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"abstract": "BACKGROUND\nHaemopoietic stem-cell transplantation (HCT) conditioning regimens that can reduce risk of relapse without increasing non-relapse mortality are needed. We aimed to test the safety of timed-sequential delivery of low-dose versus high-dose myeloablative busulfan in older patients and patients with comorbidities.\n\n\nMETHODS\nThis non-stratified, open-label, randomised phase 2 trial was done at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients with haematological cancers aged between 5 and 75 years were eligible to participate in the study. Patients who had HIV or uncontrollable infections were excluded. Eligible patients were randomly assigned (1:1 by a computer-generated programme in block sizes of four) to receive a total intravenous busulfan dose to achieve an area under the curve of 16 000 μmol/min (16K group) or 20 000 μmol/min (20K group) on the basis of pharmacokinetic analysis, plus intravenous fludarabine 40 mg/m2 for 4 days. The investigators and the research nurses were masked to the block size to conceal allocation. The primary outcome was day 100 non-relapse mortality. All analyses were by modified intention to treat, including only patients who received at least one dose of the study drug. No interim analyses were planned and accrual is complete. This study is registered with ClinicalTrials.gov, number NCT01572662.\n\n\nRESULTS\nBetween April 18, 2012, and Dec 9, 2015, 98 patients were enrolled. 49 patients were randomly assigned to the 16K group and 49 to the 20K group, one of which was removed from the study before starting the intervention. Median age was 60 years (IQR 54-67). 50 (52%) patients had an HCT-specific comorbidity index score of 3 or more, and 41 (42%) had a high or very high Disease Risk Index score. Day 100 non-relapse mortality was 4% (95% CI 0-10) in the 16K group and 6% (0-13) in the 20K group (p=0·65). Infection was the most common grade 3-5 toxicity in both the 20K group (25 [52%] of 48 patients) and the 16K group (24 [49%] of 49 participants). Mucositis (nine [19%] of 48 patients vs three [6%] of 49 patients), idiopathic pneumonia syndrome (nine [19%] of 48 patients vs two [4%] of 49 patients), and culture-negative neutropenic fever (16 [33%] of 48 patients vs eight [16%] of 49 patients) were more common in the 20K group than in the 16K group.\n\n\nCONCLUSIONS\nMyeloablative doses of busulfan administered in a timed-sequential manner with fludarabine is associated with low non-relapse mortality in older patients and patients with comorbidities. Additional studies are required to show whether this approach can reduce the risk of relapse.\n\n\nBACKGROUND\nCancer Center Support Grant (US National Cancer Institute, National Institutes of Health).",
"affiliations": "Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: upopat@mdanderson.org.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.;Department of Stem Cell Transplantation and Cellular Therapy, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.",
"authors": "Popat|Uday R|UR|;Mehta|Rohtesh S|RS|;Bassett|Roland|R|;Chen|Julianne|J|;Valdez|Benigno C|BC|;Kawedia|Jitesh|J|;Ahmed|Sairah|S|;Alousi|Amin M|AM|;Anderlini|Paolo|P|;Al-Atrash|Geath|G|;Bashir|Qaiser|Q|;Ciurea|Stefan O|SO|;Hosing|Chitra M|CM|;Im|Jin S|JS|;Jones|Roy|R|;Kebriaei|Partow|P|;Khouri|Issa|I|;Marin|David|D|;Nieto|Yago|Y|;Olson|Amanda|A|;Oran|Betul|B|;Parmar|Simrit|S|;Rezvani|Katayoun|K|;Qazilbash|Muzaffar H|MH|;Shah|Nina|N|;Srour|Samer A|SA|;Shpall|Elizabeth J|EJ|;Champlin|Richard E|RE|;Andersson|Borje S|BS|",
"chemical_list": "D014740:Vidarabine; D002066:Busulfan; C024352:fludarabine",
"country": "England",
"delete": false,
"doi": "10.1016/S2352-3026(18)30156-X",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2352-3026",
"issue": "5(11)",
"journal": "The Lancet. Haematology",
"keywords": null,
"medline_ta": "Lancet Haematol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000368:Aged; D002066:Busulfan; D002648:Child; D015897:Comorbidity; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D019337:Hematologic Neoplasms; D006801:Humans; D008297:Male; D008875:Middle Aged; D013997:Time Factors; D016896:Treatment Outcome; D014740:Vidarabine; D055815:Young Adult",
"nlm_unique_id": "101643584",
"other_id": null,
"pages": "e532-e542",
"pmc": null,
"pmid": "30389035",
"pubdate": "2018-11",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "10204198;1066183;11215840;12538483;12855568;14716342;15142880;15459007;15931632;16193083;16551971;17067911;18489993;18776081;19652066;19962759;20404137;20716774;21441963;22323482;22959335;24744269;25243624;26022709;26527780;27991894;28336325;28380315;3321587;3470054;8558211;8652810",
"title": "Fludarabine with a higher versus lower dose of myeloablative timed-sequential busulfan in older patients and patients with comorbidities: an open-label, non-stratified, randomised phase 2 trial.",
"title_normalized": "fludarabine with a higher versus lower dose of myeloablative timed sequential busulfan in older patients and patients with comorbidities an open label non stratified randomised phase 2 trial"
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"companynumb": "US-OTSUKA-2018_035866",
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"abstract": "A 61-year-old man with essential thrombocythemia (ET) presented with acute myocardial infarction (AMI) and underwent primary percutaneous coronary intervention. After stent deployment from the left main (LM) to the left anterior descending artery, intravascular ultrasound revealed thrombi formation in the whole stent. Two days later, optical frequency domain imaging confirmed stent malapposition and thrombi remaining in only the LM. The stent malapposition and ET might have contributed to this phenomenon. He underwent an additional stent expansion and aggressive anti-thrombotic regimen. AMI complicated with ET carries increased risks of in-stent thrombi formation and requires careful revascularization and aggressive pharmacotherapy.",
"affiliations": "Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiology, Japanese Red Cross Kyoto Daiichi Hospital, Japan.;Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiology, Japanese Red Cross Kyoto Daiichi Hospital, Japan.;Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan.;Department of Cardiology, Japanese Red Cross Kyoto Daiichi Hospital, Japan.",
"authors": "Shoji|Keisuke|K|;Yanishi|Kenji|K|;Shiraishi|Jun|J|;Nakanishi|Naohiko|N|;Zen|Kan|K|;Nakamura|Takeshi|T|;Hyogo|Masayuki|M|;Shirayama|Takeshi|T|;Matoba|Satoaki|S|;Sawada|Takahisa|T|",
"chemical_list": "D000925:Anticoagulants",
"country": "Japan",
"delete": false,
"doi": "10.2169/internalmedicine.2083-18",
"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 3062683610.2169/internalmedicine.2083-18Case ReportIn-stent Massive Thrombi Formation During Primary Percutaneous Coronary Intervention in a Patient with Acute Myocardial Infarction Complicated with Essential Thrombocythemia Shoji Keisuke 1Yanishi Kenji 1Shiraishi Jun 2Nakanishi Naohiko 1Zen Kan 1Nakamura Takeshi 1Hyogo Masayuki 2Shirayama Takeshi 1Matoba Satoaki 1Sawada Takahisa 2\n1 Department of Cardiovascular Medicine, Kyoto Prefectural University of Medicine, Japan\n2 Department of Cardiology, Japanese Red Cross Kyoto Daiichi Hospital, JapanCorrespondence to Dr. Kenji Yanishi, yanishi@koto.kpu-m.ac.jp\n\n10 1 2019 1 5 2019 58 9 1287 1293 4 9 2018 16 10 2018 Copyright © 2019 by The Japanese Society of Internal MedicineThe Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).A 61-year-old man with essential thrombocythemia (ET) presented with acute myocardial infarction (AMI) and underwent primary percutaneous coronary intervention. After stent deployment from the left main (LM) to the left anterior descending artery, intravascular ultrasound revealed thrombi formation in the whole stent. Two days later, optical frequency domain imaging confirmed stent malapposition and thrombi remaining in only the LM. The stent malapposition and ET might have contributed to this phenomenon. He underwent an additional stent expansion and aggressive anti-thrombotic regimen. AMI complicated with ET carries increased risks of in-stent thrombi formation and requires careful revascularization and aggressive pharmacotherapy. \n\nessential thrombocythemiaacute myocardial infarctionin-stent thrombi formation\n==== Body\nIntroduction\nEssential thrombocythemia (ET) is a chronic myeloproliferative neoplasm of unknown cause characterized by an increased number of platelets. The disease provokes thrombosis and hemorrhaging as typical complications. The complication of thrombosis in particular affects the prognosis of patients with ET. Treatment strategies for ET are stratified by age, the number of platelets and the history of thrombosis and hemorrhaging. In general, anagrelide and hydroxycarbamide are effective in cases at a high risk of thrombosis.\n\nSome cases of acute coronary syndrome (ACS) related to ET have been reported. However, treatment strategies for ACS with ET have not been sufficiently established. We herein report our experience of a case of acute myocardial infarction (AMI) complicated with in-stent massive thrombi formation, probably due to stent malapposition and ET. In addition, based on the present experience, we discuss strategies of primary percutaneous coronary intervention (PCI) and drug therapies after primary PCI.\n\nCase Report\nA 61-year-old man presented with acute onset of chest pain at rest. He called an ambulance and suffered cardiopulmonary arrest in the ambulance. He was transferred to our emergency department after successful defibrillation. He had a medical history of ET and had been treated with anagrelide 2 mg and clopidogrel 75 mg per day. His coronary risk factors were hypertension and dyslipidemia.\n\nOn an initial examination, his blood pressure was 162/98 mmHg, and his pulse rate was 105 bpm. A physical examination showed a regular heart rhythm with no murmurs, rough respiratory sounds in both lungs, and no edema in the lower extremities. Laboratory tests were almost normal except for leukocytosis and thrombocytosis (white blood cells: 14,470/μL, platelets: 86.3×104/μL). Electrocardiography showed ST-segment elevation in the V1 to V4 leads. Transthoracic echocardiography revealed severe hypokinesis in the anteroseptal wall. Emergency coronary angiography (CAG) showed total occlusion in only the proximal left anterior descending artery (LAD) and no significant stenosis in other coronary arteries (Fig. 1A-E).\n\nFigure 1. Findings of initial and post-reperfusion CAG. Initial and post-reperfusion CAG findings are shown. The right coronary artery (A, B) and left circumflex coronary artery had no severe stenosis. There was total occlusion from the LAD ostium (C, D, E). Initial CAG after recanalization showed thrombolysis in myocardial infarction (TIMI) grade II flow in the LAD (F).\n\nAfter administration of oral aspirin 200 mg and intravenous heparin (total dose: 8,000 U), he underwent primary PCI. An intra-aortic balloon pump (IABP) was inserted via the right femoral artery, and a 7-Fr guiding catheter was advanced through the left radial artery to the left coronary artery ostium. A guidewire was successfully crossed into the diagonal branch distal to the occlusion, and initial recanalization was achieved by an aspiration thrombectomy catheter. Angiography showed thrombolysis in myocardial infarction (TIMI) grade II flow in the LAD (Fig. 1F). After advancing another guidewire to the LAD, intravascular ultrasound (IVUS) revealed diffuse plaque and considerable thrombi formation from the left main (LM) to the LAD. After pre-dilatation with a 2.5×13-mm balloon, a 4.0×24-mm drug-eluting stent (DES) was deployed from the LM to the LAD. Post-dilatation with a 3.5×12-mm balloon to the LAD and a 4.5×6.0-mm balloon to the LM was performed. Finally, another guidewire was re-crossed via the strut of the main branch stent to the left circumflex (LCX), and the stent strut was dilated from the LM to the LCX by a 3.0×4.0-mm balloon.\n\nHowever, CAG revealed multiple dye defects in the stented lesion (Fig. 2A-C). Repeated IVUS revealed significant thrombi formation in the whole stent (Fig. 2D and E), although the activated clotting time (ACT) was sufficiently prolonged to 240 seconds. Argatroban and prasugrel 20 mg were immediately administered due to apprehension of heparin-induced thrombocytopenia (HIT) or clopidogrel resistance, and aspiration thrombectomy was repeatedly performed. Given the final IVUS findings of reduced thrombi in the stent and no obvious stent malapposition, we finished the primary PCI procedure (Fig. 2H and I).\n\nFigure 2. Findings of CAG and IVUS immediately after deploying a DES at primary PCI. CAG immediately after deploying a DES revealed a lot of defects in the stent (A, B, C). IVUS showed multiple thrombi in the whole stent and near the stent distal edge (D, E, F white arrow). Figure G is an enlarged version of Fig. B. The arrowheads of D, E, and F in Fig. G indicate the points of the IVUS images of Fig. D, E, and F. Final CAG revealed a reduction of thrombi in the stented lesion and thrombolysis in myocardial infarction (TIMI) grade III flow in the LAD (H, I).\n\nAfter being transferred to the intensive-care unit, the patient continued to receive dual anti-platelet therapy (DAPT) with aspirin 100 mg and prasugrel 3.75 mg. In addition, ACT and activated partial thromboplastin time (APTT) were controlled with argatroban infusion (180 seconds < ACT <220 seconds or 1.5-3.0 times the reference value APTT) while IABP support was also provided. The peak creatine phosphokinase (CPK) level was 4,525 IU/L.\n\nTwo days after primary PCI (Day 3), CAG showed no apparent thrombi in the stent and moderate stenosis near the stent distal edge. Optical frequency domain imaging (OFDI) showed intimal dissection with thrombus near the stent distal edge and no thrombi in the LAD but revealed that in-stent thrombi and incomplete stent apposition still remained in the LM (Fig. 3A-C). Aspiration thrombectomy, intracoronary thrombolysis with urokinase (60,000 U) and additional stent expansion with a 5.0×6.0-mm balloon were performed. However, newer thrombi formation appeared in the guiding catheter during the procedure (Fig. 3E). Therefore, we decided to discontinue further PCI procedures for the moderate stenosis near the stent distal edge because of procedure-related risks of thrombi formation.\n\nFigure 3. Findings of CAG and OFDI 2 days later after primary PCI. We performed CAG and OFDI two days after primary PCI. In OFDI, we noted remnant thrombi (A, white arrow) and incomplete stent apposition in the LM (A, yellow arrow) and no thrombi and complete apposition in the LAD (B). Intimal dissection and thrombi were observed near the stent distal edge (C). The arrowheads of A, B, and C in Fig. D showed points of OFDI views of Fig. A, B, and C. The thrombus was retrieved using an aspiration catheter from the coronary artery (E, arrowhead) and guiding catheter (E, small arrow).\n\nA further examination for excessive thrombophilia indicated no coagulopathy, including HIT. The dosage of anagrelide was increased from 2 to 3 mg, and apixaban 10 mg was added as an anti-coagulant drug. Platelet function testing showed that the effects of aspirin and prasugrel were in the therapeutic range. He had no additional thromboembolism or cardiovascular events during hospitalization and was discharged with a platelet count of 40.6×104/μL. The administration of apixaban was ended after three months because follow-up CAG revealed no restenosis, and the platelet count was able to be controlled within the normal range. CAG after nine months showed no in-stent restenosis and regression of the moderate stenosis in the mid-LAD (Fig. 4A-C). OFDI showed that the stent was completely covered with neointima over the full length, and the intimal dissection in the mid LAD was completely healed (Fig. 4D-F).\n\nFigure 4. Findings of follow-up CAG and OFDI nine months later. Follow-up CAG nine months later revealed no in-stent restenosis. In addition, the moderate stenosis in the mid LAD had improved (A, B, C). OFDI showed that the stent was completely covered with neointima over the full length with no thrombi from the LM to the LAD. (D, E, F). The arrowheads of D, E, and F in Fig. G showed points of OFDI views of Fig. D, E, and F.\n\nDiscussion\nWe experienced a case of AMI with ET that presented with massive in-stent thrombi formation in the culprit lesion. Our findings suggested that the primary causes of thrombi formation were the thrombophilia predisposition based on ET and the stent malapposition of the LM. We will now discuss potential drug treatments after PCI and strategies of primary PCI for cases of AMI with ET.\n\nET is a clonal disorder of multipotential stem cells and characterized by an absolute increase in the platelet count and an increase in vascular complications. Thrombosis is a major complication of ET and worsens the life expectancy of the patient (1). ACS is also a thrombotic complication of ET, and the incidence of MI in patients with ET was reported to be 9.4% (2). Even young patients with ET developed ACS in some cases (3,4), and ET might also be a risk factor of ACS. Treatment strategies for ACS with ET have not been fully established yet. Primary PCI (4-8), percutaneous transluminal coronary recanalization (9) and coronary artery bypass grafting (10) were previously reported as methods of revascularization. When AMI patients with ET present with massive thrombi in the culprit coronary lesions, aspiration thrombectomy or intracoronary thrombolysis without stent deployment might be optimal strategies for revascularization. In cases with underlying atherosclerotic plaque in the culprit lesions, additional balloon angioplasty or stent deployment should also be considered.\n\nAn underlying abnormal status of coagulation and fibrinolysis, such as HIT or anti-phospholipid antibody syndrome, might accelerate thrombi formation in the stented site. Some ACS patients with ET developed sub-acute thrombosis (SAT) after stent deployment. Possible reasons for SAT development were withdrawal of anti-platelet drugs because of bleeding complications in the puncture site (11) or the absence of cytoreductive drugs because of occult ET (12).\n\nAdequate anti-platelet therapy for preventing thrombotic events and cytoreduction therapy for controlling platelet count play key roles in treating ET. Low-dose aspirin was recommended for preventing thrombotic events in ET cases (13,14). Although DAPT was also established after stent-based PCI for ACS or stable coronary artery disease, appropriate anti-platelet therapy after stent deployment for ACS patients with ET has not been established. Some reports describe the combination of aspirin and thienopyridines as the usual DAPT administered after PCI for ACS with ET, with these patients showing no major cardiac complications.\n\nIn the present patient, we considered the additional administration of other platelet P2Y12 inhibitors at loading doses, as clopidogrel resistance was suspected immediately after we confirmed significant thrombi formation in the whole stent by IVUS. It was reported that prasugrel and ticagrelor reduced the rate of MI or stent thrombosis (ST) compared with clopidogrel (15,16). The PRAGUE-18 trial reported that the primary endpoint (i.e., death, reinfarction, urgent vessel revascularization or serious bleeding) did not show any significant differences between ticagrelor and prasugrel (17). However, prasugrel and ticagrelor tended to increase the rate of major bleeding compared with clopidogrel. Based on these reports, if clopidogrel resistance is suspected, we suggest that prasugrel or ticagrelor at a loading dose be actively administered. Because it was reported that ticagrelor exhibited an antiplatelet effect earlier than prasugrel, ticagrelor at a loading dose might be suitable in cases of ST, such as in the present patient.\n\nIn our patient, an anticoagulant drug was administered in addition to DAPT after the second PCI in order to prevent stent thrombosis. We considered this anticoagulant drug to be effective because it exerted its antiplatelet action by suppressing thrombin generation. In ET cases complicated with recurrent thrombotic events (brachial artery occlusion) after PCI, warfarin in addition to DAPT and cytoreduction therapy was administered in order to prevent repeat thrombosis (18). The European Society of Cardiology stated that triple therapy with aspirin, clopidogrel and an anticoagulant drug should be considered in patients with a high ischemic risk due to ACS or other anatomical/procedure characteristics that outweigh the bleeding risk (19). Warfarin, in combination with aspirin or given alone, was superior to aspirin alone in reducing death or nonfatal reinfarction after MI (20). Furthermore, rivaroxaban (2.5 mg twice daily) plus aspirin had better cardiovascular outcomes than aspirin alone among patients with stable atherosclerotic vascular disease (21). However, these reports showed that the additional administration of warfarin or rivaroxaban increased the risk of major bleeding than aspirin alone. At present, two types of anticoagulants-vitamin K antagonists (VKAs) and direct oral anticoagulants (DOACs)-are available, and DOACs have been shown to be superior to VKAs in preventing bleeding complications (19). In cases with ST, we suggest that an anticoagulant in addition to DAPT is effective in terms of preventing reinfarction after MI, but patients must be closely monitored for complications of major bleeding. The present patient suffered neither ischemic events nor major bleeding complications during the triple therapy regimen.\n\nGenerally, thrombolytic therapy with or without PCI is not recommended for cases of ACS other than ST-elevated myocardial infarction, even if thrombus is involved (22,23). In the case of platelet-based thrombus, thrombolytic therapy promotes the activity of platelets. For cases that show massive thrombosis in coronary arteries, the use of platelet membrane glycoprotein (GP) IIb/IIIa inhibitors is recommended in other countries. However, because the effectiveness was not proven in the trial of GP IIb/IIIa inhibitors, no GP IIb/IIIa inhibitors are currently available in Japan (24). Systemic thrombolytic therapy has been reported to be effective for early coronary stent thrombosis (25). We therefore decided to administer a small amount of urokinase on the premise of performing PCI. However, it was difficult to determine whether or not thrombolytic therapy produced good outcomes in the present case. Because no GP IIb/IIIa inhibitors are currently available in Japan, it may be necessary to consider systemic thrombolytic therapy, such as urokinase or tissue plasminogen activator (t-PA), depending on the patient. Therefore, further evidence concerning thrombolytic therapy in patients with ST is desired.\n\nIt is also important to control the platelet count in patients who present with thromboembolism related to ET. Reducing the number of platelets is a particularly important treatment target in high-risk ET cases in order to prevent thrombus or hemorrhagic events, which may lead to serious outcomes. At present, anagrelide is approved for the treatment of ET or chronic myelogenous leukemia (26). It was reported that the main mechanism of action of thrombocytopenia is the suppression of platelet production by selectively acting on megakaryocytes, a precursor of platelets. The target platelet count using cytoreduction therapy is uncertain for thromboembolism related to ET after PCI. According to the British Society for Haematology guideline, the treatment target of platelet count should be <40×104/μL in high-risk patients (>60 years of age, ET-related thrombotic or hemorrhagic event, or a platelet count of >150×104/μL) (27). In our case, the platelet count was successfully controlled by increasing the anagrelide dosage.\n\nIncomplete stent apposition to the culprit vessel wall may be a major cause of thrombus formation. In our case, stent malapposition that was not detected by the initial IVUS survey might have contributed to the massive thrombi formation. However, OFDI revealed that the stent had been successfully implanted in the LAD with complete strut apposition, and stent apposition was incomplete only in the LM. We believed that the stent deployed in primary PCI was not crimped to the vessel wall of the LM due to the large amount of thrombi. Furthermore, we were able to detect stent malapposition by OFDI two days after primary PCI because the thrombus attached to the LM disappeared following the administration of DAPT and an anticoagulant drug. Given these findings, we suggested that LM stent malapposition was a major factor influencing thrombi formation throughout the stented lesion in the first PCI procedure.\n\nPrimary stenting is an established revascularization strategy of PCI for ACS. However, we must consider the PCI strategy carefully, as stent deployment in the acute phase in ET cases carries a risk of SAT. If it seems that TIMI III can be obtained by aspiration thrombectomy or balloon expansion, it may be preferable to perform drug therapies or IABP without stent deployment. However, stent deployment is often necessary in clinical practice due to dissection by balloon expansion and massive thrombi. We therefore suggest that the minimum lumen area inside the stent must first be obtained by balloon expansion. In addition, it may be necessary to confirm complete stent apposition by OFDI or optical coherence tomography (OCT), which can assess the vascular wall more clearly than conventional IVUS.\n\nAccording to previous reports regarding unstable angina, DAPT and cytoreductive drugs were administered before performing PCI, and PCI was then performed without complications such as distal embolization and SAT (18,28). Under stable conditions, sufficient drug therapy should precede PCI, whereas under unstable conditions, stent-less PCI might be preferable as a revascularization strategy among ACS patients with ET. When deploying a stent in cases of ACS with high platelet counts or a large amount of thrombi in the culprit lesion due to ET, we should carefully perform PCI in order to ensure complete stent apposition and consider an aggressive anti-thrombotic therapy, such as triple therapy including an anticoagulant drug.\n\nConclusion\nWe encountered a case of AMI with ET that presented with massive in-stent thrombi formation in the culprit lesion. Appropriate stent apposition and aggressive medication combined with anti-thrombotic regimen and cytoreductive drugs contributed to good clinical outcomes in this patient.\n\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. \nDan K , Yamada T , Kimura Y , et al \nClinical features of polycythemia vera and essential thrombocythemia in Japan: retrospective analysis of a nationwide survey by the Japanese Elderly Leukemia and Lymphoma Study Group . Int J Hematol \n83 : 443 -449 , 2006 .16787877 \n2. \nRossi C , Randi ML , Zerbinati P , Rinaldi V , Girolami A \nAcute coronary disease in essential thrombocythemia and polycythemia vera . J Intern Med \n244 : 49 -53 , 1998 .9698024 \n3. \nPande S , Joshi R , Pande R \nEssential thrombocythemia in a young man treated for myocardial infarction . BMJ Case Reports \n3 : 2010 \n(Epub ahead of print) .\n4. \nBhat T , Ahmed M , Baydoun H , Ghandour Z , Bhat A , McCord D \nAcute ST-segment elevation myocardial infarction in a young patient with essential thrombocythemia: a case with long-term follow-up report . J Blood Med \n5 : 123 -127 , 2014 .25093003 \n5. \nChang H , Shim CY , Cheong JW , et al \nCoronary artery intervention after cytostatics treatment in unstable angina patient with essential thrombocythemia. A case report and literature review . Korean J Intern Med \n21 : 146 -149 , 2006 .16913448 \n6. \nDoesch C , Krämer B , Geisler T , et al \nChallenges in the treatment of patients with essential thrombocythemia and acute coronary syndrome . J Thromb Thrombolysis \n25 : 193 -197 , 2008 .17701105 \n7. \nTortorella G , Calzolari M , Tieghi A , Muià N , Piccin A , Gugliotta L \nAcute coronary syndrome (ACS) in patients with essential thrombocytemia (ET). What is the best treatment? \nInt J Cradiol \n203 : 225 -227 , 2016 .\n8. \nWatanabe T , Fujinaga H , Ikeda Y \nAcute myocardial infarction in a patient with essential thrombocythemia who underwent successful stenting-a case report . Angiology \n56 : 771 -774 , 2005 .16327955 \n9. \nMizuta E , Takeda S , Sasaki N , et al \nAcute myocardial infarction in a patient with essential thrombocythemia: successful treatment with percutaneous transluminal coronary recanalization . Circ J \n69 : 1000 -1002 , 2005 .16041176 \n10. \nDaya SK , Gowda RM , Landis WA , Khan IA \nEssential thrombocythemia-related acute ST-segment elevation myocardial infarction. A case report and literature review . Angiology \n55 : 319 -323 , 2004 .15156266 \n11. \nTurgut T , Harjai KJ , Edupuganti R , et al \nAcute coronary occlusion and in-stent thrombosis in a patient with essential thrombocythemia . Cathet Cardiovasc Diagn \n45 : 428 -433 , 1998 .9863754 \n12. \nIsilak Z , Tezcan M , Atalay M , Kardesoglu E \nAcute myocardial infarction and sub-acute stent thrombosis associated with occult essential thrombocythemia . Chin Med J (Engl) \n127 : 3512 -3513 , 2014 .25269924 \n13. \nTefferi A , Barbui T \nEssential thrombocythemia and polycythemia vera: focus on clinical practice . Mayo Clin Proc \n90 : 1283 -1293 , 2015 .26355403 \n14. \nRumi E , Cazzola M \nHow I treat essential thrombocythemia . Blood \n128 : 2403 -2414 , 2016 .27561316 \n15. \nWiviott SD , Braunwald E , McCabe CH , et al \nPrasugrel versus clopidogrel in patients with acute coronary syndromes . N Engl J Med \n357 : 2001 -2015 , 2007 .17982182 \n16. \nWallentin L , Becker RC , Budaj A , et al \nTicagrelor versus clopidogrel in patients with acute coronary syndromes . N Engl J Med \n361 : 1045 -1057 , 2009 .19717846 \n17. \nMotovska Z , Hlinomaz O , Miklik R , et al \nPrasugrel versus ticagrelor in patients with acute myocardial infarction treated with primary percutaneous coronary intervention multicenter randomized PRAGUE-18 study . Circulation \n134 : 1603 -1612 , 2016 .27576777 \n18. \nKumagai N , Mitsutake R , Miura S , et al \nAcute coronary syndrome associated with essential thrombocythemia . J Cardiol \n54 : 485 -489 , 2009 .19944327 \n19. \nValgimigli M , Bueno H , Byrne RA , et al \n2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS: The Task Force for dual antiplatelet therapy in coronary artery disease of the European Society of Cardiology (ESC) and of the European Association for Cardio-Thoracic Surgery (EACTS) . Eur Heart J \n39 : 213 -260 , 2018 .28886622 \n20. \nHurlen M , Abdelnoor M , Smith P , Erikssen J , Arnesen H \nWarfarin, aspirin, or both after myocardial infarction . N Engl J Med \n347 : 969 -974 , 2002 .12324552 \n21. \nEikelboom JW , Connolly SJ , Bosch J , et al \nRivaroxaban with or without aspirin in stale cardiovascular disease . N Engl J Med \n377 : 1319 -1330 , 2017 .28844192 \n22. \nBar FW , Verheugt FW , Col J , et al \nThrombolysis in patients with unstable angina improves the angiographic but not the clinical outcome. Results of UNASEM, a multicenter, randomized, placebo-controlled, clinical trial with anistreplase . Circulation \n86 : 131 -137 , 1992 .1617766 \n23. \nThe Thrombolysis in Myocardial Ischemia (TIMI) III B investigators \nEffects of tissue plasminogen activator and a comparison of early invasive and conservative strategies in unstable angina and non-Q wave myocardial infarction. Results of TIMI IIIB trial . Circulation \n89 : 1545 -1556 , 1994 .8149520 \n24. \nNakagawa Y , Nobuyoshi M , Yamaguchi T , et al \nEfficacy of abciximab for patients undergoing balloon angioplasty data from Japanese Evaluation of c7E3 Fab for Elective and Primary PCI Organization in Randomized Trial (JEPPORT) . Circ J \n73 : 145 -151 , 2009 .19023152 \n25. \nKoduganti SC , Shankar SJ \nSystemic thrombolytic therapy for earlt coronary stent thrombosis . Indian Heart J \n58 : 245 -248 , 2006 .19033624 \n26. \nSilverstein MN , Petitt RM , Solberg LA Jr, Fleming JS , Knight RC , Schacter LP \nAnagrelide: a new drug for treating thrombocytosis . N Eng J Med \n318 : 1292 , 1988 .\n27. \nHarrison CN , Bareford D , Butt N , et al \nGuideline for investigation and management of adults and children presenting with a thrombocytosis . Br J Haematol \n149 : 352 -375 , 2010 .20331456 \n28. \nFujimura M , Akaike M , Kato M , et al \nAggressive antiplatelet therapy before coronary stent implantation in acute coronary syndrome with essential thrombocythemia-a case report . Angiology \n54 : 485 -490 , 2003 .12934770\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "0918-2918",
"issue": "58(9)",
"journal": "Internal medicine (Tokyo, Japan)",
"keywords": "acute myocardial infarction; essential thrombocythemia; in-stent thrombi formation",
"medline_ta": "Intern Med",
"mesh_terms": "D000925:Anticoagulants; D017023:Coronary Angiography; D054059:Coronary Occlusion; D054855:Drug-Eluting Stents; D006083:Graft Occlusion, Vascular; D006801:Humans; D007431:Intraoperative Complications; D008297:Male; D008875:Middle Aged; D009203:Myocardial Infarction; D062645:Percutaneous Coronary Intervention; D011475:Prosthesis Failure; D013920:Thrombocythemia, Essential; D013927:Thrombosis",
"nlm_unique_id": "9204241",
"other_id": null,
"pages": "1287-1293",
"pmc": null,
"pmid": "30626836",
"pubdate": "2019-05-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12324552;12934770;15156266;16041176;1617766;16327955;16787877;16913448;17701105;17982182;19023152;19033624;19717846;19944327;20331456;22767658;25093003;25269924;26355403;26512843;27561316;27576777;28844192;28886622;3362187;8149520;9698024;9863754",
"title": "In-stent Massive Thrombi Formation During Primary Percutaneous Coronary Intervention in a Patient with Acute Myocardial Infarction Complicated with Essential Thrombocythemia.",
"title_normalized": "in stent massive thrombi formation during primary percutaneous coronary intervention in a patient with acute myocardial infarction complicated with essential thrombocythemia"
} | [
{
"companynumb": "JP-SA-2019SA171562",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
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"activesubstance": {
"activesubstancename": "CLOPIDOGREL BISULFATE"
},
"drugadditional": "3",
... |
{
"abstract": "OBJECTIVE\nTenofovir disoproxil fumarate (TDF) is associated with proximal tubular dysfunction (tubulopathy) when used in the treatment of human immunodeficiency virus (HIV) infection. We evaluated whether TDF causes tubulopathy when used as HIV preexposure prophylaxis (PrEP) and whether tubulopathy predicts clinically relevant decline (≥25%) in the estimated glomerular filtration rate (eGFR).\n\n\nMETHODS\nA subgroup analysis of the Partners PrEP Study, a randomized, placebo-controlled trial of daily oral TDF, alone or with emtricitabine (FTC), in HIV-uninfected African men and women (Clinicaltrials.gov NCT00557245). Tubulopathy was assessed in concurrently obtained urine and serum samples at the 24-month or last on-treatment visit, predefined as ≥2 of the following: tubular proteinuria, euglycemic glycosuria, increased urinary phosphate, and uric acid excretion.\n\n\nRESULTS\nOf 1549 persons studied (776 receiving FTC-TDF, 773 receiving placebo), 64% were male, and the median age was 37 years. Over a median 24 months of study-drug exposure, the frequency of tubulopathy was 1.7% for FTC-TDF versus 1.3% for placebo (odds ratio, 1.30; 95% confidence interval, .52-3.33; P = .68); Tubulopathy occurred in 2 of 52 persons (3.8%) with versus 3 of 208 (1.4%) without ≥25% eGFR decline (adjusted odds ratio, 1.39; .10-14.0; P > .99).\n\n\nCONCLUSIONS\nDaily oral FTC-TDF PrEP was not significantly associated with tubulopathy over the course of 24 months, nor did tubulopathy predict clinically relevant eGFR decline.",
