0]\t15.0 [14.0–20.0]\t18.0 [17.0–22.0]\t0.015\t\nInitial ASPECTS\t9.0 [8.0–10.0]\t9.0 [8.0–10.0]\t9.0 [8.75–9.25]\t9.0 [7.0–10.0]\t0.626\t\nCollateral score\t2.0 [1.0–3.0]\t2.0 [2.0–3.0]\t1.0 [1.0–2.0]\t0.0 [0.0–0.0]\t<0.001\t\nTime from onset to the initial CT (min)\t72.2±38.7\t73.9±39.2\t67.5±37.9\t68.0±39.2\t0.770\t\nTime from onset to IV t-PA (min)\t98.5±38.6\t101.0±38.6\t91.3±37.8\t94.2±41.3\t0.619\t\nTime interval between the CTs (min)\t71.1±19.1\t71.1±19.8\t71.1±20.4\t71.4±14.1\t0.999\t\nGroups based on tPA-eligible time window\t\t\t\t\t0.769\t\n 3-hour group\t26 (25.0)\t19 (25.3)\t3 (18.8)\t4 (30.8)\t\t\n 4.5-hour group\t78 (75.0)\t56 (74.7)\t13 (81.2)\t9 (69.2)\t\t\nIAT\t90 (86.5)\t65 (86.7)\t15 (93.8)\t10 (76.9)\t0.462\t\nStent retriever\t52 (57.8)\t35 (53.8)\t11 (73.3)\t6 (60.0)\t0.403\t\nSuccessful reperfusion\t75 (72.1)\t59 (78.7)\t11 (68.8)\t5 (38.5)\t0.014\t\nSymptomatic ICH\t5 (4.81)\t2 (2.67)\t3 (18.8)\t0 (0.0)\t0.046\t\nmRS at 3 months\t2.0 [1.0–5.0]\t2.0 [1.0–3.5]\t2.0 [0.75–5.0]\t5.0 [4.0–6.0]\t<0.001\t\nFavorable outcome at 3 months\t58 (55.8)\t49 (65.3)\t9 (56.2)\t0 (0.0)\t<0.001\t\nDeath within 3 months\t15 (14.4)\t8 (10.7)\t2 (12.5)\t5 (38.5)\t0.048\t\nTOAST, Trial of Org 10172 in Acute Stroke Treatment; ICA, internal carotid artery; M1, first segment of the middle cerebral artery; M2, second segment of the middle cerebral artery; NIHSS, National Institutes of Health Stroke Scale; ASPECTS, Alberta Stroke Program Early CT score; CT, computed tomography; IV t-PA, intravenous tissue plasminogen activator; ICH, intracranial hemorrhage; mRS, modified Rankin Score; IAT, intra-arterial therapy.\n\nValues represent a number (%), mean±standard deviation, or median [interquartile range].\n\n*Hypercholesterolemia was defined as 1) fasting cholesterol level >240 mg/dL, 2) fasting low density lipoprotein level >160 mg/dL, or 3) history of taking lipid lowering agent due to hypercholesterolemia.\n\nTable 2 Ordinal Regression Analysis for Infarct Core Expansion\nVariables\tOdds ratio (95% confidence interval)\tp value\t\nCollateral score\t9.232 (4.484–22.209)\t<0.001\t\nOcclusion site\t\t\t\n M2\tReference\t\t\n M1\t1.730 (0.259–16.666)\t0.595\t\n ICA\t5.642 (0.891–55.459)\t0.091\t\nTime from onset to IV t-PA (min)\t0.995 (0.980–1.009)\t0.462\t\nTime interval between the CT scans (min)\t0.992 (0.963–1.022)\t0.610\t\nInitial NIHSS\t1.108 (0.964–1.296)\t0.167\t\nICA, internal carotid artery; M1, first segment of middle cerebral artery; M2, second segment of middle cerebral artery; IV t-PA, intravenous tissue plasminogen activator; NIHSS, National Institutes of Health Stroke Scale; CT, computed tomography.\n==== Refs\n1 Badhiwala JH Nassiri F Alhazzani W Selim MH Farrokhyar F Spears J Endovascular thrombectomy for acute ischemic stroke: a meta-analysis JAMA 2015 314 1832 1843 26529161 \n2 Berkhemer OA Fransen PS Beumer D van den Berg LA Lingsma HF Yoo AJ A randomized trial of intraarterial treatment for acute ischemic stroke N Engl J Med 2015 372 11 20 25517348 \n3 Campbell BC Mitchell PJ Kleinig TJ Dewey HM Churilov L Yassi N Endovascular therapy for ischemic stroke with perfusion-imaging selection N Engl J Med 2015 372 1009 1018 25671797 \n4 Goyal M Demchuk AM Menon BK Eesa M Rempel JL Thornton J Randomized assessment of rapid endovascular treatment of ischemic stroke N Engl J Med 2015 372 1019 1030 25671798 \n5 Jovin TG Chamorro A Cobo E de Miquel MA Molina CA Rovira A Thrombectomy within 8 hours after symptom onset in ischemic stroke N Engl J Med 2015 372 2296 2306 25882510 \n6 Saver JL Goyal M Bonafe A Diener HC Levy EI Pereira VM Stent-retriever thrombectomy after intravenous t-PA vs. t-PA alone in stroke N Engl J Med 2015 372 2285 2295 25882376 \n7 Goyal M Menon BK van Zwam WH Dippel DW Mitchell PJ Demchuk AM Endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials Lancet 2016 387 1723 1731 26898852 \n8 Powers WJ Derdeyn CP Biller J Coffey CS Hoh BL Jauch EC 2015 American Heart Association/American Stroke Association focused update of the 2013 guidelines for the early management of patients with acute ischemic stroke