"affiliations": "Department of Epidemiology Department of Global Health Division of Disease Control, School of Public Health, Makerere University, Kampala, Uganda.;Department of Epidemiology Department of Global Health Department of Medicine, University of Washington.;Department of Epidemiology Department of Global Health Department of Medicine, University of Washington.;Department of Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.;Department of Medicine, Division of Nephrology.;Department of Global Health Kenya Medical Research Institute.;Department of Medicine, Division of Liver Diseases.;Division of Global Health Protection, Center for Global Health, Centers for Disease Control and Prevention, Atlanta, Georgia.;Department of Obstetrics and Gynecology, University of Nairobi, Kenya.;Department of Medicine, University of Manitoba, Winnipeg, Canada.;Department of Medicine, Division of Infectious Diseases, Columbia University Medical Center.;Department of Medicine, Division of Nephrology, Icahn School of Medicine at Mount Sinai, New York, New York.",
"authors": "Mugwanya|Kenneth|K|;Baeten|Jared|J|;Celum|Connie|C|;Donnell|Deborah|D|;Nickolas|Thomas|T|;Mugo|Nelly|N|;Branch|Andrea|A|;Tappero|Jordan|J|;Kiarie|James|J|;Ronald|Allan|A|;Yin|Michael|M|;Wyatt|Christina|C|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D010919:Placebos; D000068698:Tenofovir",
"country": "United States",
"delete": false,
"doi": "10.1093/infdis/jiw125",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0022-1899",
"issue": "214(7)",
"journal": "The Journal of infectious diseases",
"keywords": "PrEP; TDF nephrotoxicity; TDF toxicity; proximal tubular dysfunction",
"medline_ta": "J Infect Dis",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D019380:Anti-HIV Agents; D018890:Chemoprevention; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D010919:Placebos; D065129:Pre-Exposure Prophylaxis; D051437:Renal Insufficiency; D000068698:Tenofovir; D016482:Urinalysis; D055815:Young Adult",
"nlm_unique_id": "0413675",
"other_id": null,
"pages": "1050-7",
"pmc": null,
"pmid": "27029778",
"pubdate": "2016-10-01",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": "20299966;19838127;17589197;24829212;22784038;22784037;22784040;19414839;23769234;19262355;24784763;21544066;16470120;25651245;21091279;15312219;4124087;25531343;23143096;24058300;22313955;50513;22113526;20520594;24499951;10672378",
"title": "Low Risk of Proximal Tubular Dysfunction Associated With Emtricitabine-Tenofovir Disoproxil Fumarate Preexposure Prophylaxis in Men and Women.",
"title_normalized": "low risk of proximal tubular dysfunction associated with emtricitabine tenofovir disoproxil fumarate preexposure prophylaxis in men and women"
} | [
{
"companynumb": "US-CIPLA LTD.-2016KE19285",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "EMTRICITABINE"
},
"drugadditional": "1",
... |
{
"abstract": "Inflammatory bowel disease (IBD) affects young people of reproductive age. Therefore, a broad discussion is needed about the possible disease effects in pregnancy, as well as the risks of fetal exposure to the medications used, especially biological therapy. This study aimed to describe the management of 4 Crohn's disease patients who received anti-TNF therapy during pregnancy and present a literature review. We reported 4 cases composed of young women who became pregnant while receiving anti-TNF agents. The patients presented a satisfactory response to the clinical treatment and the pregnancies progressed without complications. We did not observe maternal or embryonic toxicity, or unfavorable outcomes. The available data point to inflammatory activity as the main risk factor for unfavorable gestational evolution to date, and showed anti-TNF therapy to be safe during pregnancy and breastfeeding. However, the benefits and risks must be discussed with the patient and management decisions should be taken on an individual basis.",
"affiliations": "Medical School, Department of Internal Medicine, São Paulo State University (UNESP), Botucatu, Brazil.;Medical School, Department of Internal Medicine, São Paulo State University (UNESP), Botucatu, Brazil.;Medical School, Department of Internal Medicine, São Paulo State University (UNESP), Botucatu, Brazil.;Medical School, Department of Internal Medicine, São Paulo State University (UNESP), Botucatu, Brazil.;Medical School, Department of Surgery, São Paulo State University (UNESP), Botucatu, Brazil.;Medical School, Department of Surgery, São Paulo State University (UNESP), Botucatu, Brazil.;Medical School, Department of Internal Medicine, São Paulo State University (UNESP), Botucatu, Brazil.",
"authors": "Silva|Elen Farinelli de Campos|EFC|;Baima|Júlio Pinheiro|JP|;de Barros|Jaqueline Ribeiro|JR|;Renosto|Fernanda Lofiego|FL|;de Sibia|Carina de Fatima|CF|;Saad-Hossne|Rogério|R|;Sassaki|Ligia Yukie|LY|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000493921",
"fulltext": "\n==== Front\nCase Rep GastroenterolCase Rep GastroenterolCRGCase Reports in Gastroenterology1662-0631S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000493921crg-0012-0608Case SeriesAnti-TNF Exposure during Pregnancy in Crohn's Disease Patients Silva Elen Farinelli de Campos aBaima Júlio Pinheiro ade Barros Jaqueline Ribeiro aRenosto Fernanda Lofiego ade Sibia Carina de Fatima bSaad-Hossne Rogério bSassaki Ligia Yukie a*aMedical School, Department of Internal Medicine, São Paulo State University (UNESP), Botucatu, BrazilbMedical School, Department of Surgery, São Paulo State University (UNESP), Botucatu, Brazil*Ligia Yukie Sassaki, Medical School, Department of Internal Medicine, São Paulo State University (UNESP), Av. Prof. Mário Rubens Guimarães Montenegro, s/n, Botucatu, SP 18618–970 (Brazil), E-Mail ligiasassaki@gmail.comSep-Dec 2018 17 10 2018 17 10 2018 12 3 608 616 30 7 2018 17 9 2018 Copyright © 2018 by S. Karger AG, Basel2018This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Inflammatory bowel disease (IBD) affects young people of reproductive age. Therefore, a broad discussion is needed about the possible disease effects in pregnancy, as well as the risks of fetal exposure to the medications used, especially biological therapy. This study aimed to describe the management of 4 Crohn's disease patients who received anti-TNF therapy during pregnancy and present a literature review. We reported 4 cases composed of young women who became pregnant while receiving anti-TNF agents. The patients presented a satisfactory response to the clinical treatment and the pregnancies progressed without complications. We did not observe maternal or embryonic toxicity, or unfavorable outcomes. The available data point to inflammatory activity as the main risk factor for unfavorable gestational evolution to date, and showed anti-TNF therapy to be safe during pregnancy and breastfeeding. However, the benefits and risks must be discussed with the patient and management decisions should be taken on an individual basis.\n\nKeywords\nPregnancyAnti-TNF therapyBiological therapyCrohn's diseaseInflammatory bowel disease\n==== Body\nIntroduction\nInflammatory bowel disease (IBD) is a term used to describe Crohn's disease and ulcerative colitis, characterized by chronic inflammation of the gastrointestinal tract. IBD mainly affects young people of reproductive age [1], therefore, a broad discussion about the disease effect on pregnancy is needed, as well as a discussion about maternal-fetal safety in exposure to the current medications, especially immunobiological agents.\n\nStudies are controversial about the disease effects on fetal growth and development. In general, the health of the baby depends on the type, intensity, and extent of IBD, both before and during pregnancy, as well as depending on the medications used by the mother during gestation [1]. Despite many discussions about the subject, it is suggested that the IBD treatment should be maintained in pregnant patients aiming at reducing the risk of disease activity [1]. There is evidence that the disease activity is more detrimental to gestation and consequently to the fetus than the medical therapy itself [1].\n\nA recent study regarding the use of biological therapy for IBD in pregnant women, carried out in London, showed that anti-TNF therapy is considered to be of low risk and can be used in preconception and during the first two quarters of gestation [2]. Anti-TNF therapy currently available such as etanercept, infliximab, adalimumab, and golimumab is classified as category B by the FDA, indicating that no teratogenic effect has been observed in animal studies, but adequate and controlled safety data in humans are still limited [1]. As mentioned previously, the present study presents 4 case reports of patients exposed to anti-TNF therapy during pregnancy and a literature review on the subject.\n\nCase Reports\nCase 1\nA 30-year-old woman, Caucasian, single, presented with Crohn's disease of ileocolonic extension and fistulizing behavior (Montreal Classification A2, L3, B3), diagnosed in 2004. The patient was treated with combined therapy, receiving azathioprine and infliximab (5 mg/kg) since December 2006. In September 2008, she was admitted to hospital to undergo a perianal abscess drainage. She presented perianal discharge, pain, and discomfort. In March 2009 the infliximab was optimized to 10 mg/kg, aiming at the treatment of ulcerated lesions in the rectum and sigmoid. The patient maintained moderate activity in the sigmoid and rectum as shown by the colonoscopy performed in May 2012. In June 2012, the patient opted for the suspension of all medications due to a 6-week pregnancy (first gestation). After 40 days of medication discontinuation, the patient returned to the emergency room presenting intense abdominal pain, vomiting, diarrhea (20 stools/day), and tenesmus. Laboratory exams showed hematocrit 28.8%, hemoglobin 9.6 g/dL, and C-reactive protein (CRP) 4.4 mg/dL. Prednisone 40 mg/day and antibiotic therapy were prescribed. The patient presented significant improvement of symptoms and returned to receiving infliximab (5 mg/kg). She maintained the biological therapy until the 28th week of gestation, demonstrating adequate disease clinical control. The baby was born at 34 weeks of gestation, by C-section, without complications. The vaccines were postponed for 6 months.\n\nCase 2\nA 26-year-old woman, a student, married, was diagnosed with Crohn's disease of ileum involvement (Montreal Classification A2, L1, B2) since October 2007. The colonoscopy performed in July 2007 showed terminal ileum presenting edema, erythema, friability, and ulcers covered by fibrin and ileocecal valve stenosis. Although receiving clinical treatment, having prednisone 1 mg/kg/day and azathioprine 2 mg/kg/day, the patient presented recurrent episodes of abdominal pain, abdominal discomfort and distension, malaise, and vomit, as well as weight loss compatible with intestinal subocclusion. She was admitted to hospital and underwent an abdominal computed tomography (CT). The CT showed thickening of intestinal loops and intense blurring of the peritoneal fat in ileal topography. The patient underwent surgery compatible with terminal ileum resection followed by ileo-ascending anastomosis. As postoperative Crohn's disease recurrence prevention, the patient received infliximab 5 mg/kg combined with azathioprine. A new colonoscopy showed no lesions in the neoterminal ileum or in the ileocolonic anastomosis (Rutgeerts score i0) (Fig. 1). After 6 months of combined therapy, the patient discontinued the use of azathioprine. In October 2011, the patient became pregnant. She maintained the infliximab use during the first two gestation trimesters. The baby was born at term, in good clinical condition, by C-section.\n\nCase 3\nA 32-year-old woman, married, a mother of 1 child, was diagnosed with ileocolonic Crohn's disease (Montreal Classification A2, L3, B1) in April 2013. On this occasion, the patient presented an increase in the number of bowel movements, liquid stools with blood and mucus, abdominal pain, and pain in the perianal region. Laboratory exams showed a mild inflammatory process (CRP 1.2 mg/dL, albumin 4.2 g/dL, hematocrit 38.7%, hemoglobin 12.8 g/dL). The colonoscopy showed inflammation in the terminal ileum and the presence of erosions in the colon (Fig. 2). She started clinical treatment with mesalazine 3 g/day, but the medication was changed to azathioprine due to being disease refractory. After 30 days of azathioprine use, the patient presented abdominal pain, nausea, and vomiting, consistent with acute pancreatitis secondary to azathioprine use. The laboratory tests confirmed the diagnosis: amylase 174 U/L (30–110), lipase 1,621 U/L (< 300), leukocytes 15,100 × 103/mm3, and serum lactate dehydrogenase 489 U/L (< 350). An abdominal ultrasound was performed, and no changes were seen in the pancreas. The patient was hospitalized and received hospital discharge 7 days later. After 2 months, adalimumab therapy was prescribed for IBD treatment. The patient presented clinical improvement, but maintained active lesions in the colon, evidenced by the colonoscopy performed in June 2014, which showed a linear ulcer in the distal ileum and erosions in the sigmoid and rectum (Fig. 2). In July 2014, the patient returned reporting a 7-week pregnancy. The maintenance of adalimumab was chosen, and the patient remained oligosymptomatic throughout pregnancy, maintaining mild abdominal pain, stool frequency from 3 to 5 times a day, and presence of mucus and blood compatible with mild clinical activity. Moreover, the patient presented mild elevated serum biomarkers, such as CRP (1.7 mg/dL). Biological therapy was suspended on the 24th week of gestation. The delivery took place in January 2015 by C-section.\n\nCase 4\nA 30-year-old woman, was diagnosed with colonic Crohn's disease (Montreal Classification A2, L2, B1) in June 2013. On this occasion, she presented chronic diarrhea, abdominal pain, fever, weight loss, and painful erythematous skin lesions compatible with erythema nodosum. Laboratory exams showed an inflammatory process (CRP 6.8 mg/dL, albumin 3.5 g/dL, hematocrit 41.3%, hemoglobin 12.6 g/dL). The colonoscopy evidenced deep ulcers throughout the entire colon classified as disease in intense activity (Fig. 3). Prednisone 60 mg/day and azathioprine (2mg/kg) were initiated. The patient presented significant improvement of symptoms and maintained an outpatient follow-up. In January 2014, the patient returned presenting bloody diarrhea 3 times a day, nausea, abdominal and epigastric pain, and malaise, characterizing moderate disease clinical activity, demanding corticosteroids (CRP 3.5 mg/dl, albumin 3.6 g/dL). A colonoscopy performed in May 2014 showed active disease in the colon, rectum, and anal canal (Fig. 3). Due to the persistence of the clinical and endoscopic disease activity, adalimumab therapy was initiated in June 2014, combined with azathioprine. Approximately 30 days after starting the drug, the patient returned pregnant, showing improvement in intestinal symptoms. She suspended azathioprine use according to obstetric orientation. Adalimumab therapy was discontinued on the 24th gestational week. The patient remained in disease clinical remission and the baby was born in March 2015 by C-section.\n\nDiscussion/Conclusion\nThe IBD effect on pregnancy is largely attributed to the disease activity and to the collateral effects of medication [1]. A comprehensive meta-analysis of 12 studies including 3,907 IBD women compared to 320,531 controls showed an increase in preterm birth, low birth weight, congenital abnormalities, and C-section rates [3]. Regarding the cases presented, we observed one preterm birth and no low birth weight or congenital abnormalities. None of the mothers presented a history of miscarriage and all the babies were born by C-section. The high C-section rate was based on the women's preferences for delivery.\n\nDisease activity is indicated as the main risk factor for negative outcomes during pregnancy [1]. Therefore, as the first recommendation, the patient should be in disease remission at conception, favoring a gestation with lower risks of gestational adversities [1]. Only one of the patients was in clinical and endoscopic remission at the time of conception. Despite this, the gestations occurred without complications.\n\nIBD treatment should be maintained in patients who wish to become pregnant. Most medications offer a low risk to the fetus, except for methotrexate and thalidomide [1]. Aminosalicylates are considered low-risk medications, and folate supplementation should be considered for sulfasalazine-treated mothers [1]. The corticosteroids cross the placental barrier, but are readily converted into less active metabolites, resulting in low fetal blood levels. Some studies cite an orofacial malformation risk in fetuses whose mothers were exposed to corticosteroids in the first trimester of pregnancy, but the data are conflicting in the literature [4]. The antibiotics ciprofloxacin and metronidazole should be avoided in the first trimester due to fetal malformation risk [5]. Thiopurines, classified as Class D by the FDA, are shown to be safe when considering the infection risk acquired in the first years of life as well as considering their possible effect on the physical and mental development of the children [6].\n\nRegarding biological therapy, studies have shown that anti-TNF agents are considered safe and do not increase the risk of adverse events during pregnancy [7], although the medication serum level can be detected for up to 6 months in the neonates of exposed mothers [8]. Therefore, live attenuated vaccines, such as rotavirus, oral polio, and BCG, are not indicated in immunosuppressed patients and should be postponed for 6 months or more in children exposed to anti-TNF agents in the gestational period [1, 8]. Only one baby had the vaccines delayed. The other three babies received the vaccines according to the official calendar.\n\nThe Second European Consensus on Reproduction and Pregnancy in IBD states that there is no contraindication to infliximab use in pregnancy [1]. The medication crosses the placental barrier, especially in the third trimester [9]; therefore, it is recommended to interrupt the treatment between the 24th and 26th week of gestation [1]. Adalimumab acts similarly to infliximab [8]. The anti-TNF agent serum level, both in the umbilical cord and in the newborn blood, may be high and can be detected until more than 6 months of life [8]. Despite this, there are few reports of side effects, including congenital malformation [10].\n\nA prospective, multicenter study of 41 IBD carriers exposed to an anti-TNF agent (infliximab or adalimumab) showed no congenital malformation, and rates of miscarriage and low birth weight were the same as in the general population [11]. In this study, there was a higher frequency of preterm delivery (attributed to the underlying disease), but all occurred between 34 and 36 weeks of gestation with no perinatal complications during the first month of follow-up [11].\n\nThe major studies regarding infliximab use in Crohn's disease come from two main sources of registration: the Infliximab Safety Database [12] and Crohn's Therapy Resource Evaluation and Assessment Tool (TREAT) [13]. The Infliximab Safety Database consists of a retrospective database including 96 pregnant women exposed to infliximab for Crohn's disease or rheumatoid arthritis treatment. Of the 96 pregnancies evaluated, there were no fetal losses and only 2 cases of congenital anomaly occurred, a rate equal to the general population. In the prospective TREAT registry, 66 Crohn's disease pregnant women were reported, and 36 received infliximab during the pregnancy. There was no difference in the spontaneous abortion and neonatal complication rates among pregnant women who received or did not receive biological therapy and no fetal malformation was detected [13].\n\nData on vedolizumab safety in pregnancy is limited. There are documented cases of spontaneous abortions, and 1 case of congenital corpus callosum agenesis anomaly was reported in one live birth from a healthy volunteer exposed to a single dose of vedolizumab 79 days before conception [14]. No new safety concerns have been identified for pregnancy outcomes in females directly or indirectly exposed to vedolizumab. Vedolizumab should be used during pregnancy only if the benefits to the mother outweigh the risks to the mother and to the unborn child [14].\n\nRegarding breastfeeding, some studies have detected insignificant drug serum levels in breast milk [15]. Lactation should always be stimulated and medications maintained, respecting individual recommendations for each drug.\n\nWe reported the management and evolution of 4 Crohn's disease patients who underwent biological therapy during pregnancy. In all cases, the gestation occurred without complications and the babies were born without complications. The data available so far point to inflammatory activity as the main risk factor for unfavorable gestational evolution and show that anti-TNF agents are safe during pregnancy and breastfeeding. Nevertheless, the benefits and risks must be discussed with the patient and management decisions should be taken on an individual basis.\n\nStatement of Ethics\nThe study was approved by the Research Ethics Committee of Botucatu Medical School at São Paulo State University (protocol 1.809.851/2016).\n\nDisclosure Statement\nThe authors have no conflicts of interest to declare.\n\nFunding Sources\nThis research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.\n\nAuthor Contributions\nAll authors contributed to this manuscript. Elen Farinelli de Campos Silva, Júlio Pinheiro Baima, Jaqueline Ribeiro de Barros, and Ligia Yukie Sassaki contributed to the conception and design of the study, the acquisition, analysis, and interpretation of data, drafting the article, revising it critically for important intellectual content, and final approval of the version to be submitted. Fernanda Lofiego Renosto, Carina de Fatima de Sibia, and Rogério Saad-Hossne contributed to the acquisition, analysis, and interpretation of data and revising the article critically for important intellectual content.\n\nAcknowledgements\nWe thank Botucatu Medical School at São Paulo State University (UNESP) for its support with this paper.\n\nFig. 1 Case 2. Colonoscopy showed no lesions in the neoterminal ileum or in the ileocolonic anastomosis (Rutgeerts score i0).\n\nFig. 2 Case 3. Colonoscopy performed in June 2013 showing inflammation in the terminal ileum (a) and erosions in the colon (b). Colonoscopy performed in June 2014 showing a linear ulcer in the distal ileum (c) and erosions in the sigmoid and rectum (d).\n\nFig. 3 Case 4. Colonoscopy performed in June 2013 evidenced deep ulcers throughout the entire colon classified as disease in intense activity (a, b). Colonoscopy performed in May 2014 showed active disease in the colon and rectum (c, d).\n==== Refs\nReferences\n1 van der Woude CJ Ardizzone S Bengtson MB Fiorino G Fraser G Katsanos K European Crohn's and Colitis Organization The second European evidenced-based consensus on reproduction and pregnancy in inflammatory bowel disease J Crohn's Colitis 2015 2 9 (2) 107 24 25602023 \n2 Vermeire S Carbonnel F Coulie PG Geenen V Hazes JM Masson PL Management of inflammatory bowel disease in pregnancy J Crohn's Colitis 2012 9 6 (8) 811 23 22595185 \n3 Cornish J Tan E Teare J Teoh TG Rai R Clark SK A meta-analysis on the influence of inflammatory bowel disease on pregnancy Gut 2007 6 56 (6) 830 7 17185356 \n4 McConnell RA Mahadevan U Pregnancy and the patient with Inflammatory Bowel Disease: fertility, treatment, delivery, and complications Gastroenterol Clin North Am 2016 6 45 (2) 285 301 27261899 \n5 Gaidos JK Kane SV Managing IBD Therapies in pregnancy Curr Treat Options Gastroenterol 2017 3 15 (1) 71 83 28181180 \n6 Huang VW Chang HJ Kroeker KI Management of inflammatory bowel disease during pregnancy and breastfeeding varies widely: a need for further education Can J Gastroenterol Hepatol 2016 ID 6193275: 13 pages \n7 Mahadevan U McConnell RA Chambers CD Drug safety and risk of adverse outcomes for pregnant patients with Inflammatory Bowel Disease Gastroenterology 2017 2 152 (2) 451 462.e2 27769809 \n8 Julsgaard M Christensen LA Gibson PR Gearry RB Fallingborg J Hvas CL Concentrations of adalimumab and infliximab in mothers and newborns, and effects on infection Gastroenterology 2016 7 151 (1) 110 9 27063728 \n9 Mahadevan U Wolf DC Dubinsky M Cortot A Lee SD Siegel CA Placental transfer of anti-tumor necrosis factor agents in pregnant patients with inflammatory bowel disease Clin Gastroenterol Hepatol 2013 3 11 (3) 286 92 23200982 \n10 Hoxha A Calligaro A Di Poi E Peccatori S Favaro M Del Ross T Pregnancy and foetal outcomes following anti-tumor necrosis factor alpha therapy: A prospective multicentre study Joint Bone Spine 2017 3 84 (2) 169 73 27344079 \n11 Bortlik M Machkova N Duricova D Malickova K Hrdlicka L Lukas M Pregnancy and newborn outcome of mothers with inflammatory bowel diseases exposed to anti-TNF-α therapy during pregnancy: three-center study Scand J Gastroenterol 2013 8 48 (8) 951 8 23834232 \n12 Katz JA Antoni C Keenan GF Smith DE Jacobs SJ Lichtenstein GR Outcome of pregnancy in women receiving infliximab for the treatment of Crohn's disease and rheumatoid arthritis Am J Gastroenterol 2004 12 99 (12) 2385 92 15571587 \n13 The Crohn7's Therapy, Resource, Evaluation, and Assessment Tool Registry (TREAT) Janssen Biotech, Inc Available from: https://clinicaltrials.gov/ct2/show/NCT00553176 \n14 Mahadevan U Vermeire S Lasch K Abhyankar B Bhayat F Blake A Vedolizumab exposure in pregnancy: outcomes from clinical studies in inflammatory bowel disease Aliment Pharmacol Ther 2017 4 45 (7) 941 50 28169436 \n15 Ben-Horin S Yavzori M Kopylov U Picard O Fudim E Eliakim R Detection of infliximab in breast milk of nursing mothers with inflammatory bowel disease J Crohn's Colitis 2011 12 5 (6) 555 8 22115374\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1662-0631",
"issue": "12(3)",
"journal": "Case reports in gastroenterology",
"keywords": "Anti-TNF therapy; Biological therapy; Crohn's disease; Inflammatory bowel disease; Pregnancy",
"medline_ta": "Case Rep Gastroenterol",
"mesh_terms": null,
"nlm_unique_id": "101474819",
"other_id": null,
"pages": "608-616",
"pmc": null,
"pmid": "30483038",
"pubdate": "2018",
"publication_types": "D002363:Case Reports",
"references": "22595185;25602023;28181180;15571587;27063728;17185356;27344079;22115374;27725926;23200982;28169436;23834232;27769809;27261899",
"title": "Anti-TNF Exposure during Pregnancy in Crohn's Disease Patients.",
"title_normalized": "anti tnf exposure during pregnancy in crohn s disease patients"
} | [
{
"companynumb": "BR-JNJFOC-20190210986",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "INFLIXIMAB"
},
"drugadditional": "1",
"... |
{
"abstract": "Computer-assisted propofol sedation (CAPS) is now approved for moderate sedation of American Society of Anesthesiologists (ASA) class I and II patients undergoing routine endoscopy. As the first US medical center to adopt CAPS for routine clinical use, we compared patient and endoscopist satisfaction with CAPS versus midazolam and fentanyl (MF) sedation.\n\n\n\nPatients who underwent elective outpatient upper endoscopy and colonoscopy with CAPS were compared with concurrent patients sedated with MF. The primary end points were patient satisfaction (measured by the validated Patient Sedation Satisfaction Index [PSSI]), and endoscopist satisfaction (Clinician Sedation Satisfaction Index [CSSI]). Secondary end points included procedural success rates, polyp detection rates, adverse events, and procedure/recovery times. Multivariable regression was used for comparative analysis.\n\n\n\nCAPS was utilized to sedate 244 patients, of whom 55 underwent upper endoscopy, 173 colonoscopy, and 16 double procedures. During the same period, 75 upper endoscopies, 223 colonoscopies, and 30 doubles were performed with MF on similar patients. For upper endoscopy, the procedural success rate was 98.2% for CAPS versus 98.7% for MF (P = .96), whereas for colonoscopy, the success rate was 98.9% vs 98.8% (P = .59). Colonoscopic polyp detection rate was 54.5% for CAPS and 59.3% for MF (P = .67). Procedure times were similar between CAPS and MF. For CAPS, the mean recovery time was 26.4 vs 39.1 minutes for MF (P < .001). One CAPS patient required mask ventilation, 4 experienced asymptomatic hypotension or desaturation, and 5 experienced marked agitation resulting from undersedation. For MF, 5 patients had hypotension or desaturation, and 8 experienced undersedation. For colonoscopy, the CAPS group had higher PSSI scores for sedation adequacy, the recovery process and global satisfaction, and higher CSSI scores for ease of sedation administration, the recovery process and global satisfaction. For upper endoscopy and doubles, the CAPS CSSI score was higher for the recovery process only. All P values were adjusted for confounding by using regression analysis.\n\n\n\nIn low-risk patients, CAPS appears to be effective and efficient. CAPS is associated with higher satisfaction than MF for colonoscopies and, to a lesser extent, upper endoscopies.",
"affiliations": "From the *Digestive Disease Institute and †Department of Anesthesia, Virginia Mason Medical Center, Seattle, Washington.",
"authors": "Lin|Otto S|OS|;Kozarek|Richard A|RA|;Tombs|Deborah|D|;La Selva|Danielle|D|;Weigel|Wade|W|;Beecher|Ryan|R|;Jensen|Ana|A|;Gluck|Michael|M|;Ross|Andrew|A|",
"chemical_list": "D006993:Hypnotics and Sedatives; D015742:Propofol",
"country": "United States",
"delete": false,
"doi": "10.1213/ANE.0000000000001898",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0003-2999",
"issue": "125(3)",
"journal": "Anesthesia and analgesia",
"keywords": null,
"medline_ta": "Anesth Analg",
"mesh_terms": "D000368:Aged; D000072080:Anesthesiologists; D016292:Conscious Sedation; D004360:Drug Therapy, Computer-Assisted; D004724:Endoscopy; D005260:Female; D006801:Humans; D006993:Hypnotics and Sedatives; D007022:Hypotension; D008297:Male; D008875:Middle Aged; D017060:Patient Satisfaction; D015742:Propofol; D011446:Prospective Studies; D012189:Retrospective Studies; D016896:Treatment Outcome; D014481:United States",
"nlm_unique_id": "1310650",
"other_id": null,
"pages": "804-811",
"pmc": null,
"pmid": "28319511",
"pubdate": "2017-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D064888:Observational Study",
"references": null,
"title": "The First US Clinical Experience With Computer-Assisted Propofol Sedation: A Retrospective Observational Comparative Study on Efficacy, Safety, Efficiency, and Endoscopist and Patient Satisfaction.",
"title_normalized": "the first us clinical experience with computer assisted propofol sedation a retrospective observational comparative study on efficacy safety efficiency and endoscopist and patient satisfaction"
} | [
{
"companynumb": "US-PFIZER INC-2017426581",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "FENTANYL"
},
"drugadditional": null,
... |
{
"abstract": "Eccrine poromas are rare, benign adnexal tumors that often occur as solitary papules. Rarely, eccrine poromas can present as multiple lesions, which is referred to as eccrine poromatosis. We report a case of eccrine poromatosis occuring on the palms and soles occuring after chemotherapy in a patient with a history of acute myeloid leukemia.",
"affiliations": "New York Presbyterian/Weill Cornell Medical College.",
"authors": "Garshick|Marisa|M|;DeFilippis|Ersilia M|EM|;Harp|Joanna|J|;Gaan|Jalong|J|",
"chemical_list": "D003561:Cytarabine; D005047:Etoposide; D003630:Daunorubicin",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1087-2108",
"issue": "20(11)",
"journal": "Dermatology online journal",
"keywords": null,
"medline_ta": "Dermatol Online J",
"mesh_terms": "D000971:Antineoplastic Combined Chemotherapy Protocols; D003561:Cytarabine; D003630:Daunorubicin; D005047:Etoposide; D006801:Humans; D015470:Leukemia, Myeloid, Acute; D008297:Male; D008875:Middle Aged; D057091:Poroma; D033581:Stem Cell Transplantation; D013544:Sweat Gland Neoplasms",
"nlm_unique_id": "9610776",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "25419754",
"pubdate": "2014-11-15",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Eccrine poromatosis in a patient with acute myeloid leukemia following chemotherapy.",
"title_normalized": "eccrine poromatosis in a patient with acute myeloid leukemia following chemotherapy"
} | [
{
"companynumb": "US-ACCORD-032894",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "ETOPOSIDE"
},
"drugadditional": null,
"druga... |
{
"abstract": "Background: Clozapine is a second-generation antipsychotic used in treatment-resistant Schizophrenia (TRS). Clozapine Induced Gastrointestinal Hypomotility (CIGH) is the commonest cause of clozapine related death, yet remains under-recognised and under-monitored.Aims and hypothesis: To review the pharmacological management of CIGH. We hypothesised that pharmacological interventions would reduce the incidence of adverse outcomes associated with CIGH.Methods: We retrospectively reviewed consecutive patients treated on clozapine over a one year period on a male acute psychiatric ward. Information on patient demographics, CIGH symptomatology, treatment and outcome were extracted.Results: In total, 14 male patients with a mean age of 43 years (standard deviation 10 years) were included. Of these, 9 patients experienced CIGH during admission, in all cases presenting as constipation. Among patients experiencing CIGH, 8 of 9 (89%) patients received one or more interventions. This was most commonly a stimulant, or osmotic laxative. By discharge, the 8 patients treated were in full remission of CIGH symptoms.Conclusions: A high proportion of patients treated with clozapine experience CIGH, presenting most commonly as constipation. Whilst potentially life-threatening, CIGH can be successfully treated in an acute inpatient setting. Active monitoring of CIGH symptoms in patients initiated, or reinitiated on clozapine is recommended.Key pointsA high proportion of patients treated with Clozapine experience constipation, the cardinal feature of Clozapine Induced Gastrointestinal Hypomotility.Whilst potentially life-threatening, CIGH can be successfully treated in an acute inpatient setting with simple interventions.Active monitoring of CIGH symptoms in patients initiated, or reinitiated on clozapine is recommended.Future research on the potential benefit of prophylactic intervention would be beneficial.",
"affiliations": "Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.;Epsom and St Helier University Hospitals NHS Trust.;Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.;Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.",
"authors": "Blackman|Graham|G|;Kapila|Adisha|A|;Grosskopf|Charlotte Maria|CM|;Dratcu|Luiz|L|",
"chemical_list": "D014150:Antipsychotic Agents; D005765:Gastrointestinal Agents; D003024:Clozapine",
"country": "England",
"delete": false,
"doi": "10.1080/13651501.2019.1710538",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1365-1501",
"issue": "24(1)",
"journal": "International journal of psychiatry in clinical practice",
"keywords": "Clozapine; Schizophrenia; constipation; hypomotility; side effects",
"medline_ta": "Int J Psychiatry Clin Pract",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D003024:Clozapine; D003248:Constipation; D005765:Gastrointestinal Agents; D005767:Gastrointestinal Diseases; D005769:Gastrointestinal Motility; D006801:Humans; D008297:Male; D008875:Middle Aged; D011567:Psychiatric Department, Hospital; D012189:Retrospective Studies; D012559:Schizophrenia",
"nlm_unique_id": "9709509",
"other_id": null,
"pages": "18-19",
"pmc": null,
"pmid": "31910056",
"pubdate": "2020-03",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Focussing on the fundaments - assessing and treating Clozapine Induced Gastrointestinal Hypomotility.",
"title_normalized": "focussing on the fundaments assessing and treating clozapine induced gastrointestinal hypomotility"
} | [
{
"companynumb": "GB-MYLANLABS-2020M1040946",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLOZAPINE"
},
"drugadditional": "3",
... |
{
"abstract": "Parvovirus B19 is a single-stranded DNA virus that typically has an affinity for erythroid progenitor cells in bone marrow and leads to pure red cell aplasia. This is a common pathogen in humans, and the expression of the infection depends on the host's hematologic and immunologic status. Here, we report a female patient who developed severe and persistent anemia after kidney transplant while being on immunosuppressive therapy. The parvovirus B19 immunoglobulin M test was positive, and the virus was detected by polymerase chain reaction as parvovirus B19 (23.5 million copies/mL) in the blood sample. Bone marrow examination revealed giant pronormoblasts. She responded well to intravenous immunoglobulin without adverse event. Hemoglobin levels gradually increased, and normal levels were achieved at 3 months posttreatment. Although her renal function did not deteriorate, severe anemia (with hemoglobin level 5 g/dL) recurred 3 times during 12 months posttransplant.",
"affiliations": "From the Department of Nephrology, Cukurova University Faculty of Medicine, Adana, Turkey.",
"authors": "Kaya|Bulent|B|;Paydas|Saime|S|",
"chemical_list": "D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007166:Immunosuppressive Agents",
"country": "Turkey",
"delete": false,
"doi": "10.6002/ect.MESOT2018.P63",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1304-0855",
"issue": "17(Suppl 1)",
"journal": "Experimental and clinical transplantation : official journal of the Middle East Society for Organ Transplantation",
"keywords": null,
"medline_ta": "Exp Clin Transplant",
"mesh_terms": "D000328:Adult; D004334:Drug Administration Schedule; D005260:Female; D006801:Humans; D016867:Immunocompromised Host; D016756:Immunoglobulins, Intravenous; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D016030:Kidney Transplantation; D009894:Opportunistic Infections; D010322:Parvoviridae Infections; D016732:Parvovirus B19, Human; D012008:Recurrence; D012010:Red-Cell Aplasia, Pure; D016896:Treatment Outcome; D014775:Virus Activation",
"nlm_unique_id": "101207333",
"other_id": null,
"pages": "195-197",
"pmc": null,
"pmid": "30777553",
"pubdate": "2019-01",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Recurrence of Pure Red Cell Aplasia in a Kidney Transplant Recipient Due to Reactivation of Parvovirus B19 Infection Despite Two Cycles of Intravenous Immunoglobulin Therapy.",
"title_normalized": "recurrence of pure red cell aplasia in a kidney transplant recipient due to reactivation of parvovirus b19 infection despite two cycles of intravenous immunoglobulin therapy"
} | [
{
"companynumb": "PHHY2019TR161526",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "LANSOPRAZOLE"
},
"drugadditional": "3",
"dru... |
{
"abstract": "BACKGROUND\nNon-Helicobacter pylori species (NHPS) are newly emerging bacteria that naturally inhabit birds and mammals apart from humans and rarely cause diseases in humans. In recent years, a rise in the number of cases associated with NHPS infections in humans has been observed. Among them, infections with Helicobacter (H.) canis are sporadic and challenging to recognise clinically. To date, ten cases of H. canis infections in mainly immunocompromised humans have been reported in the literature. Transmission pathway is most likely zoonotic via the faecal-oral route during close contacts with dogs and cats or may result from a contaminated sheep milk intake. No clear guidelines for successful antibiotic regimen are known. Important additional risk factor for infection might be biologic agents and Janus kinase inhibitors (JAKi) used in the treatment of rheumatoid arthritis (RA) and other conditions. Herein we present the first case of H. canis bacteraemia in a RA patient treated with novel JAKi tofacitinib.\n\n\nMETHODS\nA 65-year-old female patient with RA and rituximab-induced hypogammaglobulinemia treated with tofacitinib, methotrexate, and methylprednisolone came to a planned visit in our outpatient rheumatology clinic. She presented with a history of back pain that significantly worsened 2 days before visit. She had numbness and tingling sensation in both legs and muscle weakness. Neurological examination was within a normal range. The patient was afebrile, had no chills, and was haemodynamically stable. She was in close contact with her pet dogs. Laboratory examination showed increased markers of inflammation. She was found to have H. canis bacteraemia with underlying multilevel degenerative lumbar spinal stenosis. Identification of H. canis was performed by MALDI-TOF MS and 16 S rRNA gene sequence analysis of isolate from subcultured positive aerobic blood culture bottles. Antimicrobial susceptibility testing showed low minimum inhibitory concentrations to amoxicillin-clavulanate, cefotaxime, ceftriaxone, meropenem, and gentamicin. She was treated with combined antibiotic regimen (ceftriaxone, doxycycline) for 14 days, which resulted in total remission of the infection.\n\n\nCONCLUSIONS\nClinicians should recognise H. canis infection risk in patients with recent pet exposure and predisposing factors such as immunodeficiency disorders or diseases that demand immunosuppressive drug therapy. A minimum of two weeks of antibiotic therapy is suggested.",
"affiliations": "Division of Internal Medicine, Department of Rheumatology, University Medical Centre Maribor, Ljubljanska ulica 5, 2000, Maribor, Slovenia.;Division of Internal Medicine, Department of Rheumatology, University Medical Centre Maribor, Ljubljanska ulica 5, 2000, Maribor, Slovenia.;National Laboratory for Health, Environment and Food, Maribor, Slovenia.;Division of Internal Medicine, Department of Rheumatology, University Medical Centre Maribor, Ljubljanska ulica 5, 2000, Maribor, Slovenia. iztok.holc@gmail.com.",
"authors": "Mihevc|Matic|M|;Koren Krajnc|Metka|M|;Bombek Ihan|Maja|M|;Holc|Iztok|I|",
"chemical_list": "D010880:Piperidines; D011743:Pyrimidines; C479163:tofacitinib; D008775:Methylprednisolone; D008727:Methotrexate",
"country": "England",
"delete": false,
"doi": "10.1186/s12941-021-00426-x",
"fulltext": "\n==== Front\nAnn Clin Microbiol Antimicrob\nAnn Clin Microbiol Antimicrob\nAnnals of Clinical Microbiology and Antimicrobials\n1476-0711\nBioMed Central London\n\n426\n10.1186/s12941-021-00426-x\nCase Report\nHelicobacter canis bacteraemia in a rheumatoid arthritis patient treated with tofacitinib: case report and literature review\nMihevc Matic 1\nKoren Krajnc Metka 1\nBombek Ihan Maja 2\nHolc Iztok iztok.holc@gmail.com\n\n13\n1 grid.412415.7 0000 0001 0685 1285 Division of Internal Medicine, Department of Rheumatology, University Medical Centre Maribor, Ljubljanska ulica 5, 2000 Maribor, Slovenia\n2 grid.439263.9 National Laboratory for Health, Environment and Food, Maribor, Slovenia\n3 grid.8647.d 0000 0004 0637 0731 Faculty of Medicine, Department of Internal Medicine, University of Maribor, Maribor, Slovenia\n8 4 2021\n8 4 2021\n2021\n20 2228 4 2020\n17 3 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\nNon-Helicobacter pylori species (NHPS) are newly emerging bacteria that naturally inhabit birds and mammals apart from humans and rarely cause diseases in humans. In recent years, a rise in the number of cases associated with NHPS infections in humans has been observed. Among them, infections with Helicobacter (H.) canis are sporadic and challenging to recognise clinically. To date, ten cases of H. canis infections in mainly immunocompromised humans have been reported in the literature. Transmission pathway is most likely zoonotic via the faecal-oral route during close contacts with dogs and cats or may result from a contaminated sheep milk intake. No clear guidelines for successful antibiotic regimen are known. Important additional risk factor for infection might be biologic agents and Janus kinase inhibitors (JAKi) used in the treatment of rheumatoid arthritis (RA) and other conditions. Herein we present the first case of H. canis bacteraemia in a RA patient treated with novel JAKi tofacitinib.\n\nCase presentation\n\nA 65-year-old female patient with RA and rituximab-induced hypogammaglobulinemia treated with tofacitinib, methotrexate, and methylprednisolone came to a planned visit in our outpatient rheumatology clinic. She presented with a history of back pain that significantly worsened 2 days before visit. She had numbness and tingling sensation in both legs and muscle weakness. Neurological examination was within a normal range. The patient was afebrile, had no chills, and was haemodynamically stable. She was in close contact with her pet dogs. Laboratory examination showed increased markers of inflammation. She was found to have H. canis bacteraemia with underlying multilevel degenerative lumbar spinal stenosis. Identification of H. canis was performed by MALDI-TOF MS and 16 S rRNA gene sequence analysis of isolate from subcultured positive aerobic blood culture bottles. Antimicrobial susceptibility testing showed low minimum inhibitory concentrations to amoxicillin-clavulanate, cefotaxime, ceftriaxone, meropenem, and gentamicin. She was treated with combined antibiotic regimen (ceftriaxone, doxycycline) for 14 days, which resulted in total remission of the infection.\n\nConclusions\n\nClinicians should recognise H. canis infection risk in patients with recent pet exposure and predisposing factors such as immunodeficiency disorders or diseases that demand immunosuppressive drug therapy. A minimum of two weeks of antibiotic therapy is suggested.\n\nKeywords\n\nHelicobacter canis\nZoonosis\nRheumatoid arthritis\nImmunocompromised\nTofacitinib\nHypogammaglobulinemia\nTreatment\nissue-copyright-statement© The Author(s) 2021\n==== Body\nBackground\n\nHelicobacter species are newly emerging Gram-negative spiral bacteria with unclear epidemiology and zoonotic transmission pathway [1]. To date, more than 35 species have been validated [2]. Generally, we classify them as Helicobacter (H.) pylori and non-Helicobacter pylori species (NHPS). H. pylori infects up to 50% of the human population and has been associated with peptic ulcers, chronic gastritis, and gastric cancer in humans [1]. Contrary, NHPS naturally inhabit birds and mammals apart from humans and rarely cause diseases in humans [1]. They have been associated with three groups of diseases: (a) gastrointestinal diseases (diarrhoea, gastric cancer), (b) bacteraemia, arthritis, cellulitis, and (c) hepatobiliary diseases (cholecystitis, hepatitis, hepatic cancer) [2–4]. In recent years, a rise in the number of NHPS infections in humans has been observed [1, 3, 4].\n\nHelicobacter canis is a member of the NHPS that inhabits lower intestinal as well as hepatobiliary tract of dogs and cats [5]. According to an extensive PubMed/MEDLINE [6] search (keywords: Helicobacter canis, clinical case, infection) in April 2020, ten clinical cases of H. canis infection associated with human diseases have been described [5, 7–15]. An overview of clinical cases is presented in Table 1. Eight of them describe bacteraemia in patients with recent exposure to dogs or cats [5, 8–11, 13–15]. Lately, transmission between sheep and human contact was demonstrated, recognising sheep as an additional reservoir of H. canis [16]. Infection of humans with H. canis is most likely zoonotic via the faecal-oral route during close contacts with dogs and cats or may result from a contaminated sheep milk intake [14, 16]. Another predisposing factor might be an incompetent immune system of the host. Two previous cases described H. canis bacteraemia in patients with primary immunodeficiency diseases (X-linked hypogammaglobulinemia, common variable immune deficiency) [8, 13]. Another two cases described H. canis bacteraemia in patients treated with immunosuppressive drugs [11, 14]. Table 1 Review of H. canis human infections case reports\n\nAuthor [reference]\tGender, age\tImmune system competency\tPet contact\tClinical presentation\tDetection\tTreatment\t\nBurnens et al. [7]\tMale, \n\n5 years\n\n\tNR\tNR\tGastroenteritis\tStool: Rotavirus, H. canis\tNR\t\nGerrard et al. [8]\tMale, 27 years\tX-linked hypogammaglobulinemia\tDog\tRecurrent fever, bilateral cellulitis\tBlood culture: H. canis, F. rapinni\tDoxycycline and metronidazole p.o. 5 months\t\nLeemann et al. [9]\tMale, 44 years\tImmunocompetent\tDog, cats\tMultifocal cellulitis, subfebrile\tBlood culture: H. canis\tCeftriaxone 2 g daily i.v. 2 weeks\t\nPrag et al. [10]\tFemale, 7 months\tImmunocompetent\tCat\tAcrocyanosis, intermittent fever\tBlood culture: H. canis\tAmpicillin and gentamicin i.v. followed by mecillinam p.o. 10 days\t\nAlon et al. [11]\tMale, 78 years\tDiffuse large B cell lymphoma (R-CHOP)\tDogs\tSubfebrile episodes,\n\nparoxysmal AF\n\n\tBlood culture: H. canis\tH. pylori eradication regimen\t\nTankovic et al. [12]\tFemale, 52 years\tCrohn’s disease (mesalazine)\tCat\tEpigastralgia\tDuodenal biopsy: H. canis\tNot treated\t\nAbidi et al. [13]\tFemale, 57 years\tCVID, pulmonary sarcoidosis (prednisone), splenectomy\tDogs, cats\tRecurrent fever, chills, and sweats for 3 months\tBlood culture: H. canis\tCeftriaxone 2 g daily i.v. 2 weeks, doxycycline 100 mg p.o. 6 weeks\t\nVan der Vusse et al. [14]\tFemale, 41 years\tKidney transplant (tacrolimus, prednisone, mycophenolate mofetil)\tDog\tFever and cough\tBlood culture: H. canis\tCefuroxime 1.5 g 3 times daily i.v. 3 days followed by ciprofloxacin 500 mg p.o. 10 days\t\nShakir et al. [5]\tMale, 49 years\tImmunocompetent\tDogs, cats\tCellulitis\tBlood culture: H. canis\tOne dose of vancomycin 1.5 g i.v., doxycycline 100 mg twice daily p.o. 5 days, amoxicillin/clavulanic acid 500 mg daily p.o. 8 weeks\t\nGutiérrez-Arroyo et al. [15]\tMale, 2 months\tNR\tNR\tCardiorespiratory arrest\tBlood culture: H. canis\tDeath\t\nH Helicobacter; F Flexispira; NR not reported; p.o. per os; i.v. intravenous; R-CHOP rituximab-cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin), oncovin (vincristine), prednisone; AF atrial fibrillation; CVID common variable immunodeficiency\n\nOne class of drugs that could represent a risk factor for H. canis infection and that interfere with host immune system are biologic agents and Janus kinase inhibitors (JAKi) used in the treatment of rheumatoid arthritis (RA) and other conditions [17]. Kourbeti et al. have shown that biologic agents used in the treatment of RA are associated with 1.5-2-fold increased risk of opportunistic infections, especially for mycobacterial and viral infections [18]. However, no data for NHPS are available.\n\nOne of the common biologic agents used for RA management is rituximab (RTX), a B-cell depleting drug [17]. A common side effect of RTX treatment is secondary hypogammaglobulinemia which has been observed in up to 40% of patients treated with RTX [19]. It is unclear whether a reduction in immunoglobulins correlates to a higher risk of infection. Recent large cohort study, investigating RTX infection profiles, concluded that only patients with lower immunoglobulin G (IgG) levels before RTX initiation had increased risk for severe infection events within 12 months of RTX initiation [20].\n\nOn the other hand, JAKi (e.g., tofacitinib, baricitinib) are novel drugs that reversibly inhibit JAK and interfere with cytokine function and signal transduction to the nucleus via the JAK/STAT pathway [17]. Compared to patients treated with biologic agents, patients treated with JAKi have a higher risk of herpes zoster infection, whereas the risk for other infections is like one observed in patients treated with biologic agents [21].\n\nHerein we present a case of bacteraemia caused by H. canis in a female RA patient treated with tofacitinib and secondary rituximab-induced IgM/IgG hypogammaglobulinemia who was in close contact with her pet dogs. To the best of our knowledge, H. canis infection in a patient treated with tofacitinib has not been described before.\n\nCase presentation\n\nA 65-year patient with seropositive RA and arterial hypertension came to a planned visit in our outpatient rheumatology clinic. She was diagnosed with RA in 1996 based on the American Rheumatism Association revised criteria for RA classification [22]. During 1996–2008, she was treated with methylprednisolone, a combination of methylprednisolone and methotrexate (MTX), and a combination of adalimumab, MTX and methylprednisolone, respectively. Between 2009 and 2018, she was treated with a combination of RTX, MTX, and methylprednisolone. However, in 2017 she noticed occasional itchy erythema on hands after RTX application. Additionally, the same year, low levels of IgM (< 0.18 g/L; reference value 0.4–2.3 g/L) and IgG (6.43 g/l; reference value 7.0–16.0 g/L) immunoglobulins were found. Therefore, in 2018, her treatment was changed to a combination of tofacitinib 5 mg twice daily, MTX 10 mg once weekly, and methylprednisolone 2 mg every second day.\n\nIn the outpatient clinic, the patient presented with a history of back pain that significantly worsened 2 days before visit with severe pain radiating to both legs, numbness and tingling sensation in both legs, and muscle weakness. She was unstable while walking. Neurological examination was within a normal range. The patient was afebrile, had no chills, and was haemodynamically stable. Laboratory examination showed normal blood leukocyte count (9.21 × 109/L; reference value 4.00–10.00 × 109/L), mild neutrophilia (7.88 × 109/L; reference value 1.50–7.40 × 109/L), mild anaemia (haemoglobin 116 g/l; reference value 120–150 g/L), increased C-reactive protein (98 mg/L; reference value < 5 mg/L), increased sedimentation rate (39 mm/h; reference value < 15 mm/h), and negative procalcitonin (0.07 ng/mL; reference value < 0.5 ng/mL). She was admitted to the hospital because of a suspected spondylodiscitis. Immunosuppressive therapy was discontinued. As the patient was afebrile, had no chills, no left shift leukocytosis, negative procalcitonin and there was a possibility that increased markers of inflammation reflected the baseline disease (RA), no empirical antibiotic therapy was initiated.\n\nThe first day, a chest X-ray showed no abnormalities. Magnetic resonance imaging of the lumbosacral spine revealed multilevel (L3-S1) degenerative lumbar spinal stenosis (Fig. 1). However, no signs of spondylodiscitis were found. After consultation with a neurosurgeon, there was no indication for surgical intervention. Fig. 1 Magnetic resonance imaging of the lumbosacral spine revealing multilevel (L3-S1) degenerative lumbar spinal stenosis\n\nThe same day, blood samples were collected for culture. Blood was drawn in 4 blood culture bottles (two aerobic, two anaerobic). After 5 days of incubation (BACT/ALERT VIRTUO, BioMerieux), both aerobic bottles flagged positive. Gram stain showed the presence of Gram-negative spiral rods (Fig. 2). As it was difficult to establish the exact morphology of rods in Gram stain, another smear stained with Acridine Orange was performed (Fig. 3). Direct identification from bottles using Sepsityper kit and MALDI-TOF MS (Bruker Daltonik) did not yield any result. Suspecting an organism of fastidious growth after performing Gram stain, bottles were then subcultured on a set of several different media, including blood agar, Colombia agar with 5% horse blood (BioMerieux), Colombia agar with 5% sheep blood (BioMerieux) and Brucella agar (Oxoid), all under different temperature (37 and 42 °C) and atmosphere conditions, including aerobic with 5% CO2 and microaerophilic atmosphere. After 48 h, the only media with visible growth, though extremely scant, was Colombia sheep agar incubated in microaerophilic atmosphere at 37 °C. After 72-96 h, growth was observed on all media incubated in microaerophilic conditions, at 37 °C as well as 42 °C, although the growth was better at 37 °C. Shiny translucent colonies of round or irregular shape were best observed on Brucella agar (Fig. 4). After 6 days of incubation, a phenomenon of swarming was observed on Colombia sheep agar, incubated in microaerophilic conditions at 37 °C (Fig. 5). The result of identification by MALDI-TOF MS from culture was H. canis. However, score was insufficient for reliable result (1.88). Fig. 2 Gram stain of a positive aerobic blood culture bottle. Black arrows indicate pale, thin Gram-negative spiral-shaped rods\n\nFig. 3 Acridine orange stain of a positive aerobic blood culture bottle. White arrows indicate spiral-shaped rods\n\nFig. 4 Brucella agar plate after 3 days of incubation at 37 °C in microaerophilic conditions showing translucent round or irregularly shaped colonies\n\nFig. 5 Colombia sheep agar plate after 6 days of incubation at 37 °C in microaerophilic conditions showing swarming phenomenon\n\nAdditionally, 16 S rRNA sequence analysis of isolate was performed. DNA from pure culture was extracted with Chelex 100 Resin (BioRad). Amplification of the full (1,5 kb) 16 S rRNA gene was performed as described previously by Bianciotto et al. [23]. Amplified 16 S rDNA were sequenced on 3500 Genetic Analyzer using the BigDye Terminator Kit (Applied Biosystems). The forward and reverse strands were aligned using BioNumerics v7.5 (Applied Maths) and the 16 S rDNA sequence was then compared with entries in MicrobeNet (https://www.cdc.gov/microbenet/index.html).\n\nThe 16 S rRNA sequence analysis confirmed identification of H. canis previously obtained with MALDI-TOF MS. Antimicrobial susceptibility testing, performed with gradient E-test MIC method (ETEST - BioMerieux), showed low minimum inhibitory concentrations (MICs) to amoxicillin-clavulanate, cefotaxime, ceftriaxone, meropenem, and gentamicin (Table 2). Table 2 Results of antimicrobial susceptibility testing of H. canis isolated strain\n\nAntimicrobial substance\tAmoxicillin-clavulanate\tCefotaxime\tCeftriaxone\tMeropenem\tGentamicin\t\nMIC [µg/mL]\t0.016\t0.125\t0.25\t0.25\t0.064\t\nMIC minimum inhibitory concentration\n\nOn the 9th day, after H. canis infection identification, combined antibiotic regimen with ceftriaxone 2 g daily intravenously and doxycycline 100 mg twice daily perorally for 14 days was initiated. The antibiotic regimen was chosen according to previous case reports [5, 13]. Five days after combined antibiotic treatment initiation, markers of inflammation decreased (leukocyte blood count 5.31 × 109/L, C-reactive protein 11 mg/L).\n\nIn between, due to anaemia and increased markers of inflammation, other foci of inflammation or malignancy were investigated [24]. However, none were found. Ultrasound of the abdomen revealed gallstones. Esophagogastroduodenoscopy showed chronic superficial gastritis. Ultrasound of the heart showed no significant abnormalities. Additionally, serology testing for Borrelia burgdorferi, Leptospira spp., and stool culture (Salmonella spp., Shigella spp., Campylobacter spp., Yersinia spp., E. coli O157, Shiga toxin-producing E. coli) were negative.\n\nBefore discharge, blood samples for control blood cultures were collected. All were sterile. Furthermore, primary sterile samples were tested for 16 S rRNA gene sequencing. All samples were negative for 16 S rRNA gene of Helicobacter species at discharge.\n\nDiscussion and conclusions\n\nIn this case report, we described a female patient with bacteraemia caused by H. canis and RA treated with tofacitinib in combination therapy. Infection occurred 8 months after treatment initiation. According to previous case reports (Table 1), clinical presentation of H. canis bacteraemia is diverse. Three case reports described multifocal cellulitis with or without fever episodes [5, 8, 9]. Four others described intermittent and/or recurrent fever only [10, 11, 13, 14]. One case in an infant ended with a cardiorespiratory arrest [15]. Our case described a patient with lumboischialgia that resulted from multilevel degenerative lumbar spinal stenosis. Apart from increased markers of inflammation and clinical presentation of spinal stenosis, our patient had asymptomatic H. canis bacteraemia. We present the first case describing laboratory findings of H. canis bacteraemia only. However, our patient received chronic non-steroidal anti-inflammatory drug and paracetamol therapy which could mask febrile episodes frequently presented in other patients [25].\n\nImportant risk factor for H. canis bacteraemia might be an incompetent immune system. Majority of previous patients with bacteraemia were immunocompromised. One case described bacteraemia in a patient with X-linked hypogammaglobulinemia [8]. Another case described a patient with common variable immune deficiency, sarcoidosis, and splenectomy [13]. Furthermore, two case reports described patients receiving immunosuppressive drugs. The first case described a patient with B cell lymphoma treated with R-CHOP chemotherapy [11]. The second case described a kidney transplant patient treated with tacrolimus, mycophenolate mofetil, and prednisone [14]. Our patient had a combination of both risk factors.\n\nOn the one hand, she had RTX-induced hypogammaglobulinemia. On the other hand, she was treated with tofacitinib, MTX, and a low methylprednisolone dose. A recent large cohort study found that patients with RA, receiving tofacitinib in combination with MTX, have had 3.0% risk of severe infections, among them, 0.2% risk for tuberculosis (TBC), 4.1% risk for herpes zoster, and 0.6% risk for opportunistic infections excluding TBC [26]. The risk of serious infections was higher in patients older than 65 years [26].\n\nAnother factor contributing to a low number of H. canis case reports might be challenging and easily overlooked laboratory recognition. H. canis can grow in standard aerobic blood cultures, however, in general, micro-aerophilic atmosphere conditions (37 or 42 °C) are needed for growth [5]. Furthermore, it is relatively inert biochemically - catalase, urease, and nitrate negative [13]. Until recently, identifying fastidious organisms like NHPS was challenging in most clinical laboratory settings. Because of their low biochemical reactivities, differentiation methods relying on isolates’ biochemical characteristics were unsuccessful. With the development and implementation of newer identification methods like MALDI-TOF MS and molecular methods like 16 S rRNA gene sequence analysis, accurate identification of these fastidious microorganisms became readily available [5, 13, 27].\n\nCurrently, no recommendations for treatment of H. canis bacteraemia are available. Previous case reports described different treatment regimens. Some patients were treated with amoxicillin-clavulanate [5] or ceftriaxone [9], whereas others were treated with a combination of ceftriaxone and doxycycline [13] or a combination of cefuroxime and ciprofloxacin [14]. A minimum of 2 weeks and a maximum of 8 weeks of therapy were described. We successfully treated our patient with a combination of ceftriaxone and doxycycline in a duration of 14 days. To point out, this is the third case where results of in vitro antimicrobial susceptibility testing are presented. Like our results, Leeman et al. found susceptibility of H. canis to amoxicillin, amoxicillin-clavulanate, ceftriaxone, piperacillin-tazobactam, imipenem, metronidazole, and clindamycin [9]. Other study found susceptibility to nalidixic acid only [10]. Clear recommendations for optimal antibiotic treatment regimen of H. canis infections cannot be made. However, this is the fifth case where either a third-generation cephalosporin or doxycycline was used and resulted in complete remission of H. canis infection [8, 9, 13, 14].\n\nIn conclusion, H. canis infections are rare and difficult to diagnose. Clinicians should recognise risk for infection in patients with recent exposure to dogs, cats or sheep while not improving with standard therapy. Risk further increases with underlying comorbidities, especially, autoimmune diseases, immunodeficiency disorders, or use of immunosuppressive agents. A minimum of 2 weeks of therapy is suggested [13].\n\nAbbreviations\n\nCVID Common variable immune deficiency\n\nH. canis Helicobacter canis\n\nH. pylori Helicobacter pylori\n\nIgG Immunoglobulin G\n\nIgM Immunoglobulin M\n\nJAKi Janus kinase inhibitors\n\nMALDI-TOF MS Matrix-assisted laser desorption/ionisation-time of flight mass spectrometry\n\nMTX Methotrexate\n\nNHPS Non-Helicobacter pylori species\n\nRA Rheumatoid arthritis\n\nR-CHOP Rituximab -cyclophosphamide, hydroxydaunorubicin, oncovin, prednisone\n\nrRNA Ribosomal ribonucleic acid\n\nRTX Rituximab\n\nMIC Minimum inhibitory concentration\n\nAuthors’ contributionss\n\nIH recognised clinical case and managed the patient. MM took the lead in writing the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nThe authors have no sources of funding to declare.\n\nAvailability of data and materials\n\nThe datasets are available from the corresponding author on reasonable request.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nWritten informed consent for publication of their clinical details and/or clinical images was obtained from the patient. A copy of the consent form is available for review by the Editor of this journal.\n\nCompeting interests\n\nThe authors have none to declare.\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. Mladenova-Hristova I Grekova O Patel A Zoonotic potential of Helicobacter spp J Microbiol Immunol Infect 2017 50 3 265 9 10.1016/j.jmii.2016.11.003 28655571\n2. Péré-Védrenne C Flahou B Loke MF Ménard A Vadivelu J Other Helicobacters, gastric and gut microbiota Helicobacter 2017 22 Suppl1 e12407 10.1111/hel.12407\n3. Fox JG The non-H pylori helicobacters: their expanding role in gastrointestinal and systemic diseases Gut 2002 50 2 273 83 10.1136/gut.50.2.273 11788573\n4. Ménard A Smet A Review: other Helicobacter species Helicobacter. 2019 10.1111/hel.12645 31486233\n5. Shakir SM Powers-Fletcher MV Slechta ES Fisher MA Helicobacter canis bacteraemia and cellulitis in a patient with end-stage renal disease JMM Case Rep 2017 4 11 e005126 10.1099/jmmcr.0.005126 29255610\n6. U.S. National Institutes of Health, National Library of Medicine. Assessed 10 April 2020. http://www.ncbi.nlm.nih.gov/pubmed/.\n7. Burnens AP Stanley J Schaad UB Nicolet J Novel Campylobacter-like organism resembling Helicobacter fennelliae isolated from a boy with gastroenteritis and from dogs J Clin Microbiol 1993 31 7 1916 7 10.1128/JCM.31.7.1916-1917.1993 8349774\n8. Gerrard J Alfredson D Smith I Recurrent bacteremia and multifocal lower limb cellulitis due to Helicobacter-like organisms in a patient with X-linked hypogammaglobulinemia Clin Infect Dis 2001 33 10 E116-8 10.1086/323405 11595979\n9. Leemann C Gambillara E Prod’hom G Jaton K Panizzon R Bille J First case of bacteremia and multifocal cellulitis due to Helicobacter canis in an immunocompetent patient J Clin Microbiol 2006 44 12 4598 600 10.1128/jcm.01453-06 17005753\n10. Prag J Blom J Krogfelt KA Helicobacter canis bacteraemia in a 7-month-old child FEMS Immunol Med Microbiol 2007 50 2 264 7 10.1111/j.1574-695X.2007.00271.x 17567285\n11. Alon D Paitan Y Ben-Nissan Y Chowers M Persistent Helicobacter canis bacteremia in a patient with gastric lymphoma Infection 2010 38 1 62 4 10.1007/s15010-009-9067-6 19756417\n12. Tankovic J Smati M Lamarque D Delchier JC First detection of Helicobacter canis in chronic duodenal ulcerations from a patient with Crohn’s disease Inflamm Bowel Dis 2011 17 8 1830 1 10.1002/ibd.21610 21744440\n13. Abidi MZ Wilhelm MP Neff JL Hughes JG Cunningham SA Patel R Helicobacter canis bacteremia in a patient with fever of unknown origin J Clin Microbiol 2013 51 3 1046 8 10.1128/JCM.02548-12 23284025\n14. Van der Vusse ML van Son WJ Ott A Manson W Helicobacter canis bacteremia in a renal transplant patient Transpl Infect Dis 2014 16 1 125 9 10.1111/tid.12174 24372779\n15. Gutiérrez-Arroyo A Falces-Romero I Corcuera-Pindado M Romero-Gómez MP Bacteraemia in a two month-old infant Enferm Infecc Microbiol Clin 2017 35 676 7 10.1016/j.eimce.2017.11.012 27435039\n16. Sabry MA Abdel-Moein KA Seleem A Evidence of zoonotic transmission of Helicobacter canis between sheep and human contacts Vector Borne Zoonotic Dis 2016 16 10 650 3 10.1089/vbz.2016.1994 27529744\n17. Kotyla PJ Are janus kinase inhibitors superior over classic biologic agents in RA patients? BioMed Res Int 2018 2018 7492904 10.1155/2018/7492904 29862290\n18. Kourbeti IS Ziakas PD Mylonakis E Biologic therapies in rheumatoid arthritis and the risk of opportunistic infections: a meta-analysis Clin Infect Dis 2014 58 12 1649 57 10.1093/cid/ciu185 24647016\n19. Casulo C Maragulia J Zelenetz AD Incidence of hypogammaglobulinemia in patients receiving rituximab and the use of intravenous immunoglobulin for recurrent infections Clin Lymphoma Myeloma Leuk 2013 13 2 106 11 10.1016/j.clml.2012.11.011 23276889\n20. Md Yusof MY Vital EM McElvenny DM Hensor EMA Das S Dass S Predicting severe infection and effects of hypogammaglobulinemia during therapy with rituximab in rheumatic and musculoskeletal diseases Arthritis Rheumatol 2019 71 11 1812 23 10.1002/art.40937 31131994\n21. Harigai M Growing evidence of the safety of JAK inhibitors in patients with rheumatoid arthritis Rheumatology 2019 58 Suppl1 i34 42 10.1093/rheumatology/key287 30806708\n22. Arnett FC Edworthy SM Bloch DA McShane DJ Fries JF Cooper NS The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis Arthritis Rheum 1988 31 3 315 24 10.1002/art.1780310302 3358796\n23. Bianciotto V Bandi C Minerdi D Sironi M Tichy HV Bonfante P An obligately endosymbiotic mycorrhizal fungus itself harbors obligately intracellular bacteria Appl Environ Microbiol 1996 62 8 3005 10 10.1128/AEM.62.8.3005-3010.1996 8702293\n24. Bitik B Mercan R Tufan A Tezcan E Küçük H İlhan M Differential diagnosis of elevated erythrocyte sedimentation rate and C-reactive protein levels: a rheumatology perspective Eur J Rheumatol 2015 2 4 131 4 10.5152/eurjrheum.2015.0113 27708949\n25. Ludwig J McWhinnie H Antipyretic drugs in patients with fever and infection: literature review Br J Nurs 2019 28 10 610 8 10.12968/bjon.2019.28.10.610 31116598\n26. Wollenhaupt J Lee E-B Curtis JR Silverfield J Terry K Soma K Safety and efficacy of tofacitinib for up to 9.5 years in the treatment of rheumatoid arthritis: final results of a global, open-label, long-term extension study Arthritis Res Ther 2019 21 1 89 10.1186/s13075-019-1866-2 30953540\n27. Wieser A Schneider L Jung J Schubert S MALDI-TOF MS in microbiological diagnostics-identification of microorganisms and beyond (mini review) Appl Microbiol Biotechnol 2012 93 3 965 74 10.1007/s00253-011-3783-4 22198716\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1476-0711",
"issue": "20(1)",
"journal": "Annals of clinical microbiology and antimicrobials",
"keywords": "Helicobacter canis; Hypogammaglobulinemia; Immunocompromised; Rheumatoid arthritis; Tofacitinib; Treatment; Zoonosis",
"medline_ta": "Ann Clin Microbiol Antimicrob",
"mesh_terms": "D000368:Aged; D000818:Animals; D001172:Arthritis, Rheumatoid; D016470:Bacteremia; D002371:Cat Diseases; D002415:Cats; D004283:Dog Diseases; D004285:Dogs; D005260:Female; D016998:Helicobacter; D006801:Humans; D008727:Methotrexate; D008775:Methylprednisolone; D010880:Piperidines; D011743:Pyrimidines; D012756:Sheep; D016896:Treatment Outcome",
"nlm_unique_id": "101152152",
"other_id": null,
"pages": "22",
"pmc": null,
"pmid": "33827581",
"pubdate": "2021-04-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "31486233;24647016;30953540;8349774;11595979;21744440;27708949;3358796;30806708;17005753;31116598;17567285;31131994;28655571;27529744;8702293;29255610;28891140;19756417;24372779;23284025;22198716;23276889;29862290;27435039;11788573",
"title": "Helicobacter canis bacteraemia in a rheumatoid arthritis patient treated with tofacitinib: case report and literature review.",
"title_normalized": "helicobacter canis bacteraemia in a rheumatoid arthritis patient treated with tofacitinib case report and literature review"
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{