regarding endovascular treatment: a guideline for healthcare [rofessionals from the American Heart Association/American Stroke Association Stroke 2015 46 3020 3035 26123479 \n9 Song D Lee K Kim EH Kim YD Kim J Song TJ Value of utilizing both ASPECTS and CT angiography collateral score for outcome prediction in acute ischemic stroke Int J Stroke 2015 10 1018 1023 25907633 \n10 Saver JL Goyal M van der Lugt A Menon BK Majoie CB Dippel DW Time to treatment with endovascular thrombectomy and outcomes from ischemic stroke: a meta-analysis JAMA 2016 316 1279 1288 27673305 \n11 Menon BK Campbell BC Levi C Goyal M Role of imaging in current acute ischemic stroke workflow for endovascular therapy Stroke 2015 46 1453 1461 25944319 \n12 Kim YD Nam HS Kim SH Kim EY Song D Kwon I Time-dependent thrombus resolution after tissue-type plasminogen activator in patients with stroke and mice Stroke 2015 46 1877 1882 25967573 \n13 Nam HS Kim EY Kim SH Kim YD Kim J Lee HS Prediction of thrombus resolution after intravenous thrombolysis assessed by CT-based thrombus imaging Thromb Haemost 2012 107 786 794 22318312 \n14 Puetz V Dzialowski I Hill MD Demchuk AM The Alberta Stroke Program Early CT Score in clinical practice: what have we learned? Int J Stroke 2009 4 354 364 19765124 \n15 Tan JC Dillon WP Liu S Adler F Smith WS Wintermark M Systematic comparison of perfusion-CT and CT-angiography in acute stroke patients Ann Neurol 2007 61 533 543 17431875 \n16 Hacke W Kaste M Bluhmki E Brozman M Dávalos A Guidetti D Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke N Engl J Med 2008 359 1317 1329 18815396 \n17 Liebeskind DS Collateral circulation Stroke 2003 34 2279 2284 12881609 \n18 Shuaib A Butcher K Mohammad AA Saqqur M Liebeskind DS Collateral blood vessels in acute ischaemic stroke: a potential therapeutic target Lancet Neurol 2011 10 909 921 21939900 \n19 Jung S Gilgen M Slotboom J El-Koussy M Zubler C Kiefer C Factors that determine penumbral tissue loss in acute ischaemic stroke Brain 2013 136 Pt 12 3554 3560 24065722 \n20 Miteff F Levi CR Bateman GA Spratt N McElduff P Parsons MW The independent predictive utility of computed tomography angiographic collateral status in acute ischaemic stroke Brain 2009 132 Pt 8 2231 2238 19509116 \n21 Campbell BC Christensen S Tress BM Churilov L Desmond PM Parsons MW Failure of collateral blood flow is associated with infarct growth in ischemic stroke J Cereb Blood Flow Metab 2013 33 1168 1172 23652626 \n22 Bang OY Saver JL Kim SJ Kim GM Chung CS Ovbiagele B Collateral flow predicts response to endovascular therapy for acute ischemic stroke Stroke 2011 42 693 699 21233472 \n23 Leng X Fang H Leung TW Mao C Miao Z Liu L Impact of collaterals on the efficacy and safety of endovascular treatment in acute ischaemic stroke: a systematic review and meta-analysis J Neurol Neurosurg Psychiatry 2016 87 537 544 26063928 \n24 Menon BK Qazi E Nambiar V Foster LD Yeatts SD Liebeskind D Differential effect of baseline computed tomographic angiography collaterals on clinical outcome in patients enrolled in the Interventional Management of Stroke III Trial Stroke 2015 46 1239 1244 25791716 \n25 Khatri P Abruzzo T Yeatts SD Nichols C Broderick JP Tomsick TA IMS I and II Investigators Good clinical outcome after ischemic stroke with successful revascularization is time-dependent Neurology 2009 73 1066 1072 19786699 \n26 Khatri P Yeatts SD Mazighi M Broderick JP Liebeskind DS Demchuk AM Time to angiographic reperfusion and clinical outcome after acute ischaemic stroke: an analysis of data from the Interventional Management of Stroke (IMS III) phase 3 trial Lancet Neurol 2014 13 567 574 24784550\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "0513-5796",
"issue": "59(2)",
"journal": "Yonsei medical journal",
"keywords": "Acute stroke therapy; CT scan; collateral circulation; ischemic stroke; tissue plasminogen activator",
"medline_ta": "Yonsei Med J",
"mesh_terms": "D061605:Administration, Intravenous; D000368:Aged; D020520:Brain Infarction; D000072226:Computed Tomography Angiography; D005260:Female; D005343:Fibrinolytic Agents; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D015912:Thrombolytic Therapy; D014057:Tomography, X-Ray Computed; D016896:Treatment Outcome",