"abstract": "BACKGROUND\nHeart transplantation is recommended for the treatment of patients with refractory heart failure. Chest pain after heart transplantation is usually considered noncardiac owing to the denervated heart. However, data from case reports on tacrolimus-induced achalasia after heart transplantation are limited. We aimed to present a case of tacrolimus-induced achalasia that developed after heart transplantation, which was successfully relieved by laparoscopic Heller myotomy.\n\n\nMETHODS\nA 67-year-old man with a history of Type 2 diabetes mellitus, hyperlipidemia, and dilated cardiomyopathy had congestive heart failure following orthotopic heart transplantation with tacrolimus treatment 12 years ago. At the 10-year follow-up after the heart transplantation, the patient presented with persistent cough, dysphagia, heartburn, and retrosternal chest pain lasting for 2 wk. Upper endoscopy revealed no specific findings. Two years later, the patient experienced the same symptoms, including chest pain lasting for 4 wk. Esophagogram and manometry confirmed the presence of achalasia. Previous reports showed that discontinuing calcineurin inhibitor (CNI) treatment and endoscopic botulinum toxin injection could treat CNI-induced achalasia. Owing to the risk of rejection of the transplanted heart and considering the temporary benefits of botulinum toxin injection in achalasia, the patient underwent laparoscopic Heller myotomy. Dysphagia was relieved without complications. Eight months later, he had no signs of recurrence of the achalasia.\n\n\nCONCLUSIONS\nIn transplant patients with chest pain and gastrointestinal symptoms, CNI-induced achalasia may be one of the differential diagnoses. Esophagogram/manometry is useful for diagnosis.",
"affiliations": "Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.;Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan.;Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan. chi-wang@yahoo.com.tw.",
"authors": "Chen|Yu-Jen|YJ|;Tsai|Chien-Sung|CS|;Huang|Tsai-Wang|TW|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.12998/wjcc.v9.i16.3966",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960\nBaishideng Publishing Group Inc\n\njWJCC.v9.i16.pg3966\n10.12998/wjcc.v9.i16.3966\nCase Report\nChest pain in a heart transplant recipient: A case report\nChen YJ et al. Heart transplant recipient with chest pain\nChen Yu-Jen Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan\n\nTsai Chien-Sung Division of Cardiovascular Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan\n\nHuang Tsai-Wang Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 11490, Taiwan. chi-wang@yahoo.com.tw\n\nAuthor contributions: Chen YJ and Huang TW performed the surgery, reviewed the literature, and contributed to the drafting of the manuscript; Tsai CS was responsible for the revision of the manuscript for important intellectual content; all authors issued final approval for the version to be submitted.\n\nCorresponding author: Tsai-Wang Huang, PhD, Associate Professor, Chief Doctor, Division of Thoracic Surgery, Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, No. 325 Sec.2, Chenggong Road, Neihu District, Taipei 11490, Taiwan. chi-wang@yahoo.com.tw\n\n6 6 2021\n6 6 2021\n9 16 39663970\n26 11 2020\n26 1 2021\n12 4 2021\n©The Author(s) 2021. Published by Baishideng Publishing Group Inc. All rights reserved.\n2021\nhttps://creativecommons.org/licenses/by-nc/4.0/ This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.\nBACKGROUND\n\nHeart transplantation is recommended for the treatment of patients with refractory heart failure. Chest pain after heart transplantation is usually considered noncardiac owing to the denervated heart. However, data from case reports on tacrolimus-induced achalasia after heart transplantation are limited. We aimed to present a case of tacrolimus-induced achalasia that developed after heart transplantation, which was successfully relieved by laparoscopic Heller myotomy.\n\nCASE SUMMARY\n\nA 67-year-old man with a history of Type 2 diabetes mellitus, hyperlipidemia, and dilated cardiomyopathy had congestive heart failure following orthotopic heart transplantation with tacrolimus treatment 12 years ago. At the 10-year follow-up after the heart transplantation, the patient presented with persistent cough, dysphagia, heartburn, and retrosternal chest pain lasting for 2 wk. Upper endoscopy revealed no specific findings. Two years later, the patient experienced the same symptoms, including chest pain lasting for 4 wk. Esophagogram and manometry confirmed the presence of achalasia. Previous reports showed that discontinuing calcineurin inhibitor (CNI) treatment and endoscopic botulinum toxin injection could treat CNI-induced achalasia. Owing to the risk of rejection of the transplanted heart and considering the temporary benefits of botulinum toxin injection in achalasia, the patient underwent laparoscopic Heller myotomy. Dysphagia was relieved without complications. Eight months later, he had no signs of recurrence of the achalasia.\n\nCONCLUSION\n\nIn transplant patients with chest pain and gastrointestinal symptoms, CNI-induced achalasia may be one of the differential diagnoses. Esophagogram/manometry is useful for diagnosis.\n\nHeart transplantation\nRefractory heart failure\nChest pain\nAchalasia\nEsophagogram\nCase report\n==== Body\nCore Tip: Chest pain after heart transplantation usually present with noncardiac symptoms due to the denervated heart. Its differential diagnosis includes acute allograft dysfunction caused by acute myocardial infarction, myocarditis, hypertensive crisis, or infections. However, data from case reports on tacrolimus-induced achalasia after heart transplantation are limited. In this case involving a rare complication of tacrolimus-induced achalasia after heart transplantation, we successfully treated the patient with laparoscopic Heller myotomy. This case highlights that calcineurin inhibitor -induced achalasia should be considered in transplant patients with atypical chest pain. Esophagogram or manometry may be helpful for its diagnosis.\n\nINTRODUCTION\n\nHeart transplantation is the definitive treatment for patients with refractory end-stage heart failure. Although coronary artery disease develops within 3 years of heart transplantation, chest pain after heart transplantation is usually considered noncardiac because the transplanted heart is assumed to be denervated[1]. Nevertheless, atypical symptoms of chest pain in transplant patients should be evaluated further. We experienced a unique case of a heart transplant recipient who complained of chest pains and was subsequently diagnosed with achalasia after a series of investigations.\n\nAchalasia is an uncommon esophageal motility disorder of an unknown etiology characterized by failure of the relaxation of the lower esophageal sphincter (LES) and loss of esophageal peristalsis. It may be caused by trauma or medications. Previous case reports describe patients diagnosed with calcineurin inhibitor (CNI)-induced achalasia[2]. The possible mechanism for CNI-induced achalasia is the inhibition of nitric oxide synthase, resulting in esophageal motility[3,4]. However, data from case reports on tacrolimus-induced achalasia after heart transplantation are limited. We present a case of tacrolimus-induced achalasia that developed after heart transplantation, which was successfully relieved by laparoscopic Heller myotomy.\n\nCASE PRESENTATION\n\nChief complaints\n\nA 67-year-old man presented to our institution with complaints of persistent cough, difficulty in swallowing liquid and solid food, heartburn, and retrosternal chest pain lasting for 4 wk.\n\nHistory of present illness\n\nTwelve years ago, the patient underwent orthotopic heart transplantation on February 13, 2008, with tacrolimus treatment without any postoperative complications. During follow-up at 10 years after the heart transplantation, the patient complained of persistent cough, dysphagia, heartburn, and retrosternal chest pain lasting for 2 wk. Upper endoscopy showed spasm of the lower esophagus, and achalasia was suspected. However, the symptoms were relieved spontaneously.\n\nHistory of past illness\n\nHe had a history of type 2 diabetes mellitus, hyperlipidemia, and dilated cardiomyopathy with congestive heart failure status post orthotopic heart transplantation (donor: 26-year-old male).\n\nPersonal and family history\n\nThe patient did not consume alcohol or have the habit of smoking. There were no specific family health histories, such as mediastinal and pulmonary diseases or cancer.\n\nPhysical examination\n\nHe was hemodynamically stable and had normal heart sounds, fine right basal inspiratory lung rales, and normoactive bowel sounds. His blood pressure was 119/79 mmHg, heart rate was 86 beats/min, respiration rate was 18 breaths/min, and body temperature was 36.2 °C. He had no jugular vein distention, no pitting edema, symmetrical and free lung expansion and normal breathing sounds, and no palpable mass or muscle guarding over the abdominal region.\n\nLaboratory examinations\n\nLaboratory findings were as follows: white blood cell count, 7.36 × 103/μL; neutrophil count, 78.1%; and lymphocyte count, 13.9%. The endomyocardial biopsy revealed no evidence of rejection. Electrocardiogram revealed a sinus rhythm without ST-segment elevations.\n\nImaging examinations\n\nEsophagogram (Figure 1) showed failure of relaxation of the LES with a diverticulum and a dilated esophagus with the bird's beak sign. Manometry (Figure 2) revealed abnormal peristalsis of the esophagus with a high residual pressure of LES.\n\nFigure 1 Esophagogram. A dilated esophagus with the bird's beak sign, esophageal dysmotility, and failure of relaxation of the lower esophageal sphincter; Status after median sternotomy with surgical wire fixation for heart transplant.\n\nFigure 2 Manometry. Abnormal peristalsis of the esophagus with high residual pressure of the lower esophageal sphincter.\n\nFINAL DIAGNOSIS\n\nBased on the history and findings of the imaging examinations, the patient was diagnosed with CNI-induced achalasia.\n\nTREATMENT\n\nThe patient underwent laparoscopic Heller myotomy.\n\nOUTCOME AND FOLLOW-UP\n\nAfter the procedure, the symptoms of dysphagia were relieved without complications. The patient recovered well and was discharged from the hospital. At 8 mo after hospital discharge, he had no symptoms of dysphagia or recurrence of achalasia.\n\nDISCUSSION\n\nOwing to cardiac denervation, most transplant patients complain of atypical chest pain due to acute allograft dysfunction caused by acute myocardial infarction, myocarditis, hypertensive crisis, or infections[5]. Additionally, transplant patients suffer from not only atypical chest pain but also gastrointestinal symptoms. CNI-induced achalasia should be one of the differential diagnoses. Esophagogram or manometry is recommended for its diagnosis.\n\nTo the best of our knowledge, there had been no case report of tacrolimus-induced achalasia forming after heart transplantation and successfully relieved by laparoscopic Heller myotomy. Based on the onset time of achalasia in our case, operative trauma of the vagal nerve was less likely. A previous report showed that changing different CNIs and endoscopic botulinum toxin injection could treat CNI-induced achalasia[2]. In our case, switching from tacrolimus to cyclosporine was not considered owing to the risk of rejection of the transplanted heart. Moreover, the onset time of CNI-induced achalasia in our case was different from that of the previous report[2] owing to the development of dysphagia immediately after the initiation of CNI. Botulinum toxin injection was not considered owing to its temporary benefits in achalasia. Subsequently, laparoscopic Heller myotomy was considered in our case.\n\nCONCLUSION\n\nWe recommend screening for calcineurin inhibitor-induced achalasia if transplant patients complain of atypical chest pain with gastrointestinal symptoms. The condition can be diagnosed using an esophagogram or manometry.\n\nACKNOWLEDGEMENTS\n\nWe thank Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.\n\nInformed consent statement: Informed written consent was obtained from the patient to publish this report and any accompanying images.\n\nConflict-of-interest statement: The authors declare that they have no conflict of interest.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: November 26, 2020\n\nFirst decision: January 23, 2021\n\nArticle in press: April 12, 2021\n\nSpecialty type: Gastroenterology and hepatology\n\nCountry/Territory of origin: Taiwan\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): A\n\nGrade B (Very good): 0\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Zhang DM S-Editor: Zhang L L-Editor: A P-Editor: Zhang YL\n==== Refs\n1 Stark RP McGinn AL Wilson RF Chest pain in cardiac-transplant recipients. Evidence of sensory reinnervation after cardiac transplantation N Engl J Med 1991 324 1791 1794 2038368\n2 Campos M Matlock R Endoscopic Botulinum Toxin Injection for Tacrolimus-Induced Achalasia in a Renal Transplant Recipient Gastroenterology Res 2019 12 171 173 31236159\n3 Cook LG Chiasson VL Long C Wu GY Mitchell BM Tacrolimus reduces nitric oxide synthase function by binding to FKBP rather than by its calcineurin effect Kidney Int 2009 75 719 726 19177155\n4 Hämäläinen M Lahti A Moilanen E Calcineurin inhibitors, cyclosporin A and tacrolimus inhibit expression of inducible nitric oxide synthase in colon epithelial and macrophage cell lines Eur J Pharmacol 2002 448 239 244 12144947\n5 DeFilippis EM Nayor M Lewis EF Chest Pain and Shortness of Breath After a Heart Transplant JAMA Cardiol 2017 2 1271 1272 28975203\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "9(16)",
"journal": "World journal of clinical cases",
"keywords": "Achalasia; Case report; Chest pain; Esophagogram; Heart transplantation; Refractory heart failure",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "3966-3970",
"pmc": null,
"pmid": "34141754",
"pubdate": "2021-06-06",
"publication_types": "D002363:Case Reports",
"references": "28975203;12144947;2038368;31236159;19177155",
"title": "Chest pain in a heart transplant recipient: A case report.",
"title_normalized": "chest pain in a heart transplant recipient a case report"
} | [
{
"companynumb": "TW-ASTELLAS-2021US020968",
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"activesubstancename": "EVEROLIMUS"
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"abstract": "OBJECTIVE\nThe effectiveness of continuous renal replacement therapy (CRRT) increases when unplanned circuit failure is prevented. Adequate anticoagulation is an important component. Although heparin is the predominating anticoagulant, calcium chelation with citrate is an alternative, but systemic calcium monitoring and supplementation increase the complexity of CRRT. We assessed efficacy and safety of citrate delivery via integrated software algorithms against an established regional heparin protocol.\n\n\nMETHODS\nProspective computer randomisation allocated eligible patients to regional citrate or heparin between April and December 2012. Citrate fluids were Prismocitrate 18 mmol/L predilution and Prism0cal B22 dialysate. Hemosol B0 was the default fluid for heparin. The primary outcome was filter running time. Electively terminated circuits were censored. Intention-totreat (ITT) and per-protocol analyses were performed. Filter survival was compared by log-rank tests and hazard ratios were explored with a mixed-effects Cox model.\n\n\nRESULTS\n221 filters were analysed from 30 patients (of whom 19 were randomly allocated to citrate filters and 11 to heparin filters). Patients randomly allocated to citrate were older, sicker, with a higher male:female ratio, but of similar weight. Mortality was 37% in the citrate arm and 27% in the heparin arm. All deaths were attributed to underlying disease. Significant crossover occurred from the citrate arm to use of heparin. Median filter survival, by ITT, was not significantly different (citrate, 34 hours; heparin, 30.7 hours; P=0.58). Per-protocol survival favoured citrate (citrate, 42.1 hours; heparin, 24 hours; χ(2)=8.1; P=0.004). Considerable variation in filter life existed between patients, and between vascular access sites within patients. Safety end points were reached in one heparin and three citrate patients.\n\n\nCONCLUSIONS\nAlthough the per-protocol results favoured citrate when it was actually delivered, the significant crossover between treatment arms hampered more definitive conclusions. Until further studies support improved patient outcomes, increased complexity and complications suggest that anticoagulation choice be made using patient-specific indications.",
"affiliations": "School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia. matthew.brain@monash.edu.;School of Public Health and Preventive Medicine, Monash University, Melbourne, VIC, Australia.;Department of Intensive Care and Hyperbaric Medicine, The Alfred, Melbourne, VIC, Australia.;Department of Intensive Care and Hyperbaric Medicine, The Alfred, Melbourne, VIC, Australia.;Department of Intensive Care and Hyperbaric Medicine, The Alfred, Melbourne, VIC, Australia.;Department of Intensive Care and Hyperbaric Medicine, The Alfred, Melbourne, VIC, Australia.;Department of Intensive Care and Hyperbaric Medicine, The Alfred, Melbourne, VIC, Australia.;Department of Intensive Care and Hyperbaric Medicine, The Alfred, Melbourne, VIC, Australia.",
"authors": "Brain|Matthew J|MJ|;Roodenburg|Owen S|OS|;Adams|Natalie|N|;McCracken|Phoebe|P|;Hockings|Lisen|L|;Musgrave|Steve|S|;Butt|Warwick|W|;Scheinkestel|Carlos|C|",
"chemical_list": "D000925:Anticoagulants; D012965:Sodium Chloride; D006493:Heparin",
"country": "Australia",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "1441-2772",
"issue": "16(2)",
"journal": "Critical care and resuscitation : journal of the Australasian Academy of Critical Care Medicine",
"keywords": null,
"medline_ta": "Crit Care Resusc",
"mesh_terms": "D058186:Acute Kidney Injury; D000368:Aged; D000465:Algorithms; D000925:Anticoagulants; D005260:Female; D005374:Filtration; D006493:Heparin; D006801:Humans; D057194:Intention to Treat Analysis; D008297:Male; D008875:Middle Aged; D011446:Prospective Studies; D017582:Renal Replacement Therapy; D012965:Sodium Chloride; D012984:Software",
"nlm_unique_id": "100888170",
"other_id": null,
"pages": "131-7",
"pmc": null,
"pmid": "24888284",
"pubdate": "2014-06",
"publication_types": "D016428:Journal Article; D016449:Randomized Controlled Trial",
"references": null,
"title": "Randomised trial of software algorithm driven regional citrate anticoagulation versus heparin in continuous renal replacement therapy: the Filter Life in Renal Replacement Therapy pilot trial.",
"title_normalized": "randomised trial of software algorithm driven regional citrate anticoagulation versus heparin in continuous renal replacement therapy the filter life in renal replacement therapy pilot trial"
} | [
{
"companynumb": "AU-BAXTER-2014BAX039579",
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"occurcountry": "AU",
"patient": {
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{
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"activesubstance": {
"activesubstancename": "BICARBONATE ION\\CHLORIDE ION\\DEXTROSE\\LACTIC ACID\\MAGNESIUM\\PO... |
{
"abstract": "Phenytoin is used for the treatment and prevention of fits. We investigated all patients reported to have phenytoin allergy in our hospital and found 42 confirmed cases. Sixty-nine percent were female and 83.3% were Chinese. The mean age of the patients was 46.5 years. The reactions reported were maculopapular rash (71.4%), Stevens-Johnson syndrome (14.3%), fever (4.8%), generalized exfoliative dermatitis (2.4%), toxic epidermal necrolysis (2.4%), vasculitis (2.4%) and agranulocytosis (2.4%). In conclusion, the majority of reported allergic reactions to phenytoin were cutaneous (92.9%) and one fifth of these were potentially life-threatening.",
"affiliations": "Department of Rheumatology and Immunology, Tan Tock Seng Hospital, Singapore.",
"authors": "Leong|K P|KP|;Chng|H H|HH|",
"chemical_list": "D000927:Anticonvulsants; D010672:Phenytoin",
"country": "Thailand",
"delete": false,
"doi": null,
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"issn_linking": "0125-877X",
"issue": "14(2)",
"journal": "Asian Pacific journal of allergy and immunology",
"keywords": null,
"medline_ta": "Asian Pac J Allergy Immunol",
"mesh_terms": "D000328:Adult; D000927:Anticonvulsants; D004342:Drug Hypersensitivity; D005260:Female; D006769:Hospitals, General; D006801:Humans; D008297:Male; D010672:Phenytoin; D012189:Retrospective Studies; D012846:Singapore",
"nlm_unique_id": "8402034",
"other_id": null,
"pages": "65-8",
"pmc": null,
"pmid": "9177818",
"pubdate": "1996-12",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Allergic reactions to phenytoin in a general hospital in Singapore.",
"title_normalized": "allergic reactions to phenytoin in a general hospital in singapore"
} | [
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"companynumb": "SG-PFIZER INC-2015337192",
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "PHENYTOIN"
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... |
{
"abstract": "Herpes simplex virus (HSV) adenitis is a rare but important cause of morbidity in immunocompromised patients. Chronic lymphocytic leukaemia (CLL)/Small lymphocytic lymphoma (SLL) is an indolent disease which impairs the cellular and humoral immunity, predisposing patients to a myriad of infections. Clinically, herpetic adenitis can mimic large cell (Richter's) transformation in patients with CLL. To date, less than 30 cases of HSV adenitis have been reported in the literature. We report a case of a patient with CLL with no prior history of HSV infection, who presented with rapidly enlarging lymph nodes after initial response to idelalisib raising the suspicion of Richter's transformation. However, excisional biopsy of a lymph node revealed HSV adenitis along with CLL, which was confirmed by immunohistochemical staining.",
"affiliations": "Department of Hematology/Medical Oncology, Joan C Edwards School of Medicine at Marshall University, Huntington, West Virginia, USA.;Department of Pathology, Joan C Edwards School of Medicine at Marshall University, Huntington, West Virginia, USA.;Department of Hematology/Medical Oncology, Joan C Edwards School of Medicine at Marshall University, Huntington, West Virginia, USA.",
"authors": "Srivastava|Roma|R|;Griswold|Doreen|D|;Jamil|Muhammad Omer|MO|",
"chemical_list": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D011687:Purines; D052999:Quinazolinones; C552946:idelalisib",
"country": "England",
"delete": false,
"doi": "10.1136/bcr-2017-222091",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2018()",
"journal": "BMJ case reports",
"keywords": "cancer intervention; haematology (drugs and medicines); infections; malignant and benign haematology",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D001706:Biopsy; D003937:Diagnosis, Differential; D006561:Herpes Simplex; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell; D008198:Lymph Nodes; D008199:Lymphadenitis; D008297:Male; D008875:Middle Aged; D011687:Purines; D052999:Quinazolinones; D018139:Simplexvirus; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "29420244",
"pubdate": "2018-02-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "1850953;10482562;3766459;10918489;11504743;7969363;16594747;24450858;10506706;14738148;2036132;16616071;10233419;25645861",
"title": "Chronic lymphocytic leukaemia with necrotic herpetic adenitis: an elusive clinical condition.",
"title_normalized": "chronic lymphocytic leukaemia with necrotic herpetic adenitis an elusive clinical condition"
} | [
{
"companynumb": "PHHY2018US041386",
"fulfillexpeditecriteria": "2",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "IDELALISIB"
},
"drugadditional": "1",
"druga... |
{
"abstract": "BACKGROUND\nThe end-stage LIVER disease and RALtegravir-Agence Nationale de Recherche sur le Sida et les hépatites (LIVERAL-ANRS) 148 study aimed to evaluate the safety, efficacy, and pharmacokinetic parameters of raltegravir (RAL) in human immunodeficiency virus (HIV)-infected patients with end-stage liver disease (ESLD) (substudy 1) and to assess the lack of pharmacokinetic interaction between RAL and the immunosuppressive regimen introduced after liver transplant (substudy 2).\n\n\nMETHODS\nAll patients received 400 mg RAL twice daily plus 2 nucleoside reverse transcriptase inhibitors. Liver function and immunovirological parameters were monitored throughout the study. Serial blood samples were drawn to explore RAL pharmacokinetics. Plasma concentrations of protein unbound, total RAL, and RAL glucuronide were determined by liquid chromatography-tandem mass spectrometry.\n\n\nRESULTS\nTen patients with ESLD were analyzed in substudy 1. Despite an increased RAL exposure, RAL was well tolerated in all patients and no patient had to stop RAL therapy because of adverse events. Four patients were analyzed in substudy 2. No pharmacokinetic interaction was observed between cyclosporine, mycophenolic acid, and RAL. RAL tolerability was excellent; there were no episodes of acute rejection or opportunistic infection. HIV-RNA levels remained controlled and CD4 cell counts remained stable in all patients throughout the study.\n\n\nCONCLUSIONS\nThe results of the substudy 1 support RAL administration to patients with ESLD. Substudy 2 assesses the safety, tolerability, and efficacy of RAL therapy in HIV-infected patients after liver transplant. RAL might be recommended as a suitable antiretroviral therapy in HIV-infected patients undergoing liver transplant.",
"affiliations": "Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Service de Pharmacie Clinique et Pharmacocinétique, Le Kremlin-Bicêtre Département Hospitalo, Universitaire Hepatinov.;INSERM SC10-US019.;INSERM SC10-US019.;Département Hospitalo, Universitaire Hepatinov AP-HP, Hôpital Paul Brousse, Service de Virologie, Villejuif.;AP-HP, Hôpital Saint-Louis, Service des Maladies Infectieuses et Tropicales et INSERM U941, Université Paris VII Denis Diderot.;Hospices Civils de Lyon, Service des Maladies Infectieuses et Tropicales, Hôpital de la Croix-Rousse et INSERM U1052.;INSERM SC10-US019.;INSERM SC10-US019.;Département Hospitalo, Universitaire Hepatinov AP-HP, Hôpital Bicêtre, Service de Médecine Interne et Maladies Infectieuses, Le Kremlin-Bicêtre.;Département Hospitalo, Universitaire Hepatinov AP-HP, Hôpital Paul Brousse, Centre Hépato-Biliaire et INSERM UMR-S785 Villejuif, France.;Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Bicêtre, Service de Pharmacie Clinique et Pharmacocinétique, Le Kremlin-Bicêtre Département Hospitalo, Universitaire Hepatinov.;Département Hospitalo, Universitaire Hepatinov AP-HP, Hôpital Bicêtre, Service de Médecine Interne et Maladies Infectieuses, Le Kremlin-Bicêtre.",
"authors": "Barau|Caroline|C|;Braun|Joséphine|J|;Vincent|Corine|C|;Haim-Boukobza|Stéphanie|S|;Molina|Jean-Michel|JM|;Miailhes|Patrick|P|;Fournier|Isabelle|I|;Aboulker|Jean-Pierre|JP|;Vittecoq|Daniel|D|;Duclos-Vallée|Jean-Charles|JC|;Taburet|Anne-Marie|AM|;Teicher|Elina|E|;|||",
"chemical_list": "D019380:Anti-HIV Agents; D011760:Pyrrolidinones; D018894:Reverse Transcriptase Inhibitors; D000068898:Raltegravir Potassium",
"country": "United States",
"delete": false,
"doi": "10.1093/cid/ciu515",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1058-4838",
"issue": "59(8)",
"journal": "Clinical infectious diseases : an official publication of the Infectious Diseases Society of America",
"keywords": "HIV; end-stage liver disease; liver transplant; pharmacokinetics; raltegravir",
"medline_ta": "Clin Infect Dis",
"mesh_terms": "D000328:Adult; D019380:Anti-HIV Agents; D002853:Chromatography, Liquid; D064420:Drug-Related Side Effects and Adverse Reactions; D058625:End Stage Liver Disease; D005260:Female; D015658:HIV Infections; D006801:Humans; D008297:Male; D008875:Middle Aged; D010949:Plasma; D011760:Pyrrolidinones; D000068898:Raltegravir Potassium; D018894:Reverse Transcriptase Inhibitors; D053719:Tandem Mass Spectrometry; D016896:Treatment Outcome",
"nlm_unique_id": "9203213",
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"pubdate": "2014-10-15",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
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"title": "Pharmacokinetic study of raltegravir in HIV-infected patients with end-stage liver disease: the LIVERAL-ANRS 148 study.",
"title_normalized": "pharmacokinetic study of raltegravir in hiv infected patients with end stage liver disease the liveral anrs 148 study"
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"abstract": "OBJECTIVE\nThymic malignancies, comprising thymoma and thymic carcinoma, are rare. Consequently, optimal chemotherapy for advanced thymic malignancies remains controversial. Platinum-based chemotherapy is currently the consensus treatment based on the results of single-arm phase II trials and retrospective investigations. However, comparison of cisplatin-based and carboplatin-based chemotherapy has yet to be undertaken; the effectiveness of the addition of anthracycline also remains uncertain.\n\n\nMETHODS\nIn the present study, clinical trials and retrospective data regarding platinum-based chemotherapy were analyzed. The endpoint was the response rate to each chemotherapy. For advanced thymoma, we compared platinum with anthracycline-based chemotherapy and platinum with non-anthracycline-based chemotherapy. For advanced thymic carcinoma, anthracycline-based versus non-anthracycline-based chemotherapy and carboplatin-based versus cisplatin-based chemotherapy were compared. This analysis included a retrospective study of response of advanced thymic carcinoma to irinotecan and cisplatin in our institution.\n\n\nRESULTS\nThe response rate for the 314 patients from 15 studies with advanced thymoma, including both prospective and retrospective data, was 69.4% [95% confidence interval (CI) 63.1-75.0%] for platinum with anthracycline-based chemotherapy and 37.8% (95% CI 28.1-48.6%; p < 0.0001) for platinum with non-anthracycline-based chemotherapy. The response rates after anthracycline-based and non-anthracycline-based chemotherapy for advanced thymic carcinoma were similar (41.8 vs. 40.9%; p < 0.91), whereas the response rates after cisplatin-based and carboplatin-based chemotherapy for advanced thymic carcinoma differed significantly (53.6 vs. 32.8%; p = 0.0029) in 206 patients from 10 studies.\n\n\nCONCLUSIONS\nPlatinum with anthracycline-based chemotherapy is an optimal combination for advanced thymoma. For advanced thymic carcinoma, cisplatin-based chemotherapy may be superior to carboplatin-based chemotherapy.",
"affiliations": "Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo, 113-8677, Japan, y-okuma@cick.jp.",
"authors": "Okuma|Yusuke|Y|;Saito|Makoto|M|;Hosomi|Yukio|Y|;Sakuyama|Toshikazu|T|;Okamura|Tatsuru|T|",
"chemical_list": "D018943:Anthracyclines; D016190:Carboplatin; D002945:Cisplatin",
"country": "Germany",
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"doi": "10.1007/s00432-014-1800-6",
"fulltext": "\n==== Front\nJ Cancer Res Clin Oncol\nJ Cancer Res Clin Oncol\nJournal of Cancer Research and Clinical Oncology\n0171-5216\n1432-1335\nSpringer Berlin Heidelberg Berlin/Heidelberg\n\n25146529\n1800\n10.1007/s00432-014-1800-6\nOriginal Article – Clinical Oncology\nKey components of chemotherapy for thymic malignancies: a systematic review and pooled analysis for anthracycline-, carboplatin- or cisplatin-based chemotherapy\nOkuma Yusuke +81 0338232101 y-okuma@cick.jp\n\n13\nSaito Makoto 2\nHosomi Yukio 1\nSakuyama Toshikazu 3\nOkamura Tatsuru 1\n1 Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, 3-18-22 Honkomagome, Bunkyo, Tokyo, 113-8677 Japan\n2 Division of Clinical Research Support, Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital, Tokyo, Japan\n3 Division of Oncology, Research Center for Medical Sciences, The Jikei University School of Medicine, Tokyo, Japan\n22 8 2014\n22 8 2014\n2015\n141 2 323331\n2 5 2014\n7 8 2014\n© The Author(s) 2014\nOpen AccessThis article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.\nPurpose\n\nThymic malignancies, comprising thymoma and thymic carcinoma, are rare. Consequently, optimal chemotherapy for advanced thymic malignancies remains controversial. Platinum-based chemotherapy is currently the consensus treatment based on the results of single-arm phase II trials and retrospective investigations. However, comparison of cisplatin-based and carboplatin-based chemotherapy has yet to be undertaken; the effectiveness of the addition of anthracycline also remains uncertain.\n\nMethods\n\nIn the present study, clinical trials and retrospective data regarding platinum-based chemotherapy were analyzed. The endpoint was the response rate to each chemotherapy. For advanced thymoma, we compared platinum with anthracycline-based chemotherapy and platinum with non-anthracycline-based chemotherapy. For advanced thymic carcinoma, anthracycline-based versus non-anthracycline-based chemotherapy and carboplatin-based versus cisplatin-based chemotherapy were compared. This analysis included a retrospective study of response of advanced thymic carcinoma to irinotecan and cisplatin in our institution.\n\nResults\n\nThe response rate for the 314 patients from 15 studies with advanced thymoma, including both prospective and retrospective data, was 69.4 % [95 % confidence interval (CI) 63.1–75.0 %] for platinum with anthracycline-based chemotherapy and 37.8 % (95 % CI 28.1–48.6 %; p < 0.0001) for platinum with non-anthracycline-based chemotherapy. The response rates after anthracycline-based and non-anthracycline-based chemotherapy for advanced thymic carcinoma were similar (41.8 vs. 40.9 %; p < 0.91), whereas the response rates after cisplatin-based and carboplatin-based chemotherapy for advanced thymic carcinoma differed significantly (53.6 vs. 32.8 %; p = 0.0029) in 206 patients from 10 studies.\n\nConclusions\n\nPlatinum with anthracycline-based chemotherapy is an optimal combination for advanced thymoma. For advanced thymic carcinoma, cisplatin-based chemotherapy may be superior to carboplatin-based chemotherapy.\n\nKeywords\n\nThymic malignancies\nThymic carcinoma\nThymoma\nRare cancer\nChemotherapy\nissue-copyright-statement© Springer-Verlag Berlin Heidelberg 2015\n==== Body\nIntroduction\n\nStandard chemotherapy for thymomas and thymic carcinomas, collectively called thymic malignancies, remains undefined because of their rarity. For common cancers, standard chemotherapy is determined by means of phase III trials that compare experimental chemotherapy with standard chemotherapy. As is common with rare cancers, evaluation of chemotherapy for thymomas and thymic carcinomas is limited to single-arm phase II trials or retrospective analyses involving small numbers of patients. Therefore, the primary endpoint for clinical trials regarding thymoma and thymic carcinoma is usually response rate and not time to event.\n\nThe pathological classification of such tumors has been confused because of the transition to modern classifications. At present, the 2004 World Health Organization (WHO) classification (Travis et al. 2004) based on clinical prognosis has been agreed by consensus (Huang et al. 2010). Furthermore, thymoma is a functional immunological tumor that retains the immunological characteristics of the thymus, whereas thymic carcinoma is associated with loss of organotypic status. Thymoma and thymic carcinoma are rare cancers with an annual incidence of 1.3 to 3.2/100,000 persons/year (de Jong et al. 2008; Engel et al. 1999; Engels 2010). Based on the definition of the RARECARE project supported by the European Commission, rare cancer has an annual incidence of <6/100,000 persons/year. Standard chemotherapy for advanced thymoma and thymic carcinoma remains controversial because of the limited amount of available therapeutic evidence. However, there is a high level of consensus that the key drugs for the treatment of thymoma are anthracycline and cisplatin (Schmitt and Loehrer 2010), and the chemotherapy administered for thymic carcinoma is generally based on the chemotherapy administered for thymoma. Furthermore, the diagnosis of thymic malignancies is based on modern criteria reported by Bernatz et al. (1961), the Levine and Rosai classification (Levine and Rosai 1978), the Müller-Hermelink classification (1986), the 1999 WHO classification (Rosai 1999) or the 2004 WHO classification (Travis et al. 2004). Recently, prospective and retrospective investigations of chemotherapy for thymic carcinoma have been increasing, but well-designed studies are uncommon and the diagnostic reliability regarding thymic carcinoma is not always high (Weksler et al. 2013; Zucali et al. 2013).\n\nConsequently, we conducted a pooled analysis to extract and compile the data from published reports and to clarify the key drugs used for the treatment of advanced thymoma and thymic carcinoma. Furthermore, our previously published retrospective data regarding the clinical outcome of cisplatin and irinotecan combination chemotherapy for advanced thymic carcinoma have been updated (Okuma et al. 2011).\n\nMethods\n\nSelection criteria for literature and our updated data\n\nA systematic search of the PubMed databases was performed to identify all prospective clinical trials and retrospective studies involving first-line platinum-based chemotherapy for advanced or recurrent thymomas and thymic carcinomas. The search included articles from 1990 to 2013 using the search string “thymoma” OR “thymic carcinoma” AND “chemotherapy.” Among these retrieved articles, non-English language articles, case reports and reviews were excluded. The abstracts of articles of potential relevance were reviewed, and articles that were clearly relevant were selected for further analysis. Additionally, studies presented at the 2013 and 2014 ASCO annual meetings were searched to ensure that the most up-to-date articles were included in the analysis. Unfortunately, clinical trials for thymoma included patients with thymic carcinoma because of the prior criteria for pathological diagnosis. The study included all published reports that contained clinical outcomes of platinum-based combination chemotherapy (cisplatin-based vs. carboplatin-based chemotherapy and anthracycline vs. non-anthracycline combination chemotherapy) for advanced or recurrent thymoma and thymic carcinoma, with some including induction chemotherapy. In the studies regarding induction chemotherapy followed by surgery or radiotherapy, a small number of patients with Masaoka Stage III were included. In such cases, the response rate to chemotherapy alone was reported, and the time to events was ignored.\n\nWe have previously published the outcomes of nine cases of cisplatin and irinotecan combination chemotherapy (Okuma et al. 2011); in addition, we retrospectively assessed 12 such cases up until 2013 in the present study and combined the data with the above published data, including the response rates. A retrospective review was performed to collect data on the outcomes of 12 consecutive patients treated with cisplatin and irinotecan chemotherapy for advanced thymic carcinoma at Masaoka-Koga stage IVa, IVb or recurrent disease. Thymic carcinoma was confirmed by hematoxylin and eosin staining and immunohistochemistry using CD5 and/or CD117 (c-KIT) to exclude other malignant thoracic tumors at the time of initial diagnosis. The pathological review was consistently performed by a specialist in thymic malignancies (T Hishima). Recurrent disease was defined as disease that was not responsive to treatment with curative intent; all patients with recurrent disease were chemotherapy naïve and underwent chemotherapy with palliative intent. Recurrent disease was determined using chest computed tomography, magnetic resonance imaging, positron emission tomography, or bone scanning. Histology was also classified according to the 2004 WHO classification, and staging was determined using the Masaoka-Koga staging system (2010). Data were collected in accordance with the International Thymic Malignancy Interest Group (ITMIG) standard definitions and policies (Girard et al. 2011). The medical records and laboratory data for each patient were retrieved for analysis, and treatments for thymic carcinoma were assessed. Progression-free survival (PFS) was defined as the time from the first cycle of chemotherapy to the first clinical evidence of progressive disease, early discontinuation of treatment or death from any cause. Overall survival (OS) was defined as the time from the first cycle of treatment to the time of death from any cause or the last follow-up. Because of the retrospective nature of the data, these end points were chosen to reflect clinical practice. Assessment of response to chemotherapy was achieved using the Response Evaluation Criteria in Solid Tumors criteria version 1.1 (RECIST 1.1).\n\nPatient selection and statistics\n\nThe criteria for the selection included in these published reports were patients with cytologically or histologically proven advanced or recurrent thymoma or thymic carcinoma, diagnosed using the modern histological classifications. Treatment schedule, response, survival assessment and statistical analyses were performed to the extent that was possible. In all of the identified reports, patients with advanced or recurrent thymic malignancies underwent platinum-based combination chemotherapy with anthracyclines, carboplatin or cisplatin. The treatment response was determined using either RECIST criteria version 1.0, version 1.1., the WHO criteria, or the European Cooperative Oncology Group (ECOG) criteria. The diagnosis was based on modern classifications. Time to event (OS or PFS) was used as an endpoint in the present study as in the published literature; however, the period from the initiation of treatment to the date when disease progression or death was observed was used.\n\nThe proportion of patients having advanced recurrent thymomas or thymic carcinomas, including neuroendocrine carcinoma, and the response rates were compared using the chi-square test. Statistical significance was defined as p < 0.05. Statistical analyses were performed using the JMP11 software program (SAS Institute Inc., Cary, NC, USA).\n\nThe potential for publication bias of the response rates in reported studies was assessed using funnel plots, with appropriate accuracy intervals.\n\nResults\n\nThe process of identifying studies eligible for inclusion in our analysis was as follows: first, we reviewed 57 full articles from 393 published studies and meeting abstracts related to thymomas and excluded 208 case reports and review articles. Of the total 160 published articles and meeting abstracts on thymic carcinoma, we reviewed 78 full articles and excluded 82 case reports and review articles. Of these, 15 studies met the inclusion criteria.\n\nCharacteristics of the selected studies\n\nThe preliminary analysis encompassed 15 studies involving a total of 314 patients with advanced or recurrent thymoma who were treated using platinum with or without anthracycline chemotherapy. In these studies, thymic carcinoma was included because it was considered as being type C thymoma. The studies included ten prospective studies and five retrospective studies (Table 1). In addition, a total of 206 patients with advanced thymic carcinoma were included in a pooled analysis of platinum with or without anthracycline chemotherapy in ten studies, consisting of four prospective studies and six retrospective studies (Tables 2, 3). Table 1 Unified response rates of advanced thymoma patients treated with anthracycline-based or non-anthracycline-based chemotherapy regimens\n\nRegimen\tAuthor, year\tStudy design\tStage\tNo. of patients\tResponders\tRR\tPFS\tOS\t\nAnthracycline-containing regimens\t\nADOC\tFornasiero et al. (1991)\tS\tIII/IVa/IVb\t37\t34\t91.8 %\t12 mos\t15 mos\t\nPAC\tLoehrer et al. (1994)\tG\tIV\t29\t15\t51.7 %\t11.8 mos\t37.7 mos\t\nPAC (+XRT)\tLoehrer et al. (1997)\tG\tIII\t23\t16\t69.6 %\t–\t93 mos\t\nADOC\tRea et al. (1993)\tS\tIII/IVa\t16\t12\t75.0 %\t–\t66 mos\t\nADOC\tBerruti et al. (1999)\tS\tIII/IVa\t16\t13\t81.3 %\t33.2 mos\t47.5 mos\t\nPAC\tKim et al. (2004)\tG\tIII/IVa/IVb\t22\t17\t77.3 %\t–\t–\t\nPAE (+XRT)\tLucchi et al. (2006)\tS\tIII/IVA\t30\t22\t73.3 %\t–\t–\t\nCAMP\tYokoi et al. (2007)\tS\tIVa/IVb\t14\t13\t92.9 %\t–\t–\t\nDose-dense CODE\tKunitoh et al. (2009)\tG\tIVa/IVb\t27\t16\t59.3 %\t0.79 year\t6.1 year\t\nCarboAMR\tKawashima et al. (2013)\tG\tInvasive\t18\t3\t16.7 %\t7.6 mos\tNot reached\t\nTotal\t\t\t\t232\t161\t69.4 %\t\t\t\nNon-anthracycline-containing regimens\t\nPE\tGiaccone et al. (1996)\tG\tIII/IV/rec\t16\t9\t56 %\t2.2 year\t4.3 year\t\nVIP\tLoehrer et al. (2001)\tG\tIII/IVa/IVb\t20\t7\t35 %\t11.9 mos\t31.6 mos\t\nVIP\tGrassin et al. (2011)\tG\tIIIB/IVA/IVB\t16a\t4a\t25 %a\t13.1 mos\tNot reached\t\nCarboPTX\tTakeda et al. (2013)\tG\tIII/IVa/IVb\t21\t6\t42.9 %\t16.7 mos\tNot reached\t\nCDDP/DTX\tPark et al. (2013)\tG\tIII/IVa/IVb\t9\t5\t55.6 %\t–\t–\t\nTotal\t\t\t\t82\t31\t37.8 %\t\t\t\nG prospective multicenter group phase II trial, S single-center experience, mos months, RR objective response rate, ADOC adriamycin, cisplatin, vincristine and cyclophosphamide, PAC cisplatin, adriamycin and cyclophosphamide, PAE cisplatin, adriamycin and etoposide, CAMP PAC = cisplatin, adriamycin, methylprednisolone and cyclophosphamide, CODE adriamycin, cisplatin, vincristine and etoposide, PE cisplatin and etoposide, VIP vincristine, ifosfamide and cisplatin, CarboPTX carboplatin and paclitaxel\n\naIncluding four patients with thymic carcinoma in the VIP trial\n\nTable 2 Unified response rates of advanced thymic carcinoma patients treated with anthracycline-based or non-anthracycline-based chemotherapy regimens\n\nRegimen\tAuthor, year\tStudy design\tStage\tNo. of patients\tResponders\tRR\tPFS (mos)\tMST (mos)\t\nAnthracycline-based chemotherapy\t\nADOC\tAgatsuma et al. (2011)\tS\tIVa/IVb\t34\t17\t50 %\tN/A\t21.3\t\nCODE\tYoh et al. (2003)\tS\tIII/IVa/IVb\t12\t5\t42 %\t5.6\t46\t\nCarboAMRa\tKawashima et al. (2013)\tG\tInvasivea\t33\t11\t30 %\t7.6\t27.3\t\nTotal\t\t\t\t79\t33\t41.8 %\t\t\t\nNon-anthracycline-based chemotherapy\t\nVIP\tGrassin et al. (2011)\tS\tIII/IVa/IVb\t8\t2\t25 %\t–\t–\t\nCarboPTX\tLemma et al. (2011)\tG\tIII/IVa/IVb\t23\t5\t21.7 %\t5.0\t20.0\t\nCarboPTX\tIgawa et al. (2010)\tS\tIVa/IVb\t11\t4\t36 %\t7.9\t22.7\t\nCarboPTX\tTakeda et al. (2013)\tG\tIII/IVa/IVb\t39\t14\t35.9 %\t7.52\tNot reached\t\nCarboPTX\tFurugen et al. (2011)\tS\tIVa/IVb/rec\t16\t6\t37.5 %\t8.6\t49.4\t\nCDDP/DTXb\tPark et al. (2013)\tG\tIII/IVa\t18\t12\t66.7 %\t–\t–\t\nCDDP/CPT-11\tPresent study\tS\tIVa/IVb/rec\t12\t9\t75.0 %\t7.4\t52.4\t\nTotal\t\t\t\t127\t52\t40.9 %\t\t\t\nG prospective multicenter group phase II trial, S single-center experience, RR response rate, PFS progression-free survival, OS overall survival, ADOC adriamycin, cisplatin, vincristine and cyclophosphamide, CODE adriamycin, cisplatin, vincristine and etoposide, CarboAMR carboplatin and amrubicin, CarboPTX carboplatin and paclitaxel, CDDP/CPT-11 cisplatin and irinotecan, CDDP/DTX cisplatin/docetaxel\n\naThe subset for thymic carcinoma\n\nbThe accrual criteria were defined as “invasive” thymoma or thymic carcinoma, not according to any defined staging system. The chemotherapeutic setting was within the two previous regimens\n\nTable 3 Unified response rates of advanced thymic carcinoma patients treated with cisplatin-based or carboplatin-based chemotherapy regimens\n\nRegimen\tAuthor, year\tStudy design\tStage\tNo. of patients\tResponders\tRR\tPFS (mos)\tMST (mos)\t\nCisplatin-based chemotherapy\t\nADOC\tAgatsuma et al. (2011)\tS\tIVa/IVb\t34\t17\t50 %\tN/A\t21.3\t\nCODE\tYoh et al. (2003)\tS\tIII/IVa/IVb\t12\t5\t42 %\t5.6\t46\t\nVIP\tGrassin et al. (2011)\tS\tIII/IVa/IVb\t8\t2\t25 %\t–\t–\t\nCDDP/DTXa\tPark et al. (2013)\tG\tIII/IVa\t18\t12\t66.7 %\t–\t–\t\nCDDP/CPT-11\tPresent study\tS\tIVa/IVb/rec\t12\t9\t75.0 %\t7.4\t52.4\t\nTotal\t\t\t\t84\t45\t53.6 %\t\t\t\nCarboplatin-based chemotherapy\t\nCarboPTX\tLemma et al. (2011)\tG\tIII/IVa/IVb\t23\t5\t21.7 %\t5.0\t20.0\t\nCarboPTX\tIgawa et al. (2010)\tS\tIVa/IVb\t11\t4\t36 %\t7.9\t22.7\t\nCarboPTX\tTakeda et al. (2013)\tG\tIII/IVa/IVb\t39\t14\t35.9 %\t7.52\tNot reached\t\nCarboPTX\tFurugen et al. (2011)\tS\tIVa/IVb/rec\t16\t6\t37.5 %\t8.6\t49.4\t\nCarboAMRa\tKawashima et al. (2013)\tG\tInvasivea\t33\t11\t30 %\t7.6\t27.3\t\nTotal\t\t\t\t122\t40\t32.8 %\t\t\t\nG prospective multicenter group phase II trial, S single-center experience, RR response rate, PFS progression-free survival, OS overall survival, ADOC adriamycin, cisplatin, vincristine and cyclophosphamide, CODE adriamycin, cisplatin, vincristine and etoposide, CarboAMR carboplatin and amrubicin, CarboPTX carboplatin and paclitaxel, CDDP/CPT-11 cisplatin and irinotecan, CDDP/DTX cisplatin/docetaxel\n\naThe subset for thymic carcinoma\n\nA total of 12 patients who were treated with cisplatin and irinotecan combination chemotherapy as palliative-intent chemotherapy were also evaluated. Nine partial responses (75.0 %) and two stable diseases [16.7 %; total disease control was observed in 11 patients (91.7 %)] were recorded. One patient had progressive disease. There were no complete responders. The median PFS was 7.4 months [95 % confidence interval (CI) 2.2–9.2 months), while the median OS was 52.4 months (95 % CI 9.4–114.2 months). The 1- and 2-year survival rates based on the Kaplan–Meier analysis were 88.9 and 66.7 %, respectively.\n\nResponse to platinum-based chemotherapy in advanced thymoma and thymic carcinoma\n\nThe response rate of thymoma to anthracycline-based chemotherapy was 69.4 % (95 % CI 63.1–75.0 %) and 37.8 % (95 % CI 28.1–48.6 %) to non-anthracycline-based chemotherapy. The difference in the response rates between anthracycline-based chemotherapy and non-anthracycline-based chemotherapy with cisplatin was statistically significant (χ 2 test; p < 0.0001). The response rates of thymic carcinoma to anthracycline-based chemotherapy were 41.8 % (95 % CI 31.5–52.8 %) and 40.9 % (95 % CI 32.8–49.6 %) to non-anthracycline-based chemotherapy (Table 2); there was no significant difference in the response rates (χ 2 test; p < 0.82). The response rates of thymic carcinoma were 53.6 % (95 % CI 43.0–63.8 %) to cisplatin-based chemotherapy and 32.8 % (95 % CI 25.1–41.5 %) to carboplatin-based chemotherapy (Table 3); the difference in the response rates was significant (χ 2 test; p = 0.0029).\n\nPublication bias\n\nPotential publication bias was assessed using funnel plots with response rates as the outcome. The funnel plots were basically symmetrical for each of the regimen categories (Fig. 1), indicating a lack of publication bias. However, in category (A) for anthracycline-based chemotherapy for thymoma, two outliers (Fornasiero et al. 1991; Kawashima et al. 2013) from the 95 % tolerance limit were observed. We repeated our analyses excluding these two studies, the response rate in the anthracycline regimen for thymoma was 59.8 %, and the chi-square test still demonstrated a significant difference (p < 0.0001).Fig. 1 Funnel plots using response rates as an outcome for a, b thymoma and c–f thymic carcinoma in each chemotherapy category (anthracycline-based vs. non-anthracycline-based and cisplatin-based vs. carboplatin-based)\n\nDiscussion\n\nOur pooled analysis demonstrated that anthracycline-based chemotherapies involving cisplatin appeared to play a key role in improving the response rate of advanced thymoma. In addition, the response rate of advanced thymic carcinoma was significantly higher with cisplatin-based chemotherapy than with carboplatin-based chemotherapy; however, no significant difference in response rates was found between anthracycline-containing regimens and non-anthracycline-containing regimens using platinum-based chemotherapies.\n\nPlatinum-based chemotherapy in combination with anthracycline has been suggested as the key regimen for the treatment of advanced thymoma and thymic carcinoma. However, only a small number of patients have been enrolled in phase II trials or retrospective studies regarding the evaluation of therapeutic efficacy. Moreover, until the advent of the 2004 WHO classification, thymoma and thymic carcinoma were not clearly distinguished. However, recent studies have revealed these two carcinomas are different clinical entities in terms of biobehavior and biomarkers (Monica et al. 2013) and clinical outcomes. Therefore, the efficacy of chemotherapy may differ as well; however, the utility of chemotherapy itself remains unclear because none of the trials compared chemotherapy with best supportive care. The present study focused on clarifying the key drugs regarding the treatment of advanced thymic carcinoma. Einhorn’s protocol, which consists of a cisplatin- and anthracycline-based triplet or quartet regimen, such as ADOC (cisplatin, doxorubicin, vincristine and cyclophosphamide) (Fornasiero et al. 1991) or PAC (cisplatin, cyclophosphamide and adriamycin) (Loehrer et al. 1997), is conventionally used for invasive thymoma. The response rates of first-line chemotherapies for thymoma have been compared in phase II trials, and cisplatin and anthracycline have been considered the key drugs. Actually, cisplatin and anthracycline-containing regimens for thymoma have achieved significantly higher response rates than non-anthracycline regimens (Table 1). A dose-dense chemotherapy regimen for thymoma has not always improved efficacy (Kunitoh et al. 2009).\n\nChemotherapy regimens designed for the treatment of thymoma have also been used for thymic carcinoma. Only two prospective studies have assessed carboplatin and paclitaxel as palliative-intent chemotherapy for advanced stage disease, and one study has assessed induction chemotherapy (Lemma et al. 2011; Park et al. 2013; Takeda et al. 2013). The response rate achieved with carboplatin and paclitaxel was 30–40 %, whereas induction chemotherapy followed by curative-intent treatments involving cisplatin and docetaxel combination chemotherapy achieved a 66.7 % response rate in the subset of patients with thymic carcinoma (Park et al. 2013). Carboplatin-based chemotherapy is broadly used as a combination regimen with less nausea and vomiting or nephrotoxicity than that was reported in the early 2000s. However, more effective anti-emetic agents have recently become available, and consequently, cisplatin-based combination chemotherapy has become more easily available. Therefore, further clinical trials should evaluate cisplatin-based chemotherapy for thymic carcinoma. At present, any platinum-based doublet chemotherapy seems appropriate with the view of maximizing the PFS of patients with thymic carcinoma (Table 2).\n\nThe present analysis updated the data regarding the clinical outcome of patients with advanced thymic carcinoma treated using cisplatin and irinotecan, including both squamous cell carcinoma and neuroendocrine carcinoma subtypes, with a response rate of 66.7 %. In the WJTOG 4207L trial, half of the patients were re-diagnosed as having neuroendocrine carcinoma. In thymic squamous cell carcinoma, positivity for biomarkers of neuroendocrine carcinoma, such as synaptophysin, neuron-specific enolase, chromogranin A and CD57, has been previously documented (Lauriola et al. 1998). Cisplatin and irinotecan combination chemotherapy will be one of the choices for treatment as it covers a broad spectrum of subtypes as has been proven to be the case in lung cancer (Noda et al. 2002; Ohe et al. 2007).\n\nThe accurate diagnosis of thymoma and thymic carcinoma has recently been discussed as being crucial with regard to the proof of the efficacy of chemotherapy for these rare cancers. Mismatched diagnoses have been suspected in another clinical trial involving rare cancers, the multi-institutional clinical trial regarding imatinib treatment for c-KIT or platelet-derived growth factor receptor (PDGFR)-positive sarcoma (Sugiura et al. 2010). In this trial, the concordance rate between the trial sites and the central review involving immunohistochemical staining was 63.3 %. The results of such studies must be carefully interpreted because a few diagnostic errors in phase II studies with small sample sizes will result in a lack of power to test statistical hypotheses. Investigators who plan clinical trials involving thymic malignancies should incorporate a central review by reliable pathologists who have experience with thymic malignancies. Large-scale regional databases are being established in the USA, Europe and Japan as the first step to curative treatment for thymoma and thymic carcinoma (Detterbeck et al. 2013). This approach appears to be a role model for rare diseases, and the process of establishing databases will help to clarify diagnostic problems. In fact, the WJTOG 4207L trial demonstrated that in 25 % of patients the diagnosis differed between local and central review(Takeda et al. 2013). In thymic malignancies, the reproducibility of pathological diagnosis was examined in an Italian study (Zucali et al. 2013). Clinical trials of rare cancers are limited in that only small numbers of patients can be enrolled. Consequently, misdiagnosis of some patients will invalidate the results of the clinical trial. In common cancers, multi-institutional clinical trials provide a higher level of evidence than trials incorporating a single or a few institutions. However, the opposite is potentially true of clinical trials involving rare cancers. Up to 20 % of thymic malignancies are difficult to diagnose and are termed “borderline.” In fact, diagnostic agreement regarding surgical specimens was low (Zucali et al. 2013). In advanced thymic carcinoma, clinicians should note that the patients are usually diagnosed based on the examination of needle biopsy specimens. As this previous study demonstrated, diagnostic differences occurred among type A thymoma and thymic carcinoma patients (Zucali et al. 2013). Moreover, differentiating between type B thymoma and thymic carcinoma has been difficult for pathologists. In patients with type B3 thymoma, previously called “well-differentiated thymic carcinoma,” the median survival time was 99 months (95 % CI 63.4–134.6), whereas it was 48 months (95 % CI 38.4–94.1; p < 0.001) in patients with thymic carcinoma (Gao et al. 2013). Since the key drugs used for the treatment of thymoma and thymic carcinoma can differ, it is important to have the correct diagnosis to choose the optimal therapy.\n\nThe current study had a number of limitations. They included the use of mixed data from prospective and retrospective studies with different criteria, including variations in the precise histological classification of subtypes, staging or assessment criteria. Moreover, detailed patient characteristics could not be completely extracted. However, this is a common limitation in such studies involving small numbers of patients with rare cancers. Furthermore, it was not possible to include time-to-event endpoints, such as progression-free survival and overall survival, in the analysis since individual data regarding chemotherapy for thymomas and thymic carcinomas were not available. It is recommended that the efficacy of chemotherapy be evaluated using time to event, and not only tumor response endpoints (Anderson et al. 1983). Therefore, an optimal chemotherapy regimen for advanced thymomas and thymic carcinomas has still not been established. Medical oncologists should choose the chemotherapy for thymoma and thymic carcinoma based on the treatment setting and/or consideration of the side effects of the chemotherapy. Moreover, there exists a potential publication. For instance, two published studies lay outside the 95 % tolerance limit of the pooled estimate. The reasons for this may be attributed to the following: (1) The study by Fornasiero et al., which was the higher outlier, was the oldest study performed at a single institution. However, prospective studies demonstrated a similar response rate for thymoma (75 and 81.3 %); (2) the study by Kawashima et al. was the only study using amrubicin as anthracycline. Amrubicin is the only totally chemically synthesized anthracycline and commonly inhibits topoisomerase II enzyme; however, the other mechanisms of action for its anticancer activity are speculated to differ as it has weaker DNA intercalation activity than the other anthracycline agents (Noguchi et al. 2005). Therefore, amrubicin may not be the best drug choice for thymic malignancies.\n\nIn conclusion, the present pooled analysis demonstrated that platinum with anthracycline-based chemotherapy is an optimal combination for the treatment of advanced thymoma. For advanced thymic carcinoma, cisplatin-based chemotherapy may be superior to carboplatin-based chemotherapy.\n\nThe authors thank Eisei Oda, Ph.D., the biostatistician at Medical TOUKEI Corporation, for statistical advice regarding publication bias.\n\nConflict of interest\n\nNone.\n==== Refs\nReferences\n\nAgatsuma T Koizumi T Kanda S Ito M Urushihata K Yamamoto H Hanaoka M Kubo K Combination chemotherapy with doxorubicin, vincristine, cyclophosphamide, and platinum compounds for advanced thymic carcinoma J Thorac Oncol 2011 6 12 2130 2134 10.1097/JTO.0b013e31822e71c0 21892103\nAnderson JR Cain KC Gelber RD Analysis of survival by tumor response J Clin Oncol 1983 1 11 710 719 6668489\nBernatz PE Harrison EG Clagett OT Thymoma: a clinicopathologic study J Thorac Cardiovasc Surg 1961 42 424 444 13868094\nBerruti A Borasio P Gerbino A Gorzegno G Moschini T Tampellini M Ardissone F Brizzi MP Dolcetti A Dogliotti L Primary chemotherapy with adriamycin, cisplatin, vincristine and cyclophosphamide in locally advanced thymomas: a single institution experience Br J Cancer 1999 81 5 841 845 10.1038/sj.bjc.6690773 10555755\nde Jong WK Blaauwgeers JL Schaapveld M Timens W Klinkenberg TJ Groen HJ Thymic epithelial tumours: a population-based study of the incidence, diagnostic procedures and therapy Eur J Cancer 2008 44 1 123 130 10.1016/j.ejca.2007.11.004 18068351\nDetterbeck FC Asamura H Crowley J Falkson C Giaccone G Giroux D Huang J Kim J Kondo K Lucchi M Marino M Marom EM Nicholson A Okumura M Ruffini E van Schil P Stratton K Staging, Prognostic Factors CMembers of the Advisory BParticipating Institutions of the Thymic D The IASLC/ITMIG thymic malignancies staging project: development of a stage classification for thymic malignancies J Thorac Oncol 2013 8 12 1467 1473 10.1097/JTO.0000000000000017 24389429\nEngel P Marx A Muller-Hermelink HK Thymic tumours in Denmark. A retrospective study of 213 cases from 1970-1993 Pathol Res Pract 1999 195 8 565 570 10.1016/S0344-0338(99)80006-5 10483587\nEngels EA Epidemiology of thymoma and associated malignancies J Thorac Oncol 2010 5 10 Suppl 4 S260 S265 10.1097/JTO.0b013e3181f1f62d 20859116\nFornasiero A Daniele O Ghiotto C Piazza M Fiore-Donati L Calabro F Rea F Fiorentino MV Chemotherapy for invasive thymoma. A 13-year experience Cancer 1991 68 1 30 33 10.1002/1097-0142(19910701)68:1<30::AID-CNCR2820680106>3.0.CO;2-4 2049749\nFurugen M Sekine I Tsuta K Horinouchi H Nokihara H Yamamoto N Kubota K Tamura T Combination chemotherapy with carboplatin and paclitaxel for advanced thymic cancer Jpn J Clin Oncol 2011 41 8 1013 1016 10.1093/jjco/hyr089 21742653\nGao L Wang C Fang W Zhang J Lv C Fu S Outcome of multimodality treatment for 188 cases of type b3 thymoma J Thorac Oncol 2013 8 10 1329 1334 10.1097/JTO.0b013e31829ceb50 24457243\nGiaccone G Ardizzoni A Kirkpatrick A Clerico M Sahmoud T van Zandwijk N Cisplatin and etoposide combination chemotherapy for locally advanced or metastatic thymoma. A phase II study of the European Organization for Research and Treatment of Cancer Lung Cancer Cooperative Group J Clin Oncol 1996 14 3 814 820 8622029\nGirard N Lal R Wakelee H Riely GJ Loehrer PJ Chemotherapy definitions and policies for thymic malignancies J Thorac Oncol 2011 6 7 Suppl 3 S1749 S1755 10.1097/JTO.0b013e31821ea5f7 21847058\nGrassin F Paleiron N Andre M Caliandro R Bretel JJ Terrier P Margery J Le Chevalier T Ruffie P Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma. A French experience J Thorac Oncol 2011 5 6 893 897 10.1097/JTO.0b013e3181db3dee\nHuang J Detterbeck FC Wang Z Loehrer PJ Sr Standard outcome measures for thymic malignancies J Thorac Oncol 2010 5 12 2017 2023 10.1097/JTO.0b013e3181f13682 20978450\nIgawa S Murakami H Takahashi T Nakamura Y Tsuya A Naito T Kaira K Ono A Shukuya T Tamiya A Endo M Yamamoto N Efficacy of chemotherapy with carboplatin and paclitaxel for unresectable thymic carcinoma Lung Cancer 2010 67 2 194 197 10.1016/j.lungcan.2009.03.031 19409644\nKawashima Y, Inoue A, Sugawara S, Harada M, Kobayashi K, Kozuki T, Kuyama S, Sakakibara T, Maemondo M, Asahina H, Hisamoto A, Nakagawa T, Nukiwa T (2013) Phase II study of amrubicin (AMR) and carboplatin (CBDCA) for invasive thymoma (IT) and thymic carcinoma (TC): NJLCG0803. ASCO Meeting Abstracts 31(15_suppl):7530\nKim ES Putnam JB Komaki R Walsh GL Ro JY Shin HJ Truong M Moon H Swisher SG Fossella FV Khuri FR Hong WK Shin DM Phase II study of a multidisciplinary approach with induction chemotherapy, followed by surgical resection, radiation therapy, and consolidation chemotherapy for unresectable malignant thymomas: final report Lung Cancer 2004 44 3 369 379 10.1016/j.lungcan.2003.12.010 15140551\nKunitoh H Tamura T Shibata T Nakagawa K Takeda K Nishiwaki Y Osaki Y Noda K Yokoyama A Saijo N Jcog Lung Cancer Study Group TJ A phase-II trial of dose-dense chemotherapy in patients with disseminated thymoma: report of a Japan Clinical Oncology Group trial (JCOG 9605) Br J Cancer 2009 101 9 1549 1554 10.1038/sj.bjc.6605347 19809436\nLauriola L Erlandson RA Rosai J Neuroendocrine differentiation is a common feature of thymic carcinoma Am J Surg Pathol 1998 22 9 1059 1066 10.1097/00000478-199809000-00003 9737237\nLemma GL Lee JW Aisner SC Langer CJ Tester WJ Johnson DH Loehrer PJ Sr Phase II study of carboplatin and paclitaxel in advanced thymoma and thymic carcinoma J Clin Oncol 2011 29 15 2060 2065 10.1200/JCO.2010.32.9607 21502559\nLevine GD Rosai J Thymic hyperplasia and neoplasia: a review of current concepts Hum Pathol 1978 9 5 495 515 10.1016/S0046-8177(78)80131-2 361541\nLoehrer PJ Sr, Kim K, Aisner SC, Livingston R, Einhorn LH, Johnson D, Blum R (1994) Cisplatin plus doxorubicin plus cyclophosphamide in metastatic or recurrent thymoma: final results of an intergroup trial. The Eastern Cooperative Oncology Group, Southwest Oncology Group, and Southeastern Cancer Study Group. J Clin Oncol 12(6):1164–1168\nLoehrer PJ Sr Chen M Kim K Aisner SC Einhorn LH Livingston R Johnson D Cisplatin, doxorubicin, and cyclophosphamide plus thoracic radiation therapy for limited-stage unresectable thymoma: an intergroup trial J Clin Oncol 1997 15 9 3093 3099 9294472\nLoehrer PJ Sr Jiroutek M Aisner S Aisner J Green M Thomas CR Jr Livingston R Johnson DH Combined etoposide, ifosfamide, and cisplatin in the treatment of patients with advanced thymoma and thymic carcinoma: an intergroup trial Cancer 2001 91 11 2010 2015 10.1002/1097-0142(20010601)91:11<2010::AID-CNCR1226>3.0.CO;2-2 11391579\nLucchi M Melfi F Dini P Basolo F Viti A Givigliano F Angeletti CA Mussi A Neoadjuvant chemotherapy for stage III and IVA thymomas: a single-institution experience with a long follow-up J Thorac Oncol 2006 1 4 308 313 10.1097/01243894-200605000-00007 17409875\nMasaoka A Staging system of thymoma J Thorac Oncol 2010 5 10 Suppl 4 S304 S312 10.1097/JTO.0b013e3181f20c05 20859124\nMonica V Familiari U Chiusa L Rossi G Novero D Busso S Ruffini E Ardissone F Scagliotti GV Papotti M Messenger RNA and protein expression of thymidylate synthase and DNA repair genes in thymic tumors Lung Cancer 2013 79 3 228 235 10.1016/j.lungcan.2012.12.003 23276504\nMuller-Hermelink HK Marino M Palestro G Pathology of thymic epithelial tumors Curr Top Pathol 1986 75 207 268 10.1007/978-3-642-82480-7_7 3514160\nNoda K Nishiwaki Y Kawahara M Negoro S Sugiura T Yokoyama A Fukuoka M Mori K Watanabe K Tamura T Yamamoto S Saijo N Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer N Engl J Med 2002 346 2 85 91 10.1056/NEJMoa003034 11784874\nNoguchi T, Hanada M, Yamaoka T (2005) Development of a novel anti-tumor drug ‘amrubicin’, a completely synthetic anthracycline. SUMITOMO KAGAKU 2005-II:1–11\nOhe Y Ohashi Y Kubota K Tamura T Nakagawa K Negoro S Nishiwaki Y Saijo N Ariyoshi Y Fukuoka M Randomized phase III study of cisplatin plus irinotecan versus carboplatin plus paclitaxel, cisplatin plus gemcitabine, and cisplatin plus vinorelbine for advanced non-small-cell lung cancer: Four-Arm Cooperative Study in Japan Ann Oncol 2007 18 2 317 323 10.1093/annonc/mdl377 17079694\nOkuma Y Hosomi Y Takagi Y Iguchi M Okamura T Shibuya M Cisplatin and irinotecan combination chemotherapy for advanced thymic carcinoma: evaluation of efficacy and toxicity Lung Cancer 2011 74 3 492 496 10.1016/j.lungcan.2011.05.013 21665316\nPark S Ahn MJ Ahn JS Sun JM Shim YM Kim J Choi YS Kim K Shin S Ahn Y Kwon OJ Kim H Lee SJ Chang WJ Park K A prospective phase II trial of induction chemotherapy with docetaxel/cisplatin for Masaoka stage III/IV thymic epithelial tumors J Thorac Oncol 2013 8 7 959 966 10.1097/JTO.0b013e318292c41e 23722169\nRea F Sartori F Loy M Calabro F Fornasiero A Daniele O Altavilla G Chemotherapy and operation for invasive thymoma J Thorac Cardiovasc Surg 1993 106 3 543 549 8361199\nRosai J (1999) Histological typing of tumours of the thymus. In: World Health Organization International Histological Classification of Tumours. Springer, Berlin\nSchmitt J Loehrer PJ Sr The role of chemotherapy in advanced thymoma J Thorac Oncol 2010 5 10 Suppl 4 S357 S360 10.1097/JTO.0b013e3181f21129 20859133\nSugiura H Fujiwara Y Ando M Kawai A Ogose A Ozaki T Yokoyama R Hiruma T Ishii T Morioka H Mugishima H Multicenter phase II trial assessing effectiveness of imatinib mesylate on relapsed or refractory KIT-positive or PDGFR-positive sarcoma J Orthop Sci 2010 15 5 654 660 10.1007/s00776-010-1506-9 20953927\nTakeda K, Hirai F, Yamanaka T, Taguchi K, Daga H, Shimizu J, Kogure Y, Kimura T, Tanaka K, Iwamoto Y, Ono A, Sasaki H, Fukuoka J, Nishiyama K, Seto T, Ichinose Y, Nakagawa K, Nakanishi Y, West Japan Oncology Group (2013) A multicenter prospective study of carboplatin and paclitaxel for advanced thymic carcinoma: West Japan Oncology Group 4207L. ASCO Meeting Abstracts 31(15_suppl):7529\nTravis W, Brambilla W, Müller-Hermelink H, Harris C (2004) World Health Organization classification of tumors. Pathology and genetics of tumors of the lung, pleura, thymus and heart. Chapter 3. IARC press, Lyon\nWeksler B Dhupar R Parikh V Nason KS Pennathur A Ferson PF Thymic carcinoma: a multivariate analysis of factors predictive of survival in 290 patients Ann Thorac Surg 2013 95 1 299 303 10.1016/j.athoracsur.2012.09.006 23141529\nYoh K Goto K Ishii G Niho S Ohmatsu H Kubota K Kakinuma R Nagai K Suga M Nishiwaki Y Weekly chemotherapy with cisplatin, vincristine, doxorubicin, and etoposide is an effective treatment for advanced thymic carcinoma Cancer 2003 98 5 926 931 10.1002/cncr.11606 12942558\nYokoi K Matsuguma H Nakahara R Kondo T Kamiyama Y Mori K Miyazawa N Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone J Thorac Oncol 2007 2 1 73 78 10.1097/JTO.0b013e31802bafc8 17410014\nZucali PA Di Tommaso L Petrini I Battista S Lee HS Merino M Lorenzi E Voulaz E De Vincenzo F Simonelli M Roncalli M Giordano L Alloisio M Santoro A Giaccone G Reproducibility of the WHO classification of thymomas: practical implications Lung Cancer 2013 79 3 236 241 10.1016/j.lungcan.2012.11.015 23279873\n\n",
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"issue": "141(2)",
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"medline_ta": "J Cancer Res Clin Oncol",
"mesh_terms": "D018943:Anthracyclines; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002945:Cisplatin; D002986:Clinical Trials as Topic; D006801:Humans; D011379:Prognosis; D013953:Thymus Neoplasms",
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"title": "Key components of chemotherapy for thymic malignancies: a systematic review and pooled analysis for anthracycline-, carboplatin- or cisplatin-based chemotherapy.",