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"pubdate": "2018-03",
"publication_types": "D016428:Journal Article",
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"title": "Infarct Core Expansion on Computed Tomography before and after Intravenous Thrombolysis.",
"title_normalized": "infarct core expansion on computed tomography before and after intravenous thrombolysis"
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"literaturereference": "HEO J, SONG D, YOO J, BAEK J, KIM J, LEE H, ET AL. INFARCT CORE EXPANSION ON COMPUTED TOMOGRAPHY BEFORE AND AFTER INTRAVENOUS THROMBOLYSIS. . YONSEI MEDICAL JOURNAL. 2018?59 (2):310-316.",
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"abstract": "Extended-release naltrexone (XR-NTX), an opioid antagonist, and sublingual buprenorphine-naloxone (BUP-NX), a partial opioid agonist, are pharmacologically and conceptually distinct interventions to prevent opioid relapse. We aimed to estimate the difference in opioid relapse-free survival between XR-NTX and BUP-NX.\n\n\n\nWe initiated this 24 week, open-label, randomised controlled, comparative effectiveness trial at eight US community-based inpatient services and followed up participants as outpatients. Participants were 18 years or older, had Diagnostic and Statistical Manual of Mental Disorders-5 opioid use disorder, and had used non-prescribed opioids in the past 30 days. We stratified participants by treatment site and opioid use severity and used a web-based permuted block design with random equally weighted block sizes of four and six for randomisation (1:1) to receive XR-NTX or BUP-NX. XR-NTX was monthly intramuscular injections (Vivitrol; Alkermes) and BUP-NX was daily self-administered buprenorphine-naloxone sublingual film (Suboxone; Indivior). The primary outcome was opioid relapse-free survival during 24 weeks of outpatient treatment. Relapse was 4 consecutive weeks of any non-study opioid use by urine toxicology or self-report, or 7 consecutive days of self-reported use. This trial is registered with ClinicalTrials.gov, NCT02032433.\n\n\n\nBetween Jan 30, 2014, and May 25, 2016, we randomly assigned 570 participants to receive XR-NTX (n=283) or BUP-NX (n=287). The last follow-up visit was Jan 31, 2017. As expected, XR-NTX had a substantial induction hurdle: fewer participants successfully initiated XR-NTX (204 [72%] of 283) than BUP-NX (270 [94%] of 287; p<0·0001). Among all participants who were randomly assigned (intention-to-treat population, n=570) 24 week relapse events were greater for XR-NTX (185 [65%] of 283) than for BUP-NX (163 [57%] of 287; hazard ratio [HR] 1·36, 95% CI 1·10-1·68), most or all of this difference accounted for by early relapse in nearly all (70 [89%] of 79) XR-NTX induction failures. Among participants successfully inducted (per-protocol population, n=474), 24 week relapse events were similar across study groups (p=0·44). Opioid-negative urine samples (p<0·0001) and opioid-abstinent days (p<0·0001) favoured BUP-NX compared with XR-NTX among the intention-to-treat population, but were similar across study groups among the per-protocol population. Self-reported opioid craving was initially less with XR-NTX than with BUP-NX (p=0·0012), then converged by week 24 (p=0·20). With the exception of mild-to-moderate XR-NTX injection site reactions, treatment-emergent adverse events including overdose did not differ between treatment groups. Five fatal overdoses occurred (two in the XR-NTX group and three in the BUP-NX group).\n\n\n\nIn this population it is more difficult to initiate patients to XR-NTX than BUP-NX, and this negatively affected overall relapse. However, once initiated, both medications were equally safe and effective. Future work should focus on facilitating induction to XR-NTX and on improving treatment retention for both medications.\n\n\n\nNIDA Clinical Trials Network.",
"affiliations": "Department of Population Health, New York University School of Medicine, New York, NY, USA. Electronic address: joshua.lee@nyumc.org.;Department of Psychiatry, New York State Psychiatric Institute, Columbia University Medical Center, New York, NY, USA.;Department of Psychiatry, New York University School of Medicine, New York, NY, USA.;Tarzana Treatment Centers, Tarzana, CA, USA.;Department of Psychiatry and Human Behavior, Warren Alpert Medical School, Brown University, Providence RI, USA; Stanley Street Treatment and Resources, Fall River, MA, USA.;Department of Psychiatry and Behavioral Sciences, University of New Mexico School of Medicine, Albuquerque, NM, USA.;Department of Psychiatry, New York University School of Medicine, New York, NY, USA.;Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, USA; Maryland Treatment Centers, Baltimore, MD, USA.;Department of Psychiatry, New York University School of Medicine, New York, NY, USA.;Gateway Community Services Inc, Jacksonville, FL, USA.;The Emmes Corporation, Rockville, MD, USA.;The Emmes Corporation, Rockville, MD, USA.;National Institute on Drug Abuse, Rockville, MD, USA.;The Emmes Corporation, Rockville, MD, USA.;The Emmes Corporation, Rockville, MD, USA.;Evergreen Treatment Services, Seattle, WA, USA.;Department of Psychiatry, New York University School of Medicine, New York, NY, USA.;The Emmes Corporation, Rockville, MD, USA.;Maryhaven Inc, Columbus, OH, USA.;The Emmes Corporation, Rockville, MD, USA.;The Emmes Corporation, Rockville, MD, USA.;National Institute on Drug Abuse, Rockville, MD, USA.;Department of Psychiatry, New York University School of Medicine, New York, NY, USA.",
"authors": "Lee|Joshua D|JD|;Nunes|Edward V|EV|;Novo|Patricia|P|;Bachrach|Ken|K|;Bailey|Genie L|GL|;Bhatt|Snehal|S|;Farkas|Sarah|S|;Fishman|Marc|M|;Gauthier|Phoebe|P|;Hodgkins|Candace C|CC|;King|Jacquie|J|;Lindblad|Robert|R|;Liu|David|D|;Matthews|Abigail G|AG|;May|Jeanine|J|;Peavy|K Michelle|KM|;Ross|Stephen|S|;Salazar|Dagmar|D|;Schkolnik|Paul|P|;Shmueli-Blumberg|Dikla|D|;Stablein|Don|D|;Subramaniam|Geetha|G|;Rotrosen|John|J|",
"chemical_list": "D000069479:Buprenorphine, Naloxone Drug Combination; D003692:Delayed-Action Preparations; D009292:Narcotic Antagonists; D009271:Naltrexone",
"country": "England",
"delete": false,
"doi": "10.1016/S0140-6736(17)32812-X",
"fulltext": null,
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"issn_linking": "0140-6736",
"issue": "391(10118)",
"journal": "Lancet (London, England)",
"keywords": null,
"medline_ta": "Lancet",
"mesh_terms": "D000284:Administration, Oral; D000328:Adult; D000069479:Buprenorphine, Naloxone Drug Combination; D003692:Delayed-Action Preparations; D005260:Female; D006801:Humans; D007273:Injections, Intramuscular; D008297:Male; D009271:Naltrexone; D009292:Narcotic Antagonists; D009293:Opioid-Related Disorders; D012107:Research Design",
"nlm_unique_id": "2985213R",
"other_id": null,
"pages": "309-318",
"pmc": null,
"pmid": "29150198",
"pubdate": "2018-01-27",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D016449:Randomized Controlled Trial; D052061:Research Support, N.I.H., Extramural",
"references": "28446428;19588333;28733097;21529928;29049469;24602363;24500948;26066931;20424458;16461865;22065255;25703440;17564876;27898496;28068780;26599131;28609749;28473233;26639678;27121539;27521809;27687743;27028913;25818060",
"title": "Comparative effectiveness of extended-release naltrexone versus buprenorphine-naloxone for opioid relapse prevention (X:BOT): a multicentre, open-label, randomised controlled trial.",
"title_normalized": "comparative effectiveness of extended release naltrexone versus buprenorphine naloxone for opioid relapse prevention x bot a multicentre open label randomised controlled trial"
} | [
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"literaturereference": "LEE, JOSHUA D ET AL.. COMPARATIVE EFFECTIVENESS OF EXTENDED-RELEASE NALTREXONE VERSUS BUPRENORPHINE-NALOXONE FOR OPIOID RELAPSE PREVENTION (X:BOT): A MULTICENTRE, OPEN-LABEL, RANDOMISED CONTROLLED TRIAL. THE LANCET. 2017?391:309-318",
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