"title_normalized": "key components of chemotherapy for thymic malignancies a systematic review and pooled analysis for anthracycline carboplatin or cisplatin based chemotherapy"
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"abstract": "Reactivation of hepatitis B viral infection (HBVr) is a known risk in cancer patients with a history of chronic hepatitis B infection receiving cytotoxic or immunosuppressive therapies. Patients with hematologic malignancies or those who have received stem cell transplantation seem to be most at risk but reactivation has been reported with various malignancies. Reactivation can present as asymptomatic liver function test abnormalities (LFTs), with symptoms of abdominal pain, encephalopathy, or as fulminant hepatitis and liver failure. Here we report the first case of a patient with islet cell tumor on octreotide and sirolimus who developed hepatitis B reactivation with fulminant liver failure and death.",
"affiliations": "Department of Medicine, Memorial Sloan Kettering Cancer Center, Gastroenterology and Nutrition Service, New York, NY 10065, USA.;Department of Medicine, Memorial Sloan Kettering Cancer Center, Gastroenterology and Nutrition Service, New York, NY 10065, USA.",
"authors": "DeFilippis|Ersilia M|EM|;Ludwig|Emmy|E|",
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"issue": "6(5)",
"journal": "Journal of gastrointestinal oncology",
"keywords": "Hepatitis B; antiviral agents; islet cell; octreotide; sirolimus",
"medline_ta": "J Gastrointest Oncol",
"mesh_terms": null,
"nlm_unique_id": "101557751",
"other_id": null,
"pages": "E66-9",
"pmc": null,
"pmid": "26487953",
"pubdate": "2015-10",
"publication_types": "D016428:Journal Article",
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"title": "Fatal hepatitis B reactivation in a patient with islet cell tumor on octreotide and sirolimus.",
"title_normalized": "fatal hepatitis b reactivation in a patient with islet cell tumor on octreotide and sirolimus"
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"abstract": "Blunt traumatic cardiac rupture is an uncommon event in trauma and survival is rare. While multiple isolated accounts of repair of blunt cardiac rupture have been reported in the literature, there is not a single report of survival from right ventricular rupture following an emergency department thoracotomy (EDT). We report 2 cases where patients have survived such injuries and have made a full recovery. These patients are from a single institution who lost pulses on arrival to the emergency department; then underwent EDT with relief of cardiac tamponade with hemorrhage control by temporary closure, and subsequent definitive repair of right ventricular rupture in the operating room. Both were multiply injured and survived to discharge without neurologic sequelae and have made a full recovery back to their baseline function. This setting may represent an important use of EDT among blunt trauma patients, where time to survival and recovery may dependent on the speed of hemorrhage control and return of cardiac activity.",
"affiliations": "Ocala Health Trauma, Ocala Regional Medical Center, Ocala, FL, USA.;Ocala Health Trauma, Ocala Regional Medical Center, Ocala, FL, USA.;Ocala Health Trauma, Ocala Regional Medical Center, Ocala, FL, USA.;Ocala Health Trauma, Ocala Regional Medical Center, Ocala, FL, USA.",
"authors": "Weber|Courtney|C|;Farrah|Jason|J|;Garcia|Alejandro|A|;Ang|Darwin|D|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1177/0003134820919731",
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"issue": "86(5)",
"journal": "The American surgeon",
"keywords": "blunt cardiac rupture; blunt traumatic cardiac injury; emergency department; emergency department thoracotomy; resuscitative emergency department thoracotomy; thoracotomy survival; traumatic cardiac injury; traumatic cardiac rupture",
"medline_ta": "Am Surg",
"mesh_terms": "D000368:Aged; D004636:Emergency Service, Hospital; D004638:Emergency Treatment; D005260:Female; D006335:Heart Injuries; D006801:Humans; D008297:Male; D008875:Middle Aged; D012074:Remission Induction; D013908:Thoracotomy; D014949:Wounds, Nonpenetrating",
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"pubdate": "2020-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A First Report: Two Cases of Survival and Full Recovery After Blunt Cardiac Rupture Requiring Emergency Department Thoracotomy.",
"title_normalized": "a first report two cases of survival and full recovery after blunt cardiac rupture requiring emergency department thoracotomy"
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"abstract": "Ovarian cancer is the seventh most common type of cancer and the fifth leading cause of cancer death among women worldwide. The current usual therapeutic approach in this disease includes optimal cytoreductive therapy followed by platinum-based adjuvant chemotherapy, along with neoadjuvant chemotherapy prior to surgery in selected cases. The platinum-free interval (PFI) continues to be the most useful tool to assist in the selection of the subsequent therapy and to predict response to treatment. The combination of trabectedin and pegylated liposomal doxorubicin (PLD) is useful in patients with partially platinum-sensitive recurrent ovarian cancer, in patients who have previously received two or more platinum-based chemotherapy regimens, in patients who have already experienced a platinum-induced hypersensitivity reaction and in patients who have previously failed to respond to a platinum-based treatment.\nA 64-years-old postmenopausal woman with pain, abdominal distension, and an altered intestinal transit and with partially platinum-sensitive recurrent ovarian cancer, was successfully treated with a second line of trabectedin chemotherapy in combination with PLD, followed by trabectedin in monotherapy. This case proves the effectiveness of the combination of trabectedin and PLD and demonstrates how the administration of trabectedin, even in monotherapy, allows to maintain an adequate clinical response with good tolerance to the treatment during more than two years of drug administration.",
"affiliations": "Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.;Radiodiagnosis Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.;Medical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.;Gynecology Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.;Digestive and General Surgery Department, Hospital Universitario Ramón y Cajal, Madrid, Spain.;Pathological Anatomy, Hospital Universitario Ramón y Cajal, Madrid, Spain.",
"authors": "Guerra Alía|Eva María|EM|;Sempere Ortega|Cayetano|C|;Cortés Salgado|Alfonso|A|;Sanchez Martínez|Concepción|C|;Galindo Álvarez|Julio|J|;Pérez Miez|Belén|B|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH-4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000500411cro-0012-0447Case ReportMaintenance with Trabectedin in the Treatment of Platinum-Sensitive Recurrent Ovarian Cancer Guerra Alía Eva María a*Sempere Ortega Cayetano bCortés Salgado Alfonso aSanchez Martínez Concepción cGalindo Álvarez Julio dPérez Miez Belén eaMedical Oncology Department, Hospital Universitario Ramón y Cajal, Madrid, SpainbRadiodiagnosis Department, Hospital Universitario Ramón y Cajal, Madrid, SpaincGynecology Department, Hospital Universitario Ramón y Cajal, Madrid, SpaindDigestive and General Surgery Department, Hospital Universitario Ramón y Cajal, Madrid, SpainePathological Anatomy, Hospital Universitario Ramón y Cajal, Madrid, Spain*Eva María Guerra Alía, Department of Medical Oncology, Breast and Gynecologic Tumor Unit, Hospital Ramón y Cajal, Ctra. Colmenar Viejo, km 9, 100, ES–28034 Madrid (Spain), E-Mail eva_m_guerra@hotmail.comMay-Aug 2019 13 6 2019 13 6 2019 12 2 447 455 11 4 2019 12 4 2019 2019 Copyright © 2019 by S. Karger AG, Basel2019This article is licensed under the Creative Commons Attribution-NonCommercial-4.0 International License (CC BY-NC) (http://www.karger.com/Services/OpenAccessLicense). Usage and distribution for commercial purposes requires written permission.Ovarian cancer is the seventh most common type of cancer and the fifth leading cause of cancer death among women worldwide. The current usual therapeutic approach in this disease includes optimal cytoreductive therapy followed by platinum-based adjuvant chemotherapy, along with neoadjuvant chemotherapy prior to surgery in selected cases. The platinum-free interval (PFI) continues to be the most useful tool to assist in the selection of the subsequent therapy and to predict response to treatment. The combination of trabectedin and pegylated liposomal doxorubicin (PLD) is useful in patients with partially platinum-sensitive recurrent ovarian cancer, in patients who have previously received two or more platinum-based chemotherapy regimens, in patients who have already experienced a platinum-induced hypersensitivity reaction and in patients who have previously failed to respond to a platinum-based treatment.\n\nCase Presentation\nA 64-years-old postmenopausal woman with pain, abdominal distension, and an altered intestinal transit and with partially platinum-sensitive recurrent ovarian cancer, was successfully treated with a second line of trabectedin chemotherapy in combination with PLD, followed by trabectedin in monotherapy. This case proves the effectiveness of the combination of trabectedin and PLD and demonstrates how the administration of trabectedin, even in monotherapy, allows to maintain an adequate clinical response with good tolerance to the treatment during more than two years of drug administration.\n\nKey Words\nTrabectedinOvarian cancerRecurrentPlatinum\n==== Body\nIntroduction\nOvarian cancer is the seventh most common type of cancer and the fifth leading cause of cancer death among women worldwide [1]. Due to the absence of symptomatology in its early stages, the disease is diagnosed at advanced stages in 70% of cases. Therefore, chemotherapy with systemic antineoplastic agents is crucial in the treatment of this disease.\n\nAlong these lines, the development in recent years of new therapeutic agents for the treatment of ovarian cancer has resulted in an increase in the progression-free survival (PFS) rates associated with certain lines of treatment; however, overall survival (OS) figures remain practically unchanged [2].\n\nOverall, the current usual therapeutic approach in this disease includes optimal cytoreductive surgery followed by platinum-based adjuvant chemotherapy, along with neoadjuvant chemotherapy prior to surgery in selected cases [3]. However, despite the high proportion of patients who respond satisfactorily to this first line of platinum-based chemotherapy, only 15% reach full resolution and most relapse within two to five years [4]. To classify relapsed patients and establish subgroups for stratification in clinical trials, the Fifth International Ovarian Cancer Consensus Conference of the Gynaecologic Cancer Intergroup on Recurrent Disease held in Tokyo determined that patients should be classified according to the therapy-free interval (TFI). The platinum-free interval (PFI), the non-platinum-free interval (non-PFI), and the biological agent-free interval (TFIb) should also be considered. Thus far, the PFI continues to be the most useful tool to assist in the selection of the subsequent therapy and to predict response to treatment [5]. Its duration allows for differentiating between platinum-sensitive tumours (if relapse occurs 12 months after the last cycle of platinum-based chemotherapy), partially-sensitive tumours (if relapse occurs between six and twelve months after the treatment), and platinum-resistant tumours (if relapse occurs within six months of the last cycle of platinum-based chemotherapy) [3]. In case of relapse, the response to a platinum-based regimen is directly related to the duration of the PFI. Thus, if the relapse occurs in a patient with platinum-sensitive (PFI >12 months) or partially-sensitive (PFI >6 and <12 months) ovarian cancer, a second line of platinum-based combination chemotherapy is recommended. However, a non-platinum-based combination of pegylated liposomal doxorubicin (PLD) and trabectedin has also proven to be effective in patients with platinum-sensitive recurrent ovarian cancer [6].\n\nIn 2009, trabectedin – a marine-derived antineoplastic agent initially isolated from the tunicate Ecteinascidia turbinata which is currently being produced synthetically – in combination with PLD was approved for the treatment of patients with recurrent platinum-sensitive ovarian cancer [2]. The combination of trabectedin and PLD is a non-platinum-based chemotherapy presenting as an alternative in the treatment of recurrent ovarian cancer. It is especially useful in patients with partially platinum-sensitive recurrent ovarian cancer [2], in patients who have previously received two or more platinum-based chemotherapy regimens (in which case the risk of developing a hypersensitivity reaction increases to 27% after the seventh cycle or during the second line of treatment) [7], in patients who have already experienced a platinum-induced hypersensitivity reaction (15–20% of all patients receiving platinum) [8], and in patients who have previously failed to respond to a platinum-based treatment.\n\nBelow we describe the clinical case of a patient with partially platinum-sensitive recurrent ovarian cancer who was successfully treated with a second line of trabectedin chemotherapy in combination with PLD, followed by trabectedin in monotherapy. The patient maintained a clinical response and a good tolerance to the treatment more than two years after its completion.\n\nCase Presentation\nThe case in question concerns a 64-year-old Caucasian postmenopausal woman presenting with pain, abdominal distension, and an altered intestinal transit.\n\nThoracic and abdominopelvic computed tomography (CT) scans revealed massive peritoneal carcinomatosis, extensive ascites, involvement of the major omentum, extensive involvement small intestine mesentery, diffuse involvement of the parietal peritoneum, implants at the bottom of the Douglas pouch, and probable implants on the ovarian surface, although of normal size (Fig. 1). Her plasma CA-125 tumour marker levels were 1,110.9 U/mL, and those of the remaining tumour markers fell within a normal range. An omentum biopsy was compatible with high-grade serous carcinoma, with positive expression for WT-1, p53, CK-7 and negative expression for CK20 and TTF-1, with tube-ovarian-peritoneal origin.\n\nGiven the confirmed diagnosis of a primary peritoneal carcinoma of gynaecological origin stage IIIC and after assessment by a multidisciplinary committee that considers unresectable disease due to mesenteric involvement, neoadjuvant chemotherapy with intravenous (i.v.) paclitaxel 175 mg/m2 and i.v. carboplatin AUC 6 at three-week intervals was prescribed. The patient received three cycles of this treatment, showing a significant partial response on the follow-up CT scans, and plasma CA-125 tumour marker levels of 65 U/mL (levels at diagnosis: 1110.9 U/mL).\n\nSurgery was subsequently performed, achieving optimal cytoreduction, and the patient had a catheter placed for the administration of the intraperitoneal chemotherapy. The pathological study of all samples obtained during the procedure revealed a high-grade serous carcinoma.\n\nFollowing the intervention, a total of four cycles of adjuvant intraperitoneal (i.p.) chemotherapy consisting of i.v. paclitaxel 175 mg/m2 (day 1), i.p. cisplatin 75 mg/m2 (day 2), and i.p. paclitaxel 60 mg/m2 (day 8) were administered. The patient achieved a complete response, although she developed grade-2 asthenia and grade-3 neutropenia due to treatment-related toxicity that mandated a delay in the dosing and support with granulocyte-colony stimulating factors (G-CSFs).\n\nSeven months after receiving the last cycle of platinum-based chemotherapy, her CA-125 tumour marker levels were 104 U/mL, and mediastinal lymph node and peritoneal recurrence were identified in the follow-up CT scans. At this time, a germline mutation study was carried out in BRCA, being negative. Given that these findings were considered to be indicative of progression after a PFI of seven months, second-line chemotherapy was started with i.v. trabectedin 1.1 mg/m2 (day 1) in combination with i.v. PLD 30 mg/m2 (day 1) at 21-day cycles. The patient achieved a partial response after the third cycle (CA-125: 11.8 U/mL) (Fig. 2, 3).\n\nChemotherapy with trabectedin and PLD was continued; however, given that the patient experienced haematological toxicity (grade-4 neutropenia), the dose of PLD had to be reduced to 25 mg/m2 and that of trabectedin to 0.9 mg/m2 during the sixth cycle. PLD was subsequently discontinued altogether due to the onset of toxicity associated with this drug (grade-2 mucositis and grade-3 asthenia). From then on, she received i.v. trabectedin 0.9 mg/m2 in monotherapy at 21-day cycles, with good tolerance and referring only grade-1 asthenia that resolved within two to three days and did not limit her during her basic activities of daily living.\n\nAfter ten cycles of treatment, and specifically four cycles of trabectedin in monotherapy, the dose of trabectedin had to be reduced to 0.75 mg/m2 every 21 days due to the onset of grade-3 neutropenia and grade-2 thrombopenia, which mandated frequent delays in the dosing and even G-CSF support. Nevertheless, the subsequent follow-up CT scans performed periodically continued to show evidence of complete response. The patient received a total of 35 cycles of trabectedin (six in combination with PLD and then 29 in monotherapy). During this time, she maintained an excellent quality of life, experiencing no late or cumulative toxicity, and being able to perform her usual activities.\n\nBecause peritoneal progression was subsequently detected after a PFI of three years, a third line of treatment with i.v. carboplatin (area under the curve [AUC] = 4) (day 1), i.v. gemcitabine 1,000 mg/m2 (days 1 and 8 of every 21-day cycle), and i.v bevacizumab 15 mg/kg (day 1) was started. A subsequent follow-up CT scan carried out after the third cycle of this therapy showed signs of partial response. Given that the response persisted after six treatment cycles, chemotherapy was suspended and treatment with bevacizumab in monotherapy was started. The patient has received a total of 12 cycles of maintenance treatment with bevacizumab in monotherapy to date, having tolerated the treatment well and maintained a partial response.\n\nDiscussion\nTrabectedin binds to the minor groove of deoxyribonucleic acid (DNA), bending the helix towards the major groove. This binding triggers a cascade of events that affect several transcription factors, DNA binding proteins, and DNA repair pathways, resulting in alterations in the cell cycle [9]. In addition, trabectedin has also been proven to act in the tumoral microenvironment, decreasing the production of pro-inflammatory factors such as CCL2 and IL-6 [10].\n\nThe approval of trabectedin in combination with PLD for the treatment of platinum-sensitive recurrent ovarian cancer was based on the findings of a phase-III clinical trial (OVA-301 study) in which patients with platinum-sensitive recurrent ovarian cancer (PFI ≥6 months) who received trabectedin and PLD had a higher PFS than those who received PLD in monotherapy (p = 0.0170) [4]. The difference between the two treatments was even greater among the subgroup of patients with partially platinum-sensitive ovarian cancer (the PFS was 7.4 months among those treated with trabectedin combined with PLD and of only 5.5 months among those treated with PLD in monotherapy) [11]. The hazards ratio (HR) was 0.65 (95% confidence interval [CI], 0.45–0.92), indicating a 35% reduction in the rate of disease progression (DP) or death. Thus, this result significantly favours the combination of trabectedin and PLD (p = 0.0152). In the OVA-301 study, the OS of the patients with platinum-sensitive recurrent ovarian cancer (after 47.4 months of follow-up) was higher among those who had received a combination of trabectedin and PLD (median OS = 22.2 months) in comparison with those who had received PLD in monotherapy (median OS = 18.9 months) (p = 0.0835). Once more, the most significant difference was observed among the subgroup of patients with ovarian cancer partially sensitive to platinum, as the median OS was 22.4 months among the patients treated with trabectedin and PLD, and of 16.4 months among those treated with PLD in monotherapy (p = 0.0027).\n\nIt should be noted that an unanticipated exploratory analysis performed during this study revealed that the median OS was greater when the duration of the PFI was longer, in such a way that the median OS was 32.5 months with a PFI >12 months (95% CI: 28.4–38.5), 13.6 months with a PFI <6 months (95% CI: 11.7–14.8), and 20.3 months with a PFI of six to twelve months (95% CI: 17.7–21.7), respectively. The results of this study indicate that the duration of the PFI is a continuous parameter and a highly important prognostic factor of survival in patients with recurrent ovarian cancer [12]. In the case of the combination of trabectedin and PLD, the OS that characterized patients with a PFI equal to or greater than 12 months (32.5 months) in our study fell within the range of the results obtained with other platinum-based therapies [8].\n\nThus, the results of the published studies suggest the existence of a clear relationship between the duration of the PFI and overall survival (i.e., the greater the PFI, the longer the survival). As a result, the combination of trabectedin and PLD may be an effective and safe therapeutic option that could allow for lengthening the duration of the PFI and increasing the survival of these patients [2, 13].\n\nThe OVA-301 study also analysed what happened when patients with a PFI of six to twelve months were treated with a combination of trabectedin and PLD together with an additional line of subsequent platinum-based chemotherapy. In this case, the addition of a subsequent platinum-based treatment appeared to be more effective, as patients who had received the combined treatment rather than the monotherapy lived almost nine months longer after receiving the platinum-based treatment (18.6 months for the combined treatment and only 9.9 months for the PLD treatment in monotherapy; p = 0.0513) [14]. This clinical observation could be explained by in vitro and in vivo studies that support the treatment sequence-effect hypothesis, given that repeated exposure to trabectedin would select cell populations in the tumour with a deficient nucleotide excision repair (NER) system that are consequently more sensitive to platinum compounds.\n\nThe INOVATYON study (NCT013679989), in which patients with platinum-sensitive recurrent ovarian cancer are randomized to receive a platinum-based combination therapy (carboplatin and PLD) or a non-platinum-based combination therapy (PLD and trabectedin), is currently underway with a view to support this hypothesis of the sequence effect [15].\n\nIn the clinical case described in this paper, the patient achieved a partial response with a combination of trabectedin and PLD (six cycles), which she maintained for two years after continuing treatment with trabectedin in monotherapy until progression of her disease was detected. The patient tolerated the treatment well, and the duration of her PFI consequently increased. After a PFI of three years, the patient was treated with another platinum-based treatment, achieving a response and maintaining the disease under control for almost a year after finishing this second treatment. These findings pave the way towards new therapeutic options for future disease progression.\n\nThe summary of product characteristics (SmPC) of trabectedin recommends administering treatment until progression of the disease is detected provided that the patient's tolerability is acceptable and that there are no pre-defined limits with respect to the number of cycles that can be administered.\n\nConclusions\nThis case proves the effectiveness of the combination of trabectedin and PLD in a patient with platinum-sensitive recurrent ovarian cancer. In addition, it demonstrates how the administration of trabectedin, even in monotherapy, allows to maintain an adequate clinical response with good tolerance to the treatment during more than two years of drug administration. Based on the findings of this clinical case, it appears that trabectedin combined with PLD is an effective and safe alternative in patients with platinum-sensitive recurrent ovarian cancer. Furthermore, this combination could improve clinical outcomes in terms of survival if used properly within the treatment sequence. Further trials comparing different treatment sequences are needed to corroborate this hypothesis.\n\nStatement of Ethics\nAll authors state that subjects (or their parents or guardians) have given their written informed consent to publish their case, including publication of images.\n\nProcedures were in accordance with guidelines established in the Declaration of Helsinki and with the principles of Good Clinical Practices.\n\nDisclosure Statement\nThe authors declare that there is no conflict of interest.\n\nFunding Sources\nNone.\n\nAuthor Contributions\nAll authors participated in the study design, data acquisition, data analysis and the manuscript drafting and revision.\n\nAcknowledgement\nThe authors would like to express their gratitude to Meisys for helping in the elaboration of the manuscript.\n\nFig. 1 Reformatted contrast-enhanced coronal CT image showing massive ascites and omental carcinomatosis (green arrows) at diagnosis.\n\nFig. 2 Contrast-enhanced axial CT image showing a new tumoral lesion in the falciform ligament of the liver (red arrow) after seven months of first-line platinum-based therapy and downsizing of the tumoral lesion after three cycles of trabectedin + PLD (green arrow).\n\nFig. 3 Enhanced axial CT image showing an enlarged mediastinal lymph node at a prevascular level (red arrow) after seven months of first-line platinum-based therapy and downsizing of the mediastinal lymph node after three cycles of trabectedin + PLD (green arrow).\n==== Refs\nReferences\n1 Reid BM Permuth JB Sellers TA Epidemiology of ovarian cancer: a review Cancer Biol Med 2017 2 14 (1) 9 32 28443200 \n2 Poveda A Ray-Coquard I Romero I Lopez-Guerrero JA Colombo N Emerging treatment strategies in recurrent platinum-sensitive ovarian cancer: focus on trabectedin Cancer Treat Rev 2014 4 40 (3) 366 75 24296108 \n3 Gabra H Introduction to managing patients with recurrent ovarian cancer EJC Suppl 2014 12 12 (2) 2 6 26759525 \n4 Monk BJ Herzog TJ Kaye SB Krasner CN Vermorken JB Muggia FM Trabectedin plus pegylated liposomal Doxorubicin in recurrent ovarian cancer J Clin Oncol 2010 7 28 (19) 3107 14 20516432 \n5 Wilson MK Pujade-Lauraine E Aoki D Mirza MR Lorusso D Oza AM participants of the Fifth Ovarian Cancer Consensus Conference Fifth Ovarian Cancer Consensus Conference of the Gynecologic Cancer InterGroup: recurrent disease Ann Oncol 2017 4 28 (4) 727 32 27993805 \n6 Pujade-Lauraine E How to approach patients in relapse Ann Oncol 2012 9 23 Suppl 10 x128 31 22987947 \n7 Makrilia N Syrigou E Kaklamanos I Manolopoulos L Saif MW Hypersensitivity reactions associated with platinum antineoplastic agents: a systematic review. Met Based Drugs 2010 2010 \n8 González A Increasing the chances for platinum-sensitive ovarian cancer patients Future Oncol 2013 12 9 (12 Suppl) 29 35 24195528 \n9 D'Incalci M Galmarini CM A review of trabectedin (ET-743): a unique mechanism of action Mol Cancer Ther 2010 8 9 (8) 2157 63 20647340 \n10 Allavena P Signorelli M Chieppa M Erba E Bianchi G Marchesi F Anti-inflammatory properties of the novel antitumor agent yondelis (trabectedin): inhibition of macrophage differentiation and cytokine production Cancer Res 2005 4 65 (7) 2964 71 15805300 \n11 Poveda A Vergote I Tjulandin S Kong B Roy M Chan S Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer: outcomes in the partially platinum-sensitive (platinum-free interval 6-12 months) subpopulation of OVA-301 phase III randomized trial Ann Oncol 2011 1 22 (1) 39 48 20643862 \n12 Monk BJ Herzog TJ Kaye SB Krasner CN Vermorken JB Muggia FM Trabectedin plus pegylated liposomal doxorubicin (PLD) versus PLD in recurrent ovarian cancer: overall survival analysis Eur J Cancer 2012 10 48 (15) 2361 8 22541893 \n13 Mascilini F Amadio G Di Stefano MG Ludovisi M Di Legge A Conte C Clinical utility of trabectedin for the treatment of ovarian cancer: current evidence Onco Targets Ther 2014 7 7 1273 84 25050069 \n14 Kaye SB Colombo N Monk BJ Tjulandin S Kong B Roy M Trabectedin plus pegylated liposomal doxorubicin in relapsed ovarian cancer delays third-line chemotherapy and prolongs the platinum-free interval Ann Oncol 2011 1 22 (1) 49 58 20643863 \n15 Sehouli J Alfaro V González-Martín A Trabectedin plus pegylated liposomal doxorubicin in the treatment of patients with partially platinum-sensitive ovarian cancer: current evidence and future perspectives Ann Oncol 2012 3 23 (3) 556 62 21734221\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "12(2)",
"journal": "Case reports in oncology",
"keywords": "Ovarian cancer; Platinum; Recurrent; Trabectedin",
"medline_ta": "Case Rep Oncol",
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"pages": "447-455",
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"pubdate": "2019",
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"title": "Maintenance with Trabectedin in the Treatment of Platinum-Sensitive Recurrent Ovarian Cancer.",
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"abstract": "A 7-year-old previously healthy girl presented with a left-sided focal seizure without impaired consciousness and subsequently developed epilepsia partialis continua. Initial MRI was normal, and the subsequent images only showed a focal T2/FLAIR hyperintense area without cortical atrophy. She was diagnosed with Rasmussen syndrome by pathology and promptly treated with functional hemispherotomy. Rasmussen syndrome is a rare progressive neurological disorder, the only definitive cure for which is hemispheric disconnection. The disease presents a management dilemma, especially early in disease course without characteristic neuroimaging features. A high index of suspicion, multidisciplinary approach, and clear timely communication with the family are critical.",
"affiliations": "Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.;Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USA.",
"authors": "Nagahama|Yasunori|Y|;Joshi|Charuta|C|;Dlouhy|Brian|B|;Wu|Angela Y|AY|;Abel|Taylor J|TJ|;Baumbach|Gary|G|;Kawasaki|Hiroto|H|",
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"doi": "10.1016/j.ebcr.2016.11.003",
"fulltext": "\n==== Front\nEpilepsy Behav Case RepEpilepsy Behav Case RepEpilepsy & Behavior Case Reports2213-3232Elsevier S2213-3232(16)30080-910.1016/j.ebcr.2016.11.003Case ReportFunctional hemispherotomy in Rasmussen syndrome in the absence of classic MRI findings Nagahama Yasunori yasunori-nagahama@uiowa.edua⁎Joshi Charuta bDlouhy Brian aWu Angela Y. cAbel Taylor J. aBaumbach Gary cKawasaki Hiroto aa Department of Neurosurgery, University of Iowa Hospitals and Clinics, Iowa City, IA, USAb Department of Pediatrics, University of Iowa Hospitals and Clinics, Iowa City, IA, USAc Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, IA, USA⁎ Corresponding author at: Department of Neurosurgery, University of Iowa Hospitals and Clinics, 200 Hawkins Drive, Iowa City, IA 52242, USA.Department of NeurosurgeryUniversity of Iowa Hospitals and Clinics200 Hawkins DriveIowa CityIA52242USA yasunori-nagahama@uiowa.edu05 12 2016 2017 05 12 2016 7 24 27 5 10 2016 19 11 2016 25 11 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/).A 7-year-old previously healthy girl presented with a left-sided focal seizure without impaired consciousness and subsequently developed epilepsia partialis continua. Initial MRI was normal, and the subsequent images only showed a focal T2/FLAIR hyperintense area without cortical atrophy. She was diagnosed with Rasmussen syndrome by pathology and promptly treated with functional hemispherotomy. Rasmussen syndrome is a rare progressive neurological disorder, the only definitive cure for which is hemispheric disconnection. The disease presents a management dilemma, especially early in disease course without characteristic neuroimaging features. A high index of suspicion, multidisciplinary approach, and clear timely communication with the family are critical.\n\nAbbreviations\nASDs, antiseizure drugsEEG, electroencephalogramEPC, epilepsia partialis continuaEVD, external ventricular drainMRI, magnetic resonance imagingPET, positron emission tomographyRS, Rasmussen syndromeKeywords\nRasmussen's encephalitisRasmussen syndromeEarly diagnosisFunctional hemispherectomyPeri-insular functional hemispherotomy\n==== Body\n1 Introduction\nRasmussen syndrome (RS) is a rare progressive neurological disorder characterized by inflammatory reactions of unknown etiology involving one hemisphere, medically intractable epilepsy, and progressive cognitive decline [1], [2]. The only definitive cure for RS and resultant epilepsy is hemispheric disconnection either through an anatomic hemispherectomy or a functional hemispherotomy [1], [2]; focal resections have not been shown to be effective in controlling seizures or preventing the disease progression [2], [3], [4]. Immunomodulatory or immunosuppressive therapies have been investigated without clear long-term benefits [1]; there is a concern that immunological therapies may delay the definitive surgical treatment, resulting in further insults to the contralateral hemisphere and additional cognitive impairment [1]. The disease progression is variable, and the clinicians are often faced with the management dilemma as to timing of the definitive surgical intervention with significant expected postsurgical functional consequences, especially when patients may not satisfy the diagnostic criteria for RS (see the 2005 European consensus statement [2] for the criteria). This report describes a 7-year-old previously healthy girl who was diagnosed with RS very early in the disease course, despite the initial normal and subsequent non-characteristic neuroimaging features without cortical atrophy, and was promptly treated with functional hemispherotomy. The case illustrates the value of the multidisciplinary approach by experienced clinicians. The case further emphasizes the importance of clear and timely communication with the family about concern for the diagnosis in order to allow adequate family reflection and acceptance prior to the surgical intervention.\n\n2 Case report\nA 7-year-old right-handed previously healthy girl had an episode of a focal seizure without impaired consciousness, involving shaking of the entire left side of the body. After one month, she experienced a focal seizure with impairment of consciousness, consisting of stiffening followed by shaking of the left arm and leg and rolling of the eyes to the left. Her past medical history was unremarkable, including her birth and development which was initially normal for her age. Initial electroencephalogram (EEG) showed “rolandic” spikes. MRI was normal. Over the next three months, she developed frequent twitching of the left lower extremity that later became more constant during awake or sleep state, and started to interfere with ambulation, resulting in frequent falls. These symptoms progressed despite trials of multiple antiseizure drugs (ASDs), including phenytoin (up to 50 mg three times daily), levetiracetam (up to 1500 mg twice daily), oxcarbazepine (up to 300 mg three times daily), and clonazepam (up to 0.5 mg twice daily). A repeat EEG showed a background of constant slowing over the vertex and intermittent sharp waves in the vertex and right central region. Clinical concern for epilepsia partialis continua (EPC) was raised, and she was evaluated in the epilepsy clinic. The physical examination findings were significant for twitching movements involving bilateral lower extremities, much worse on the left, and circumduction gait as well as agraphesthesia and abnormal two point discrimination over the left arm. EPC was diagnosed, and concern for RS, along with the treatment options including hemispheric disconnection, was immediately communicated to the family. A repeat MRI demonstrated a new small focus of increased T2/FLAIR signal in the right posterior parafalcine frontal area without cortical atrophy or ventriculomegaly, concerning for neoplasm or cortical dysplasia (Fig. 1).Fig. 1 The MRI T2 axial sequence obtained about 6 months after the symptom onset showed a small focus of stable hyperintense signal change involving the cortex in the right posterior parafalcine frontal area (yellow arrow), which was not present on the first scan but was present on the second scan. No cortical atrophy or ventriculomegaly was noted on this scan.\n\nFig. 1\n\nShe was referred to the neurosurgery clinic for evaluation. The severity and frequency of the seizures had worsened despite a trial of intravenous immunoglobulin. She would have multiple episodes of focal seizures with secondary generalization daily. She ultimately became wheelchair-bound due to frequent and continuous shaking of the left leg. A third MRI showed stable signal abnormality without atrophy or ventriculomegaly. To establish a pathological diagnosis, after multidisciplinary discussion, the patient underwent craniotomy with intraoperative electrocorticography and lesionectomy. The areas of the lesion and the adjacent frequently spiking cortex were resected, while preserving the primary motor area (Fig. 2). Postoperatively, she continued to have EPC as well as her typical seizures without improvements in frequency or severity. The pathologic specimen showed encephalitis with gliosis, with foci of perivascular chronic inflammation, microglial clusters, and focal lymphoid aggregates primarily consisting of T-lymphocytes, consistent with RS (Fig. 3).Fig. 2 An intraoperative picture showing a resection cavity (indicated with a dotted light blue line) anteromedially within the craniotomy margin. The area of the resection, determined intraoperatively with electrocorticography, included the focal area of the T2/FLAIR hyperintensity noted on the preoperative imaging studies (indicated by a dotted yellow line).\n\nFig. 2Fig. 3 Pathologic findings consistent with Rasmussen's encephalitis included perivascular lymphocytic inflammation [A] and microglial nodules [B]. Intermixed T-lymphocytes are highlighted by CD3 immunostaining [C]. Gliosis was present, with the radially arranged spider-like projections of reactive astrocytes highlighted by glial fibrillary acidic protein immunostaining [D]. (hematoxylin–eosin, original magnifications × 40 [A], × 20 [B]; original magnification × 20 [C, D]).\n\nFig. 3\n\nSeveral days later, and within 7 months from the initial seizure and 2 months from the initial evaluation in the epilepsy clinic, she underwent right-sided peri-insular functional hemispherotomy (see the descriptions by Villemure et al. [5], [6] for the details of the procedure) and placement of an external ventricular drain (EVD) (Fig. 4). EPC resolved completely postoperatively. The EVD was removed on postoperative day 5. She had the initial expected postoperative left-sided dense hemiparesis. She started moving the left lower extremity within a few days after the hemispherotomy. She was able to ambulate with the support of physical therapists within 4 weeks from discharge.Fig. 4 An intraoperative picture taken after the peri-insular hemispherotomy was completed (taken from the primary surgeon's view and rotated for an easier view). The frontoparietal lobes are shown toward the top of the picture, and the temporal lobe is shown toward the bottom of the picture. The frontoparietal and temporal opercular cortical areas had been resected along the sylvian fissure. Note that all the major blood vessels were preserved to prevent postoperative stroke and resultant edema.\n\nFig. 4\n\nAt one year after the hemispherotomy, she continues to be seizure-free, and ASDs have been tapered down only to one medication. The patient continues to recover, and ambulation has improved significantly, despite expected loss of use of the left hand. The postoperative MRI showed expected postoperative changes, with appropriate hemispheric disconnection (Fig. 5). Although the parents noted no significant changes in her cognition preoperatively, they have noted subtle impulsiveness and decreased flexibility after the hemispherotomy. However, these symptoms have been improving significantly over time.Fig. 5 The postoperative MRI T1 axial sequence obtained about 6 weeks from the hemispherotomy showed expected postsurgical changes, including hemispheric disconnection from the underlying basal ganglia and thalamus as well as disconnection of the insular cortex (yellow arrow).\n\nFig. 5\n\n3 Discussion\nRasmussen syndrome (RS), first described by a neurosurgeon Theodore Rasmussen in the 1950s [7], is a rare progressive neurological disorder, characterized by inflammatory reaction involving one hemisphere as well as medically intractable epilepsy [1], [2]. The etiology and pathophysiology of the disease are not completely understood; however, pathological findings reveal inflammatory processes, characterized by neuronal loss and gliosis as well as cortical inflammation, with major involvement of cytotoxic T lymphocytes and microglia [1], [2]. RS is a rare disease with an incidence of a few patients per 10 million people in the pediatric age group, typically affecting children and young adults [1], [8]. These patients typically present with frequent seizures localized to one hemisphere, which may be preceded by a prodromal period involving infrequent seizures or mild weakness [1], [2], [8]. About half of the patients may experience EPC [1]. The disease course is invariably progressive, and characterized by persistent seizures, hemiparesis, and cognitive decline [1], [2], [8]. This acute phase may be followed by a residual stage of stable neurologic deficits and persistent seizures [1], [2].\n\nMRI of the brain has become an important measure of the initial and follow-up assessments in RS [9], [10]. Abnormal findings involving the affected hemisphere are heterogenous, and include hyperintense T2/FLAIR signal changes, followed by atrophy and resultant ventriculomegaly with disease progression [9], [10]. These abnormal findings initially tend to be localized to the perisylvian and insular areas [9], [10]. Early abnormal findings include cortical atrophy or swelling, abnormal cortical/subcortical signals, atrophy of the head of caudate nucleus, and ventricular enlargement [10]. Although rare, there have been reported cases of normal imaging findings on very early imaging studies [2], [4], [11], [12]. Early abnormal EEG findings include slow focal activity and progressive multifocal hemispheric ictal and interictal discharges [8].\n\nThe 2005 European consensus statement on RS is currently the accepted guideline for diagnosis [2]. Briefly, RS can be diagnosed without pathology when all of the following three criteria are satisfied: 1) clinical findings of focal seizures (with or without EPC) and unilateral cortical deficits; 2) EEG findings of unihemispheric slowing with or without epileptiform activity and unilateral seizure onset; and 3) MRI findings of unihemispheric focal cortical atrophy with at least either i) cortical or subcortical hyperintense T2/FLAIR signal or ii) hyperintense signal or atrophy of the ipsilateral caudate head [2]. When the above criteria are not all met, RS can be still diagnosed if two of the following three criteria are satisfied: 1) EPC or progressive unilateral cortical deficits; 2) MRI findings of progressive unihemispheric atrophy; and 3) histopathological findings of T cell dominated encephalitis with activated microglia and reactive astrogliosis [2].\n\nTiming of the surgical intervention can be guided in part by the severity of epilepsy as well as by presence of independent interictal discharges arising from the contralateral hemisphere associated with cognitive decline [1]. Some authors argue for early surgery to minimize neurological insults to the contralateral hemisphere from repeated seizures and consequent cognitive decline in the face of the inevitably progressive nature of the disease, even without significant deficits [13]. Success in significant seizure control without major complications, when treated by any of the modern variants of functional hemispherectomy, reaches more than 70–80% [5], [13], [14]. Importantly, better cognitive outcome has been shown to be associated with shorter presurgical seizure duration [14], [15].\n\nThis report describes a case in which a diagnosis of RS was suspected immediately by an experienced epileptologist very early in the disease course, further assessed by the multidisciplinary pediatric epilepsy team, and promptly treated with functional hemispherotomy. This case was very unique, as the initial MRI was normal and even the second and third MRI only showed a focal T2/FLAIR hyperintense area without characteristic neuroimaging features of cortical atrophy or ventriculomegaly, suggestive of a very early disease state without meeting the diagnostic criteria. Along with EPC, another pointer to the initial strong suspicion for a diagnosis of RS was the finding of agraphesthesia and abnormal two point discrimination, localizing functional deficits beyond the subsequently discovered focal MRI abnormality restricted to the frontal area. However, given the absence of significant cortical atrophy, we were not absolutely certain about the diagnosis and not able to justify the proceeding with the functional hemispherotomy, considering the inevitable functional consequences. In addition, the image findings were concerning for possible neoplasm or cortical dysplasia, in which cases an extensive resection would not be necessary.\n\nOnce the diagnosis of RS was confirmed by pathology (i.e. two of the second set of the diagnostic criteria were met, namely the clinical finding of EPC and the histopathologic finding), we promptly proceeded with the peri-insular hemispherotomy. The definitive surgical intervention was performed in a timely manner within 2 months from the initial evaluation in the epilepsy clinic, before progression of the disease to a later stage where significant cortical atrophy and ventriculomegaly are noted and hemispheric disconnection is more typically performed. Determining timing of the surgery can pose considerable management dilemma to the clinicians early in the disease course when the present deficits are limited and the expected additional postoperative deficits are significant. The prompt intervention in this case emphasizes the value of the multidisciplinary approach led by experienced neurologists and neurosurgeons. Another key to the timely intervention was that a concern for RS and treatment options, including the surgery and its consequences, were clearly discussed with the patient's family early on. The case underscores the importance and need of clear communication between the care providers and the family from the beginning in order to allow for adequate family reflection and acceptance prior to the surgery and to facilitate the decision-making process.\n\nIn conclusion, this report describes a very rare case of pathologically proven early diagnosis of RS despite the initial normal and subsequent non-characteristic neuroimaging features without significant cortical atrophy, followed promptly by the definitive surgical intervention.\n\nDisclosure\nThe authors report no conflict of interest concerning the materials or methods used in this study or the findings specified in this paper.\n==== Refs\nReferences\n1 Varadkar S. Bien C.G. Kruse C.A. Jensen F.E. Bauer J. Pardo C.A. Rasmussen's encephalitis: clinical features, pathobiology, and treatment advances Lancet Neurol 13 2014 195 205 24457189 \n2 Bien C.G. Granata T. Antozzi C. Cross J.H. Dulac O. Kurthen M. Pathogenesis, diagnosis and treatment of Rasmussen encephalitis: a European consensus statement Brain 128 2005 454 471 15689357 \n3 Piatt J.H. Jr. Hwang P.A. Armstrong D.C. Becker L.E. Hoffman H.J. Chronic focal encephalitis (Rasmussen syndrome): six cases Epilepsia 29 1988 268 279 3131134 \n4 Lee J.S. Juhasz C. Kaddurah A.K. Chugani H.T. Patterns of cerebral glucose metabolism in early and late stages of Rasmussen's syndrome J Child Neurol 16 2001 798 805 11732764 \n5 Villemure J.G. Daniel R.T. Peri-insular hemispherotomy in paediatric epilepsy Childs Nerv Syst 22 2006 967 981 16804712 \n6 Villemure J.G. Mascott C.R. Peri-insular hemispherotomy: surgical principles and anatomy Neurosurgery 37 1995 975 981 8559348 \n7 Rasmussen T. Olszewski J. Lloydsmith D. Focal seizures due to chronic localized encephalitis Neurology 8 1958 435 445 13566382 \n8 Granata T. Gobbi G. Spreafico R. Vigevano F. Capovilla G. Ragona F. Rasmussen's encephalitis: early characteristics allow diagnosis Neurology 60 2003 422 425 12578922 \n9 Bien C.G. Urbach H. Deckert M. Schramm J. Wiestler O.D. Lassmann H. Diagnosis and staging of Rasmussen's encephalitis by serial MRI and histopathology Neurology 58 2002 250 257 11805253 \n10 Chiapparini L. Granata T. Farina L. Ciceri E. Erbetta A. Ragona F. Diagnostic imaging in 13 cases of Rasmussen's encephalitis: can early MRI suggest the diagnosis? Neuroradiology 45 2003 171 183 12684722 \n11 Geller E. Faerber E.N. Legido A. Melvin J.J. Hunter J.V. Wang Z. Rasmussen encephalitis: complementary role of multitechnique neuroimaging AJNR Am J Neuroradiol 19 1998 445 449 9541296 \n12 Kaiboriboon K. Cortese C. Hogan R.E. Magnetic resonance and positron emission tomography changes during the clinical progression of Rasmussen encephalitis J Neuroimaging 10 2000 122 125 10800268 \n13 Vining E.P. Freeman J.M. Pillas D.J. Uematsu S. Carson B.S. Brandt J. Why would you remove half a brain? The outcome of 58 children after hemispherectomy-the Johns Hopkins experience: 1968 to 1996 Pediatrics 100 1997 163 171 9240794 \n14 Jonas R. Nguyen S. Hu B. Asarnow R.F. LoPresti C. Curtiss S. Cerebral hemispherectomy: hospital course, seizure, developmental, language, and motor outcomes Neurology 62 2004 1712 1721 15159467 \n15 Thomas S.G. Chacko A.G. Thomas M.M. Babu K.S. Russell P.S. Daniel R.T. Outcomes of disconnective surgery in intractable pediatric hemispheric and subhemispheric epilepsy Int J Pediatr 2012 2012 527891 22518176\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-3232",
"issue": "7()",
"journal": "Epilepsy & behavior case reports",
"keywords": "ASDs, antiseizure drugs; EEG, electroencephalogram; EPC, epilepsia partialis continua; EVD, external ventricular drain; Early diagnosis; Functional hemispherectomy; MRI, magnetic resonance imaging; PET, positron emission tomography; Peri-insular functional hemispherotomy; RS, Rasmussen syndrome; Rasmussen syndrome; Rasmussen's encephalitis",
"medline_ta": "Epilepsy Behav Case Rep",
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"nlm_unique_id": "101614202",
"other_id": null,
"pages": "24-27",
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"pmid": "28239546",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "3131134;22518176;11732764;12684722;13566382;11805253;24457189;15159467;12578922;8559348;16804712;10800268;9541296;15689357;9240794",
"title": "Functional hemispherotomy in Rasmussen syndrome in the absence of classic MRI findings.",
"title_normalized": "functional hemispherotomy in rasmussen syndrome in the absence of classic mri findings"
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"abstract": "The PT-Cy was considered as one of the mainstay protocol for graft verus host disease (GVHD) prophylaxis. Recent study demonstrated that PT-Cy combined with other immunosuppressants could further reduce the incidence of GVHD and improve the GVHD and relapse free survival (GRFS). In this prospective phase II study, we evaluated the effect of a new GVHD prophylaxis consist of PT-Cy combined with tacrolimus and low dose anti-thymoglobulin (ATG). A total of 23 patients were enrolled including 20 patients with acute lymphoblastic leukemia (ALL) and three patients with T cell lymphoma. The median age was 29 years (range, 16~58 years). Patients with HLA-matched related donor (MSD, n=7) received PT-Cy combined with tacrolimus, while patients with HLA matched unrelated (MUD, n = 2) or haplo-identical (Haplo, n = 14) donor received additional ATG at 2.5 mg/kg on day 15 or day 22 after engraftment of neutrophils. As to the acute GVHD (aGVHD), only three patients developed grade I (n = 1) or grade II (n = 2) aGVHD with 100-day incidence of all aGVHD and II-IV aGVHD at 13.0 ± 5.1% and 9.1 ± 6.1% respectively. Only two patients had mild and one had moderate chronic GVHD (cGVHD), with 1-year incidence of cGVHD and moderate/severe cGVHD at 15.2 ± 8.7% and 4.6 ± 4.4% respectively. A high incidence of CMV reactivation was documented (14/16 with MUD/Haplo donor and 2/7 with MSD) with only 1 CMV disease documented. There were two EBV reactivation without post-transplantation lymphoproliferative disease (PTLD) documented. With a median follow-up of 303 days (range, 75~700 days), three patients relapsed leading to 1-year cumulative incidence of relapse (CIR) at 12.8 ± 9.2%. Only one patient died of CMV pneumonia on day 91 with both 100-day and 1-year non-relapse mortality (NRM) at 4.6 ± 4.4%. The 1-year overall survival (OS), event-free survival (EFS) and GRFS were 95.5 ± 4.4%, 82.6 ± 9.5%, and 68.0 ± 11.3% respectively. Based on Simon's stage II design, our primary data showed that the PT-Cy+tacrolimus ± ATG protocol was promising in preventing aGVHD and cGVHD, which may translate into low NRM without increased CIR. Further clinical trial with large number of patients should be warranted. This trial was registered at www.clinicaltrials.gov as #NCT04118075.",
"affiliations": "Shanghai Institute of Hematology, Department of Hematology, Blood & Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Shanghai Institute of Hematology, Department of Hematology, Blood & Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Shanghai Institute of Hematology, Department of Hematology, Blood & Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Shanghai Clinical Research Center (SCRC), Feng Lin International Centre, Shanghai, China.;Shanghai Institute of Hematology, Department of Hematology, Blood & Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.;Shanghai Institute of Hematology, Department of Hematology, Blood & Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.",
"authors": "Jiang|Jie-Ling|JL|;Gao|Wen-Hui|WH|;Wang|Li-Ning|LN|;Wan|Ming|M|;Wang|Ling|L|;Hu|Jiong|J|",
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"doi": "10.3389/fmed.2021.630160",
"fulltext": "\n==== Front\nFront Med (Lausanne)\nFront Med (Lausanne)\nFront. Med.\nFrontiers in Medicine\n2296-858X\nFrontiers Media S.A.\n\n10.3389/fmed.2021.630160\nMedicine\nClinical Trial\nPost-transplantation Cyclophosphamide, Tacrolimus and Low-Dose ATG as GVHD Prophylaxis for Allogeneic Peripheral Stem Cell Transplantation for Adult Patients With Lymphoid Malignancies: A Single Arm Phase II Study\nJiang Jie-ling 1†\nGao Wen-hui 1†\nWang Li-ning 1\nWan Ming 2\nWang Ling 1*\nHu Jiong 1*\n\n1Shanghai Institute of Hematology, Department of Hematology, Blood & Marrow Transplantation Center, Collaborative Innovation Center of Hematology, Rui Jin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China\n2Shanghai Clinical Research Center (SCRC), Feng Lin International Centre, Shanghai, China\nEdited by: Raynier Devillier, Institut Paoli-Calmettes (IPC), France\n\nReviewed by: Ian James Martins, University of Western Australia, Australia; Benjamin Bouchacourt, Institut Paoli-Calmettes (IPC), France\n\n*Correspondence: Ling Wang cclingjar@163.com\nJiong Hu hj10709@rjh.com.cn\nThis article was submitted to Gene and Cell Therapy, a section of the journal Frontiers in Medicine\n\n†These authors have contributed equally to this work and share first authorship\n\n18 3 2021\n2021\n8 63016016 11 2020\n23 2 2021\nCopyright © 2021 Jiang, Gao, Wang, Wan, Wang and Hu.\n2021\nJiang, Gao, Wang, Wan, Wang and Hu\nThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nThe PT-Cy was considered as one of the mainstay protocol for graft verus host disease (GVHD) prophylaxis. Recent study demonstrated that PT-Cy combined with other immunosuppressants could further reduce the incidence of GVHD and improve the GVHD and relapse free survival (GRFS). In this prospective phase II study, we evaluated the effect of a new GVHD prophylaxis consist of PT-Cy combined with tacrolimus and low dose anti-thymoglobulin (ATG). A total of 23 patients were enrolled including 20 patients with acute lymphoblastic leukemia (ALL) and three patients with T cell lymphoma. The median age was 29 years (range, 16~58 years). Patients with HLA-matched related donor (MSD, n=7) received PT-Cy combined with tacrolimus, while patients with HLA matched unrelated (MUD, n = 2) or haplo-identical (Haplo, n = 14) donor received additional ATG at 2.5 mg/kg on day 15 or day 22 after engraftment of neutrophils. As to the acute GVHD (aGVHD), only three patients developed grade I (n = 1) or grade II (n = 2) aGVHD with 100-day incidence of all aGVHD and II-IV aGVHD at 13.0 ± 5.1% and 9.1 ± 6.1% respectively. Only two patients had mild and one had moderate chronic GVHD (cGVHD), with 1-year incidence of cGVHD and moderate/severe cGVHD at 15.2 ± 8.7% and 4.6 ± 4.4% respectively. A high incidence of CMV reactivation was documented (14/16 with MUD/Haplo donor and 2/7 with MSD) with only 1 CMV disease documented. There were two EBV reactivation without post-transplantation lymphoproliferative disease (PTLD) documented. With a median follow-up of 303 days (range, 75~700 days), three patients relapsed leading to 1-year cumulative incidence of relapse (CIR) at 12.8 ± 9.2%. Only one patient died of CMV pneumonia on day 91 with both 100-day and 1-year non-relapse mortality (NRM) at 4.6 ± 4.4%. The 1-year overall survival (OS), event-free survival (EFS) and GRFS were 95.5 ± 4.4%, 82.6 ± 9.5%, and 68.0 ± 11.3% respectively. Based on Simon's stage II design, our primary data showed that the PT-Cy+tacrolimus ± ATG protocol was promising in preventing aGVHD and cGVHD, which may translate into low NRM without increased CIR. Further clinical trial with large number of patients should be warranted. This trial was registered at www.clinicaltrials.gov as #NCT 04118075.\n\nallogeneic peripheral stem cell transplantation\ngraft vs. host disease\npost-transplantation cyclophosphamide\nlymphoid malignancies\nanti-thymoglobulin\n==== Body\nIntroduction\n\nGraft-versus-host disease (GVHD) is considered as a major complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) (1, 2). The post-transplantation cyclophosphamide (PT-Cy) induced immune tolerance has been translated from laboratory studies into clinical practice and clinical data confirmed that PT-Cy can be considered as the mainstay strategy for GVHD prophylaxis in allo-HSCT of HLA-matched related (MSD), unrelated (MUD) and haplo-identical (Haplo) settings (3–8).\n\nThough there are plenty clinical reports of PT-Cy for patients with acute myeloid leukemia (AML) and myelodysplasia syndrome (MDS), the studies focusing on lymphoid malignancies are still limited (9). In our previous phase II clinical trial, we reported that the incidence of grade II-IV acute GVHD (aGVHD) and moderate to severe chronic GVHD (cGVHD) were as high as 39% and 24% respectively in adult patients with lymphoid malignancies receiving PT-Cy in combination with cyclosporine as GVHD prophylaxis and using mobilized peripheral blood stem cells (PBSCs) as graft (10). Our data were consistent with the EBMT registry study which demonstrated that in MSD/MUD settings, acute lymphoblastic leukemia (ALL) and unrelated donor transplantation were associated with higher incidence of grade II-IV aGVHD, while graft of PBSCs was an important risk factor for overall cGVHD and extensive cGVHD (ext cGVHD) (11). Of note, the analysis also indicated that PT-Cy combined with two immunosuppressants or with in vivo T cell depletion agents (TCD) significantly reduced the risk of ext cGVHD, which remained as a key prognostic factor for an improved GVHD and relapse-free survival (GRFS).\n\nTo further reduce the incidence of GVHD and improve GRFS, we evaluated a new GVHD protocol of PT-Cy followed additional tacrolimus and low-dose anti-thymoglobulin (ATG) in patients with lymphoid malignancies undergoing first allo-HSCT with mobilized peripheral blood as graft.\n\nPatients and Methods\n\nPatients and Eligibility Criteria for Allo-HSCT\n\nThis was an investigator-initiated, prospective, non-randomized, single-arm phase II clinical trial (NCT 04118075). The study was approved by the Human Ethics Committee of the Rui Jin Hospital and was in accordance with the Declaration of Helsinki. The study was conducted in the Blood and Marrow Transplantation Center of Rui Jin Hospital, Shanghai Jiao Tong University School of Medicine.\n\nThe inclusion criteria were as follows: (1) adult patients (18 to 60 years old) with acute lymphoid malignancies including ALL or various non-Hodgkin's lymphoma; (2) disease status at transplantation including first or second complete remission (CR1 or CR2) for ALL; CR, partial remission (PR) for high-grade lymphoma or any stage of low-grade lymphoma; (3) patients received first allo-HSCT from MSD, MUD or Haplo donor; (4) patients with performance status ≤2 (ECOG score) with acceptable renal and hepatic function (serum creatinine ≤133 μmol/L, serum bilirubin ≤34 μmol/L, serum glutamic-pyruvic transaminase <3 times of the upper normal limit), cardiac left ventricular ejection fraction ≥50% and normal pulmonary function tests; (5) all patients provided written informed consent before allo-HSCT.\n\nConditioning and GVHD Prophylaxis Regimen\n\nAll patients received fludarabine (FLU) 30mg/m2/ d from day−7 to day−3, etoposide 400 mg/m2/d from day−7 to day−6 and intravenous busulfan (BU) at 1.6 mg/kg every 12 h for 6 doses over 3 days (from day−5 to day−3). BU was administered by infusion over 3 h and the dose of BU was based on actual body weight (ABW) or adjusted ideal body weight [AIBW, AIBW=ideal body weight (IBW)+25%(ABW-IBW)] for overweight patients. Granulocyte colony-stimulating factor (G-CSF) mobilized PBSCs were infused on day 0. GVHD prophylaxis consisted of cyclophosphamide 50 mg/kg on day 3 and day 4 followed by tacrolimus 0.5 mg/kg twice daily starting on day 5 adjusted with target therapeutic trough level of 5~15 ng/ml. Single dose of 2.5 mg/kg ATG was given on day 15 after documentation of neutrophil engraftment in patients undergo MUD or Haplo transplantation. In case of delayed ANC engraft, the dose of ATG was postponed for 7 days to day 22 or afterwards likewise. To avoid the impact of donor lymphocyte infusion (DLI) on the development of aGVHD, no prophylactic DLI was allowed within day 100. DLI was only allowed in case of positive measurable residual disease (MRD) or bone marrow relapse after day 100. The conditioning and GVHD prophylaxis regimens were presented in Table 1.\n\nTable 1 Conditioning regimen and GVHD prophylaxis.\n\nDrug\tDosages\tDays\t\nFludarabine\t30mg/m2 daily\tD-7 to D-3\t\nEtopside\t400mg/m2daily\tD-7 to D-6\t\nBusulfan\t1.6mg/kg q12h\tD-5 to D-3\t\nPBSC\t/\tD 0\t\nPT-Cy\t50mg/kg daily\tD3 to D4\t\ntacrolimus\t0.5mg/kg q12h p.o.\tD5 forward\t\nATG\t2.5mg/kg once\tD15 or D22*\t\n* In case of transplantation from MUD or Haplo donor, ATG (2.5 mg/kg) was given on D15 if ANC engraftment was documented. In patients with late ANC engraftment, ATG was delayed to D22 or weekly basis afterward.\n\nSupportive Care\n\nAcute and chronic GVHD were diagnosed and graded according to standard guidelines (12, 13). In case of grade I–IV aGVHD, the first line treatment was methylprednisolone 1~2 mg/kg/day (i.v.) alone or combined with basiliximab. If no response, ruxolitinib was added as second line treatment. For cytomegalovirus (CMV), prophylaxis ganciclovir was given on day−9 to day−2. After transplantation, pre-emptive treatment ganciclovir was based on weekly monitoring and given in case of CMV DNAemia level >1 × 104 copy/ml. For Epstein-Barr virus (EBV) associated post-transplantation lymphoproliferative disease (PTLD), pre-emptive rituximab was also given based on weekly monitoring of EBV DNAemia when EBV DNA level was over >1 × 105 IU/ml. For prophylaxis of pneumocystis, sulfamethoxazole was given every other day from engraftment to 100 days after transplantation. As to the prophylaxis of invasive fungal disease (IFD), risk adapted escalation strategy was used. Specifically, all patients without previous probable or proven IFD received fluconazole (i.v.) as IFD prophylaxis in the laminar airflow unit. After patients were discharged from the BMT units, fluconazole (p.o) was given to day 100 in patients undergoing transplantation from MSD without aGVHD. While for all patients with unrelated or haplo-donor and all patients developed aGVHD requiring steroid treatment, the prophylaxis was escalated to voriconazole or posaconazole until day 100. For patients with previous documented probable or proven IFD, caspofungin or voriconazole was given in the BMT unit as secondary prevention and voriconazole or posaconazole was used sequentially until day 100. All other supportive care was according to the standard protocol of Rui Jin Hospital.\n\nStudy Endpoints\n\nThe primary endpoint of the study was the incidence of grade II to IV aGVHD at day 100. Secondary endpoints included the median time to the recovery of neutrophil or platelet, 100-day overall aGVHD and non-relapse mortality (NRM), 1-year overall cGVHD and moderate to severe cGVHD and 1-year overall survival (OS), event-free survival (EFS), cumulative incidence of relapse (CIR), NRM and GRFS. For OS, the failure was defined as death from any cause. For EFS, failure was defined as documented event of either disease relapse or death from any cause. Patients were considered to have died of NRM if there was no evidence of disease relapse or progression before death. Relapse was defined as >5% blasts in bone marrow (BM) examination or extramedullary relapse documented by biopsy in patients with ALL and positive PET-CT scan followed by biopsy in patients with lymphoma. GRFS was defined as patients without the following events including relapse, graft failure, occurrence of III-IV aGVHD and moderate or severe cGVHD.\n\nSample Size Estimation and Statistical Analysis\n\nThe study was based on assumption that the addition of tacrolimus and low dose ATG to PT-Cy decreased the incidence of grade II-IV aGVHD at day 100 to an optimal level of 15% and 40% as unacceptable high as in our previous prospective study with PT-Cy and cyclosporine. The goal of enrollment was set at 23 patients based on Simon's stage II design permitting early stop of trial if 15% was unlikely to achieve (14). With an optimal design, nine patients were enrolled in stage I. If six patients had grade II–IV aGVHD at day 100, the trial should be stopped early for futility. Otherwise, 14 more patients should be enrolled in stage II (as shown in Supplementary Table 1).\n\nThe cumulated incidence of aGVHD was calculated using relapse, death of any causes as competing risks (15). The incidence of cGVHD, relapse and NRM was summarized using cumulative incidence estimate accordingly. The OS, EFS and GRFS were calculated using the Kaplan-Meier method (16). Data for patients who were alive in CR were censored at last follow-up on September 30, 2020. The statistics was performed by SPSS and R software at Shanghai Clinical Research Center.\n\nResults\n\nPatients and Characteristics\n\nA total of 23 patients were enrolled in the study. All patients have been followed-up for a median of 303 days (range, 75~700 days). Demographic data for these patients were summarized in Table 2. The median age was 29 years (range, 16~58 years). Twenty patients were ALL including 7 with T-lineage (T-ALL), 12 with B-lineage (B-ALL) and 1 with mixed lineage ALL (Mix-ALL). Among B-ALL, 6 patients were Philadelphia chromosome positive ALL (Ph+ ALL) and received tyrosine kinase such as imatinib or dasatinib before and after allo-HSCT. All patients with ALL were in CR1. Three patients with lymphoma were also enrolled, including one with T-lymphoblastic lymphoma in PR, one with refractory Sezary syndrome and 1 with ALK+ anaplastic large cell lymphoma (ALCL) in CR3. The donors included seven from MSD, two from MUD and 14 from Haplo. In this series, the pre-transplantation status of serum CMV was positive in all patients and their donors.\n\nTable 2 Patient characteristics.\n\nCharacteristics\tValues/n\t\nAge, median (range) years\t29 (16~58)\t\nSex\t\t\n Male\t19 (82.6%)\t\n Female\t4 (17.4%)\t\nDiagnosis\t\t\nALL\t20 (87.0%)\t\n T-lineage\t8\t\n B-lineage\t12 (ph+ 6; ph− 6)\t\nLymphoma\t3 (13.0%)\t\n Sezary syndrome\t1\t\n ALCL\t1\t\n T-LBL\t1\t\nDisease status\t\t\n CR1\t20 (87.0%)\t\n PR/CR2 or beyond\t3 (13.0%)\t\nDonor type\t\t\n MSD\t7 (30.4%)\t\n MUD\t2 (8.7%)\t\n Haplo\t14 (60.9%)\t\nGVHD prophylaxis\t\t\n PT-Cy+FK506\t7 (30.4%)\t\n PT-Cy+FK506+ATG\t16 (69.6%)\t\nCMV serum status\t\t\nDonor+/Recipient+\t23 (100%)\t\n\nEngraftment and Chimerism\n\nFor all 23 patients, the median number of mononuclear cells and CD34+ cells infused was 6.7×108/kg (range, 2.3~15.7×108/kg) and 4.7×106/kg (range, 2.3~11.6×106/kg), respectively. Neutrophil engraftment occurred in all 23 patients at a median of 14 days (range, 10~20 days), and the median time of platelet recovery was 24 days (range, 9~67 days) in 22 patients. The chimerism analysis of total mononulear cells and CD3+T cells in bone marrow was performed in all patients on day 28 based on PCR of short tandem repeat (STR) unique for donor or recipient. Among them, 22 patients achieved full donor chimerism (≥99%) while one patient with haplo donor failed to achieve full donor chimerism (<60%) and quickly developed pancytopenia with loss of donor chimerism and regarded as primary graft failure. The very patient underwent salvage allo-HSCT from MUD donor and remained alive in CR at last follow-up.\n\nAcute GVHD and Chronic GVHD\n\nFor GVHD prophylaxis, ATG was given to all patients transplanted from MUD or Haplo donor on day 15 (n = 9) or day 22 (n = 7) according to the day of ANC engraftment. As to the aGVHD, only one patient developed grade I aGVHD (skin, stage II) and two patients developed grade II aGVHD (skin, stage I~II; gut, stage I, defined as diarrhea <1,000 ml/day). There was no grade III-IV aGVHD documented. At day 100, the cumulative incidence of all grade aGVHD and II–IV aGVHD were 13.0 ± 5.1% and 9.1 ± 6.1% respectively. As to the cGVHD, only two patients had mild cGVHD involving skin or liver respectively, while another patient developed moderate cGVHD, which was characterized by involvement of skin, liver and mucosa. During the follow-up, no patient had documented abnormal pulmonary function, therefore no bronchiolitis obliterans (BO) was diagnosed. The 1-year cumulated incidence of cGVHD and moderate/severe cGVHD were 15.2 ± 8.7% and 4.6 ± 4.4% respectively.\n\nInfection and Other Complications\n\nDuring the follow-up, a total of 16 patients experienced CMV reactivation. The median time to documented CMV DNAemia was 42 days (range, 30~109 days) with median CMV level of 15 (2~170)×103 copies/ml. Six patients with low viral load (<1×104 copies/ml) recovered spontaneously while ganciclovir was given in 10 patients. Among them, two patients received Haplo transplantation developed pancytopenia after ganciclovir treatment and eventually had secondary graft failure without evidence of relapse on day 60 and day 135 respectively. These two patients received subsequent 2nd allo-HSCT from MUD donor and both remained alive in CR at the last follow-up. CMV disease (pneumonia) was documented in one patient on day 55. The very patient suffered from respiratory failure and received combination therapy of ganciclovir, foscarnet, broad-spectrum antibiotics and assisted ventilation before eventually died on day 91.\n\nAs to the EBV infection, there were 2 patients with EBV DNAemia at low level of 1 and 5×103 IU/ml, which remained stable without any PTLD associated symptoms and eventually became negative in the subsequent follow-up.\n\nThere were two patients with previous documented IFD including one with proven candidiasis of liver and spleen and one with probable invasive pulmonary aspergillosis (IPA) before transplantation. With secondary prophylaxis, the patient with candidiasis had an episode of candida blood stream infection, which was controlled quickly with addition of amphotericin B to caspofungin. And the patient with IPA remained stable during the process of HSCT. A total of five patients required empirical anti-fungi treatment because of persistent febrile neutropenia with sufficient antibiotic treatment. With IFD work-up, only one patient was diagnosed as probable IPA.\n\nAs to other complications, mild hemorrhagic cystitis (HC) was documented in 4 patients and all responded well to hyperhydration with diuretics. All patients who developed HC were in the ATG group. Of note, 2 of them developed HC around day 6 (just after PT-Cy) and the other two occurred around day 35 (after ATG treatment). There was no sinusoidal obstruction syndrome (SOS) and grade III–IV liver toxicity ever documented in all 23 patients. One patient developed Guillian-Barre syndrome on day 45 with unknown cause responded well to high-dose intravenous immunoglobulin (IVIG) and fully recovered afterwards.\n\nOverall Outcome\n\nAt the last follow-up, one patient died of CMV pneumonia on day 91, making the 100-day and 1-year NRM both at 4.6 ± 4.4% (as shown in Figure 1). A total of 3 patients with T -ALL experienced relapse on day 138 (BM), 269 (extramedullary) and 678 (BM) respectively, making the 1-year CIR at 12.8 ± 9.2%. The very patient who relapsed on day 138 received DLI on day 151 and 182 following low-dose chemotherapy (CAG regimen). He achieved CR2 together with grade III aGVHD after DLI. Unfortunately, the patient relapsed again 3 months later and eventually died of disease. The other two patients were still under treatment of relapse and 19 patients remained alive in CR. The 1-year OS and EFS were 95.5 ± 4.4% and 82.6 ± 9.5% (as shown in Figures 2, 3), respectively. Overall, a total of 16 patients remained alive and free of relapse, graft failure, III-IV aGVHD and moderate to severe cGVHD with 1-year GRFS of 68.0 ± 11.3% (as shown in Figure 4).\n\nFigure 1 Analysis of non-relapse mortality (NRM).\n\nFigure 2 Kaplan-Meier analysis of overall survival (OS).\n\nFigure 3 Kaplan-Meier analysis of event- free survival (EFS).\n\nFigure 4 Kaplan-Meier analysis of GVHD and relapse-free survival (GRFS).\n\nDiscussion\n\nThe PT-Cy alone or in combination with other immunosuppressants was considered as one of the mainstay of GVHD prophylaxis strategies in various hematological malignancies (1, 2, 17–19). In a retrospective analysis from Acute Leukemia Working Party of the EBMT (AWLP-EBMT) with 423 patients transplanted in MSD and MUD setting, the diagnosis of ALL (vs. AML, p = 0.008) and PBSCs as graft (vs. BM, p = 0.01) were associated with higher incidence of II-IV aGVHD or ext cGVHD respectively. As to the GVHD protocol (PT-Cy alone or combined with other immunosuppressants), it did not impact the incidence of II–IV aGVHD, while the incidence of ext cGVHD was significantly higher for PT-Cy alone or with one immunosuppressant (18 or 20%) compare to only 8.5% for PT-Cy in combination with 2 immunosuppressants (p = 0.02). More interestingly, adding ATG to PT-Cy was independently associated with reduced risk of ext cGVHD (p < 0.001). As to the outcome of allo-HSCT, the PT-Cy with 2 additional immunosuppressants did not impact the incidence of relapse (p = 0.57) and NRM (p = 0.05), but improved both OS (p = 0.03) and GRFS (p = 0.007). Besides, adding ATG to PT-Cy did not impact the relapse rate (p = 0.61) in multivariate analysis (11).\n\nMore recently, clinical study demonstrated that ATG (2.5 mg/kg on day-1 or day-2 to−1) added as part of pre-transplantation conditioning combined with PT-Cy decreased aGVHD (12 vs. 22%, p = 0.029), reduced NRM (8 vs. 23%, p = 0.005) and lead to an improved OS (79 vs. 69%, p = 0.029) at 1 year compared to the no ATG group (20). In another retrospective study with thiotepa based conditioning and PBSCs as graft in Haplo setting, pre-transplantation ATG (1 mg/kg from day−6 to day−2) and the PT-Cy were used as GVHD prophylaxis. It showed that the 2-year cumulative incidences of III-IV aGVHD, severe cGVHD, NRM and relapse were 16, 16, 26, and 26%, respectively, which compared favorably with those of other reports using BM as graft (21).\n\nBased on the above data, we designed a new GVHD prophylaxis regimen with PT-Cy combined with tacrolimus and low-dose ATG (2.5 mg/kg) after ANC engraftment (on day 15 or day 22). Interestingly, our data demonstrated that low incidence of overall II-IV aGVHD (9.1 ± 6.1% at 100-day) could be achieved and even no III–IV aGVHD observed. Though the follow-up was still limited, we observed a trend of low incidence of cGVHD and moderate/severe cGVHD (4.6±4.4% at 1-year). Moreover, the lower incidence of GVHD was translated into lower 100-day NRM (4.6 ± 4.4%). The overall outcome concerning aGVHD/cGVHD and NRM was significantly better than our previous study using PT-Cy with cyclosporine only in the setting of lymphoid malignancies undergoing allo-HSCT with similar myeloablative conditioning and PBSCs as graft (10).\n\nESQUIROL et al. declared that single-agent of tacrolimus after PT-Cy was a valid option for haploidentical transplantation in adults with hematological malignancies (22). However, the cumulative incidence of grade II–IV and III–IV aGVHD were 23 and 14%, respectively, and the incidence of ext cGVHD was as high as 22% in their study. In another study, Carnevale-Schianca et al. reported low aGVHD incidence of 17% and cGVHD incidence of 7% using PT-Cy, tacrolimus and mycophenolate mofetil (MMF) as GVHD prophylaxis, though 46% of enrolled patients were diagnosed as AML and no patient was transplanted from haploidentical donor (23). These studies and our recent study were consistent with the AWLP-EBMT study, which demonstrated that the incidence of GVHD was significantly higher for PT-Cy alone. Thus, tacrolimus, MMF, ATG or other immunosuppressants should be considered as combination with PT-Cy.\n\nMobilized PBSC as graft tend to have higher risk of cGVHD compare to bone marrow even with PT-Cy strategy. In our previous study using PT-Cy and cyclosporine, though cGVHD was reduced compare to our historical control using cyclosporine, MMF and MTX regimen, moderate/severe cGVHD including BO was documented. With low dose ATG added to PT-Cy/tacrolimus, no cases of BO documented yet. Longer follow-up should be anticipated to confirm this observation. Thus, we speculated that the addition of low dose ATG may benefit patients undergoing PBSCT and may had limited benefit or no benefit in BMT setting, since BM was associated less cGVHD, Of course, it need to be tested.\n\nChronic GVHD was considered to be associated with the potential of GVL effect so that may be of benefit to relapse control. The analysis of EBMT registry data demonstrated that addition of ATG may increase the potential relapse rate after allo-HSCT for both ph+ or ph− ALL, but may improve GRFS (24, 25). Other report suggested that low-dose ATG added to PT-Cy protocol may have limited effect on relapse in Haplo setting (20). In our study, though with limited follow-up time, the early incidence of relapse (1-year) was not aggravated with addition of ATG for lymphoid malignancies, but longer follow-up was required to confirm. Nowadays, more emphasis has been put on post-transplantation treatments to prevent diseases relapse. For example, TKIs, hypomethylation agents and/or immune modulation therapy such as DLI or interferon, are all candidates for using, especially for AML patients. Thus, low incidence or no cGVHD may not be necessarily associated with increased relapse. A new clinical trial using the same GVHD prophylaxis in AML patients is undergoing in our center, which is focus on the relapse rate with low-dose decitabine as maintenance therapy after transplantation.\n\nAs to the safety of the protocol, we observed a quite high incidence of CMV reactivation particularly in patients transplanted from MUD or Haplo donor (14/16) vs. MSD (2/7, p<0.001). This high incidence of CMV reactivation may attribute to late addition of ATG even with low dose of 2.5 mg/kg due to its direct immune suppression and/or delay of CMV specific immune reconstitution (26). In further clinical study, reducing the dose of ATG or more effective CMV prophylaxis such as use of letermovir after ATG should be considered (27). Of note, we also observed two cases of secondary graft failure. Since no patient had graft failure immediately after ATG treatment and pancytopenia occurred after weeks of ganciclovir treatment, we speculated that low-dose ATG might increase the risk of CMV infection and indirectly increase the risk of secondary graft failure. However, further clinical trial with large number of patients should be warranted especially with letermovir prophylaxis.\n\nAs we know, this is the first clinical trial reported to evaluate the role of low-dose ATG added after PT-Cy in the setting of allo-HSCT with PBSCs as graft in lymphoid malignancies. The limitation of the study was the number of patients enrolled. Since the aim of Simon's stage II design was to reject the protocol early when it was unlikely to achieve optimal response, our initial data supported that PT-Cy + tacrolimus ±ATG was potentially effective in reduction of aGVHD/cGVHD and NRM. Further clinical trial with large number of patients should be warranted.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/Supplementary Material, further inquiries can be directed to the corresponding author/s.\n\nEthics Statement\n\nThe studies involving human participants were reviewed and approved by the Human Ethics Committee of the Rui Jin Hospital. The patients/participants provided their written informed consent to participate in this study.\n\nAuthor Contributions\n\nJH and LW designed the clinical trial, revised the manuscript. J-lJ and W-hG collected the clinical data, and wrote the manuscript. L-nW also helped to collect the clinical data. MW did the statistical analysis. All authors contributed to the article and approved the submitted version.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fmed.2021.630160/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1. Hill L Alousi A Kebriaei P Mehta R Rezvani K Shpall E . New and emerging therapies for acute and chronic graft versus host disease. Ther Adv Hematol. (2018) 9 :21–46. 10.1177/2040620717741860 29317998\n2. Luznik L Fuchs EJ . High-dose, post-transplantation cyclophosphamide to promote graft-host tolerance after allogeneic hematopoietic stem cell transplantation. Immunol Res. (2010) 47 :65–77. 10.1007/s12026-009-8139-0 20066512\n3. Luznik L O'Donnell PV Symons HJ Chen AR Leffell MS Zahurak M . HLA-haploidentical bone marrow transplantation for hematologic malignancies using nonmyeloablative conditioning and high-dose, posttransplantation cyclophosphamide. Biol Blood Marrow Transplant. (2008) 14 :641–50. 10.1016/j.bbmt.2008.03.005 18489989\n4. Luznik L Bolanos-Meade J Zahurak M Chen AR Smith BD Brodsky R . High-dose cyclophosphamide as single-agent, short-course prophylaxis of graft-versus-host disease. Blood. (2010) 115 :3224–30. 10.1182/blood-2009-11-251595 20124511\n5. Kanakry CG Tsai HL Bolanos-Meade J Smith BD Gojo I Kanakry JA . Single-agent GVHD prophylaxis with posttransplantation cyclophosphamide after myeloablative, HLA-matched BMT for AML, ALL, and MDS. Blood. (2014) 124 :3817–27. 10.1182/blood-2014-07-587477 25316679\n6. Mielcarek M Furlong T O'Donnell PV Storer BE McCune JS Storb R . Posttransplantation cyclophosphamide for prevention of graft-versus-host disease after HLA- matched mobilized blood cell transplantation. Blood. (2016) 127 :1502–8. 10.1182/blood-2015-10-672071 26764356\n7. Robinson TM O'Donnell PV Fuchs EJ Luznik L . Haploidentical bone marrow and stem cell transplantation: experience with post-transplantation cyclophosphamide. Semin Hematol. (2016) 53 :90–7. 10.1053/j.seminhematol.2016.01.005 27000732\n8. McCurdy SR Kasamon YL Kanakry CG Bolaños-Meade J Tsai HL Showel MM . Comparable composite endpoints after HLA-matched and HLA- haploidentical transplantation with posttransplantation cyclophosphamide. Haematologica. (2017) 102 :391–400.27846611\n9. Santoro N Ruggeri A Labopin M Bacigalupo A Ciceri F Gülbaş Z . Unmanipulated haploidentical stem cell transplantation in adults with acute lymphoblastic leukemia: a study on behalf of the Acute Leukemia Working Party of the EBMT. J Hematol Oncol. (2017) 10 :113. 10.3324/haematol.2016.144139 28558762\n10. Wang L Wang L Fan X Tang W Hu J . Fludarabine and intravenous busulfan conditioning with post-transplantation cyclophosphamide for allogeneic peripheral stem cell transplantationfor adult patients with lymphoid malignancies: a prospective single-arm phase II study. Front Med. (2020) 15 :108–15. 10.1007/s11684-019-0730-8 32524356\n11. Ruggeri A Labopin M Bacigalupo A Afanasyev B Cornelissen JJ Elmaagacli A . Post-transplant cyclophosphamide for graft-versus-host disease prophylaxis in HLA matched sibling or matched unrelated donor transplant for patients with acute leukemia, on behalf of ALWP-EBMT. J Hematol Oncol. (2018) 11 :40-49. 10.1186/s13045-018-0586-4 29544522\n12. Glucksberg H Storb R Fefer A Buckner CD Neiman PE Clift RA . Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation. (1974) 18 :295-304. 10.1097/00007890-197410000-00001 4153799\n13. Jagasia MH Greinix HT Arora M Williams KM Wolff D Cowen EW . National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and Staging Working Group report. Biol Blood Marrow Transplant. (2015) 21 :389–401.e1. 10.1016/j.bbmt.2015.02.025 25529383\n14. Jung SH Lee TY Kim KM George S . Admissible two-stage designs for phase II cancer clinical trials. Stat Med. (2004) 23 :561–69. 10.1002/sim.1600 14755389\n15. Gooley TA Leisenring W Crowley J Storer BE . Estimation of failure probabilities in the presence of competing risks: new representations of old estimators. Stat Med. (1999) 18 :695-706. 10.1002/(SICI)1097-0258(19990330)18:6<695::AID-SIM60>3.0.CO;2-O 10204198\n16. Kaplan EL Meier P . Nonparametric estimation from incomplete observations. J Am Stat Assoc. (1958) 53 :457-80. 10.1080/01621459.1958.10501452\n17. Mussetti A Greco R Peccatori J Corradini P . Post-transplant cyclophosphamide, a promising anti-graft versus host disease prophylaxis: where do we stand? Expert Rev Hematol. (2017) 10 :479–92. 10.1080/17474086.2017.1318054 28395546\n18. Montoro J Piñana JL Hernández-Boluda JC Hernani R Lorenzo I Pérez A . Uniform graft-versus-host disease prophylaxis with posttransplant cyclophosphamide, sirolimus, and mycophenolate mofetil following hematopoietic stem cell transplantation from haploidentical, matched sibling and unrelated donors. Bone Marrow Transplant. (2020) 55 :2147–59. 10.1038/s41409-020-0921-6 32371901\n19. Marani C Raiola AM Morbelli S Dominietto A Ferrarazzo G Avenoso D . Haploidentical Transplants with Post-Transplant Cyclophosphamide for Relapsed or Refractory Hodgkin Lymphoma: The Role of Comorbidity Index and Pretransplant Positron Emission Tomography. Biol Blood Marrow Transplant. (2018) 24 :2501–08. 10.1016/j.bbmt.2018.07.025 30041010\n20. El-Cheikh J Devillier R Dulery R Massoud R Al Chami F Ghaoui N . Impact of Adding Antithymocyte Globulin to Posttransplantation Cyclophosphamide in Haploidentical Stem-Cell Transplantation. Clin Lymphoma Myeloma Leuk. (2020) 20 :617–23. 10.1016/j.clml.2020.04.003 32457025\n21. Peric Z Mohty R Bastos J Brissot E Battipaglia G Belhocine R . Thiotepa and antithymocyte globulin-based conditioning prior to haploidentical transplantation with posttransplant cyclophosphamide in high-risk hematological malignancies. Bone Marrow Transplant. (2020) 55 :763–72. 10.1038/s41409-019-0726-7 31673080\n22. Esquirol A Pascual MJ Ortiz M Piñana JL Ferra C Garcia Cadenas I . Single-agent GvHD prophylaxis with tacrolimus after post-transplant high-dose cyclophosphamide is a valid option for haploidentical transplantation in adults with hematological malignancies. Bone Marrow Transplant. (2017) 52 :1273–79. 10.1038/bmt.2017.111 28604667\n23. Carnevale-Schianca F Caravelli D Gallo S Coha V D'Ambrosio L Vassallo E . Post-Transplant Cyclophosphamide and Tacrolimus-Mycophenolate Mofetil Combination Prevents Graft-versus-Host Disease in Allogeneic Peripheral Blood Hematopoietic Cell Transplantation from HLA-Matched Donors. Biol Blood Marrow Transplant. (2017) 23 :459-66. 10.1016/j.bbmt.2016.12.636 28039079\n24. Giebel S Labopin M Czerw T Socié G Blaise D Ghavamzadeh A . Impact of anti-thymocyte globulin on results of allogeneic peripheral blood stem cell transplantation for patients with Philadelphia-positive acute lymphoblastic leukaemia: An analysis by the Acute Leukemia Working Party of the EBMT. Eur J Cancer. (2019) 106 :212–9. 10.1016/j.ejca.2018.11.003 30528805\n25. Czerw T Labopin M Giebel S Socié G Volin L Fegueux N . Anti-thymocyte globulin improves survival free from relapse and graft-versus-host disease after allogeneic peripheral blood stem cell transplantation in patients with Philadelphia-negative acute lymphoblastic leukemia: An analysis by the Acute Leukemia Working Party of the EBMT. Cancer. (2018) 124 :2523-33. 10.1002/cncr.31354 29603136\n26. Huntley D Giménez E Pascual MJ Remigia MJ Amat P Vázquez L . Reconstitution of cytomegalovirus-specific T-cell immunity following unmanipulated haploidentical allogeneic hematopoietic stem cell transplantation with posttransplant cyclophosphamide. Bone Marrow Transplant. (2020) 55 :1347–56. 10.1038/s41409-020-0865-x 32205853\n27. Marty FM Ljungman P Chemaly RF Maertens J Dadwal SS Duarte RF . Letermovir prophylaxis for cytomegalovirus in hematopoietic cell transplantation. N Engl J Med. (2017) 377 :2433–44. 10.1056/NEJMoa1706640 29211658\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2296-858X",
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"journal": "Frontiers in medicine",
"keywords": "allogeneic peripheral stem cell transplantation; anti-thymoglobulin; graft vs. host disease; lymphoid malignancies; post-transplantation cyclophosphamide",
"medline_ta": "Front Med (Lausanne)",
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"nlm_unique_id": "101648047",
"other_id": null,
"pages": "630160",
"pmc": null,
"pmid": "33816524",
"pubdate": "2021",
"publication_types": "D016428:Journal Article",
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"title": "Post-transplantation Cyclophosphamide, Tacrolimus and Low-Dose ATG as GVHD Prophylaxis for Allogeneic Peripheral Stem Cell Transplantation for Adult Patients With Lymphoid Malignancies: A Single Arm Phase II Study.",
"title_normalized": "post transplantation cyclophosphamide tacrolimus and low dose atg as gvhd prophylaxis for allogeneic peripheral stem cell transplantation for adult patients with lymphoid malignancies a single arm phase ii study"
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"companynumb": "CN-SA-2021SA259915",
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"activesubstancename": "LAPINE T-LYMPHOCYTE IMMUNE GLOBULIN"
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"abstract": "Magnetic resonance imaging (MRI) is a non-invasive test with a low complication rate even when using contrast agents. Nevertheless, even routine examinations can cause serious complications, as this case illustrates.\n\n\n\nApproximately one minute after receiving an intravenous contrast agent containing gadoteric acid (Dotarem®), a woman suffered a generalised seizure and lost.\n\n\n\nAnaphylactic shock can occur as a rare complication of MRI with contrast enhancement. The examination should not be performed without a clear indication.",
"affiliations": null,
"authors": "Broch|Line|L|;Wester|Simone|S|;Haslund|Anniken|A|;Edland|Astrid|A|",
"chemical_list": "D003287:Contrast Media",
"country": "Norway",
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"keywords": null,
"medline_ta": "Tidsskr Nor Laegeforen",
"mesh_terms": "D061605:Administration, Intravenous; D000707:Anaphylaxis; D003287:Contrast Media; D005260:Female; D006801:Humans; D008279:Magnetic Resonance Imaging",
"nlm_unique_id": "0413423",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "32463188",
"pubdate": "2020-05-26",
"publication_types": "D016428:Journal Article",
"references": null,
"title": "Anaphylactic reaction to MRI contrast agent.",
"title_normalized": "anaphylactic reaction to mri contrast agent"
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{
"abstract": "Cryptococcus gattii is a species that has received more recognition in the recent past as distinct from Cryptococcus neoformans. C gattii is known to cause meningeal disease in both immunocompetent and immunosuppressed hosts. Patients may be clinically asymptomatic until immunosuppressive conditions occur such as corticosteroid treatment or an HIV infection. HIV-associated cryptococcal infections are most often due to C neoformans. C gattii is found in a minority. Speciation and subtyping of Cryptococcus are not always accomplished. In many parts of the world, there is no availability for speciation of Cryptococcus. Travel history may provide a clue to the most probable species. This case demonstrates a case of C gattii meningitis with a multiplicity of complications. These include advanced HIV disease secondary to nonadherence, immune reconstitution inflammatory syndrome, and superior sagittal sinus thrombosis. The patient represented diagnostic and therapeutic dilemmas over time. Headache was the primary symptom in cryptococcal meningitis, immune reconstitution inflammatory syndrome, and superior sagittal sinus thrombosis. All are discussed in detail as potential etiologies for the primary disease. Isavuconazonium is a relatively new broad-spectrum antifungal azole that was used as salvage therapy.",
"affiliations": "UCLA-Kern Medical, Bakersfield, CA, USA.;UCLA-Kern Medical, Bakersfield, CA, USA.;UCLA-Kern Medical, Bakersfield, CA, USA.;UCLA-Kern Medical, Bakersfield, CA, USA.;UCLA-Kern Medical, Bakersfield, CA, USA.;UCLA-Kern Medical, Bakersfield, CA, USA.;UCLA-Kern Medical, Bakersfield, CA, USA.",
"authors": "Okudo|Jerome|J|;Civelli|Valerie F|VF|0000-0002-1052-0144;Narang|Vishal K|VK|;Johnson|Royce H|RH|;Khan|Nadir|N|;Andruszko|Brittany|B|;Heidari|Arash|A|",
"chemical_list": "D000935:Antifungal Agents; D009570:Nitriles; D011725:Pyridines; D014230:Triazoles; C508735:isavuconazole",
"country": "United States",
"delete": false,
"doi": "10.1177/2324709620959880",
"fulltext": "\n==== Front\nJ Investig Med High Impact Case Rep\nJ Investig Med High Impact Case Rep\nHIC\nsphic\nJournal of Investigative Medicine High Impact Case Reports\n2324-7096 SAGE Publications Sage CA: Los Angeles, CA \n\n10.1177/2324709620959880\n10.1177_2324709620959880\nCase Report\nA Rare Case of Cryptococcus gattii Meningitis in\nAdvanced HIV Disease, Sagittal Thrombosis, and Immune Reconstitution Syndrome,\nResolved With Isavuconazonium\nOkudo Jerome MD1 https://orcid.org/0000-0002-1052-0144Civelli Valerie F. MD1 Narang Vishal K. MD1 Johnson Royce H. MD1 Khan Nadir MD1 Andruszko Brittany PharmD1 Heidari Arash MD1 1 UCLA—Kern Medical, Bakersfield, CA,\nUSA\nValerie F. Civelli, MD, Department of\nMedicine, UCLA Kern Medical, 1700 Mount Vernon Avenue, Bakersfield, CA 93306,\nUSA. Email: vcivelli@yahoo.com\n16 9 2020 \nJan-Dec 2020 \n8 23247096209598801 6 2020 3 8 2020 11 8 2020 © 2020 American Federation for Medical\nResearch2020American Federation for Medical\nResearchThis article is distributed under the terms of the Creative Commons\nAttribution-NonCommercial 4.0 License (https://creativecommons.org/licenses/by-nc/4.0/) which\npermits non-commercial use, reproduction and distribution of the work\nwithout further permission provided the original work is attributed as\nspecified on the SAGE and Open Access page (https://us.sagepub.com/en-us/nam/open-access-at-sage).Cryptococcus gattii is a species that has received more\nrecognition in the recent past as distinct from Cryptococcus neoformans.\nC gattii is known to cause meningeal disease in both\nimmunocompetent and immunosuppressed hosts. Patients may be clinically\nasymptomatic until immunosuppressive conditions occur such as corticosteroid\ntreatment or an HIV infection. HIV-associated cryptococcal infections are most\noften due to C neoformans. C gattii is found in a minority.\nSpeciation and subtyping of Cryptococcus are not always\naccomplished. In many parts of the world, there is no availability for\nspeciation of Cryptococcus. Travel history may provide a clue\nto the most probable species. This case demonstrates a case of C\ngattii meningitis with a multiplicity of complications. These\ninclude advanced HIV disease secondary to nonadherence, immune reconstitution\ninflammatory syndrome, and superior sagittal sinus thrombosis. The patient\nrepresented diagnostic and therapeutic dilemmas over time. Headache was the\nprimary symptom in cryptococcal meningitis, immune reconstitution inflammatory\nsyndrome, and superior sagittal sinus thrombosis. All are discussed in detail as\npotential etiologies for the primary disease. Isavuconazonium is a relatively\nnew broad-spectrum antifungal azole that was used as salvage therapy.\n\nCryptococcus gattiicryptococcal meningitissuperior sagittal sinus thrombusthrombus in HIVIRISisavuconazoniumazolescover-dateJanuary-December 2020typesetterts1\n==== Body\nIntroduction\nThere are approximately 1 million cases of cryptococcosis each year worldwide and an\nestimated 650 000 associated deaths. Patients with advanced HIV disease comprise the\nmajority.1-3\n\nCryptococcus has 37 known species but only 2 have been identified as\npathogenic for cryptococcosis: C neoformans and C\ngattii. In 1970, C gattii was first described in\nAustralia as a subspecies of C neoformans. It is a fungus\nassociated with several ecologic niches.4-6 In 1999, C\ngattii emerged in British Columbia and the northwest United States.\nC gattii was recognized as a separate species from C\nneoformans in 2002.7\n\nC neoformans is globally ubiquitous and accounts for nearly all\nmeningeal infections in patients with HIV. C gattii has a more\nrestricted distribution and accounts up to 15% of cryptococcal meningeal infections\nin endemic areas. The geographic range appears to be expanding with the continued\nstudy of C gattii.6,8\n\nC neoformans and C gattii are encapsulated,\nheterobasidiomycetous fungi. The asexual form is recovered from clinical cases and\nis an encapsulated yeast that reproduces by budding.9 The respiratory tract is the primary portal of entry.9 Lymphohematogenous dissemination is responsible for seeding other organs\nincluding the meninges (see Figure\n1).\n\nFigure 1. Encapsulated yeast inhaled into the respiratory tract. Lymphohematogenous dissemination.4\n\nThe lungs and the central nervous system (CNS) are the most common clinical sites of\ninfection.2,9\nInvolvement of the parenchyma of the brain and meninges occurs in 40% to 86% of patients.10 Characteristic manifestations of CNS disease include meningitis,\ncryptococcomas, and spinal cord granulomas. Patients typically present with signs\nand symptoms of meningitis including fever, headache, nausea, vomiting, focal\nneurologic deficits, memory loss, or change in consciousness including\ncloudy/delirium, obtundation/stupor, and coma.9,11\n\nOne of the most critical determinants of outcome for cryptococcal meningoencephalitis\nis the control of intracranial pressure (ICP). Approximately 50% of HIV-infected\npatients with cryptococcal meningoencephalitis demonstrate an elevated baseline ICP\n>250 mm H2O of CSF. Lumbar puncture (LP) is recommended. An opening\npressure of ≥250 mm H2O with symptoms warrants medical therapy. CSF\ndrainage should be performed sufficiently to achieve a closing pressure of <200\nmm H2O or 50% reduction of initial opening pressure.1,12\n\nNeuroimaging is performed in patients with suspected cryptococcal\nmeningitis.1,9\nIt does not alter management once cryptococcus is diagnosed. Magnetic resonance\nimaging (MRI) is preferred in patients with HIV disease and may demonstrate\nleptomeningeal enhancement or focal brain disease.9 LP for high ICP is much more important to both follow and treat elevated\nICP.\n\nCerebrospinal fluid (CSF) analysis in cryptococcosis typically reveals a lymphocytic\npleocytosis with elevated protein and decreased glucose levels. Cell counts vary\nfrom <20 cells/cmm to >100 cells/cmm.13,14 Low lymphocyte proliferative\nresponses after stimulation with antigens are particularly noted in persons with\nactive HIV disease. The CSF formula is that of chronic meningitis and is, therefore,\nthe differential diagnosis.15\n\nMycologic diagnosis is accomplished by a variety of methods including positive India\nink examination of CSF and blood, fungal cultures, and cryptococcal antigen (CrAg)\ndetection in blood and spinal fluid.9,14\n\nManagement of C gattii meningitis is approached with consideration\nfor 3 risk groups: HIV-infected individuals, organ transplant recipients, and\nostensibly immune normal hosts. For each respective risk group, therapeutic\nalgorithms have been articulated. This includes an induction phase, consolidation\nphase, and a maintenance phase. Induction therapy for meningoencephalitis involves\nfungicidal regimens, such as a polyene and flucytosine. It is followed by\nsuppressive regimens using fluconazole. Recognition of increased ICP is critical and\nshould be addressed as a separate problem from meningitis. See reference guidelines\nby the Infectious Diseases Society of America (IDSA).1\n\nThe host response to C gattii depends on the competency of the\nhost’s innate and adaptive immune systems. Host immunodeficiencies of the innate\nsystem may eventuate into clinical cryptococcal disease if there is macrophage\nfailure. For the adaptive immune system, cryptococcal disease progression is\nfacilitated in the setting of a predominately Th-2 response. There is a depletion of\nCD4+ T-helper (Th)-1 and Th-17 cells, as well as an increase in Th-2\ncells. Failure to produce a Th-1 dominate response means failed host protection\nagainst cryptococcal infection.\n\nHIV infection may be considered a failure of host cellular responses in the\nprogressed phase of disease. Initially, however, HIV selectively infects CD4+\nT-cells incognito and replicates intracellularly. It is undetected by the innate or\nthe adaptive systems. There is pathogenic hyperactivation and proliferation of\ninfected CD4+ T cells specific for antigens other than HIV. Eventually,\nCD4+ T-cell depletion results and accelerates HIV disease progression.16\n\nImmune reconstitution inflammatory syndrome (IRIS) is an immunologic exacerbation\nbased on improved host response to antiretroviral therapy. Potential treatment\nchallenges related to IRIS are well described in HIV and cryptococcal meningeal\ncoinfection.8,9\nSimilar to cryptococcal meningitis and HIV-encephalitis, the presenting symptoms\ncommonly include headache, fever, and meningismus.8 Increased ICP, hydrocephalus, and systemic inflammation can also occur.\n\nCerebral venous thrombosis (CVT) is the rarest complication of venous thrombosis in\ncryptococcal meningitis and is difficult to diagnose.17,18 Complaints of headaches\nrequire cerebral vascular imaging for diagnosis. Evidence-based recommendations\nindicate anticoagulation treatment to reduce the risk of cardiovascular\ncomplications and death. The American Heart Association and American Stroke\nAssociation recommend anticoagulation for 3 to 6 months in provoked CVT, and 6 to 12\nmonths in unprovoked CVT.18\n\nCVT occurs at an annual incidence of 3 to 5 per million and tends to affect women and\nyounger individuals.17 Risk factors for CVT include thrombophilia, infection, trauma,\nimmobilization, reproductive (especially puerperium and pregnancy), malignancy,\nmedications, inflammatory, hematological, endocrine, systemic, and intracranial abnormalities.18 Multiple risk factors of thrombosis may coexist as demonstrated in our case\n(advanced HIV disease, IRIS, and cryptococcus infection). The impact of multiple\nrisk factors for venous thrombosis and its implications for management highlights\nthe need for early comprehensive risk assessment.\n\nProphylactic strategies are considered. A heightened awareness of the potential\ndifficulty in achieving adequate anticoagulation due to drug-drug interaction in\npatients on antiretroviral regimens is merited.\n\nMethods\nKern Medical Institutional Review Board approval was obtained for review of the\npatient’s record. A literature search was conducted on PubMed, ResearchGate, Google\nScholar, and major journal databases including Infectious Diseases Society of\nAmerica, Centers for Disease Control and Prevention, and Clinical Infectious\nDiseases. The following search terms were applied: Cryptococcus\ngattii, cryptococcal meningitis, superior sagittal sinus thrombus,\ncerebral venous thrombosis, thrombus in HIV, IRIS, isavuconazonium, azole side\neffects, ICP, and meningitis. Twenty-three reference articles were pulled.\n\nCase Presentation\nA 45-year-old Caucasian man was diagnosed with HIV disease at another institution. He\nwas nonadherent with antiretroviral therapy. One month after diagnosis, he presented\nto our institution with a severe headache and vomiting for 2 days.\n\nOn physical examination, his temperature was 37.3 °C, the pulse was 63 beats per\nminute, the respiratory rate was 21 breaths per minute, and the blood pressure was\n140/91 mm Hg. The oxygen saturation was 97%, while the patient was breathing ambient\nair. He was in mild distress secondary to his headache. The general physical\nexamination was unremarkable except for mild meningismus. The neurologic examination\nrevealed normal mental status, cranial nerves, motor, gait, and balance.\n\nComplete blood count with differential revealed lymphocytopenia (0.9 × 103\ncells/µL) and routine chemistry was all normal except for mild transaminitis\n(aspartate aminotransferase 56, alanine aminotransferase 141 units/L). His absolute\nCD4+ cell count was 38 cells/µL, and his HIV-1 RNA polymerase chain reaction\nrevealed 35 284 copies/mL.\n\nLP demonstrated an opening pressure of 340 mm H2O. The CSF analysis\nrevealed a red blood cell count of 10 cells/cmm, a white blood cell count of 24\ncells/cmm, lymphocytes of 73%, monocytes of 25%, neutrophils of 1%, and eosinophils\nof 1%. CSF glucose was 56 mg/dL and CSF protein was 75 mg/dL. Analysis of the CSF\nwith India ink was positive for Cryptococcus species. Latex\nagglutination assay of CSF revealed a CrAg titer of 1:2046. Subsequently, the blood\nwas positive for yeast. Serum assay revealed a CrAg titer of 1:4096.\n\nChest radiographs showed 2 irregular noncalcified densities of the right lower lobe\nwith early central cavitation. Bron-choalveolar lavage confirmed\nCryptococcus. Neuroimaging of the head was found to be\nnegative.\n\nCryptococcal meningitis with pulmonary cryptococcoma was diagnosed. The patient was\nadmitted and started on induction therapy with intravenous liposomal amphotericin B\n(AmB) and oral flucytosine. After a 14-day course, he was discharged home on\nconsolidation therapy with fluconazole and antiretroviral therapy. He was followed\nclosely by the infectious disease clinic.1 Fungal isolates from blood and CSF were demonstrated to be C\ngattii.\n\nThe patient was hospitalized 9 times over a 12-month period for recurrence of fever,\nheadache, and elevated ICP. Therapeutic LPs with CSF removal were intermittently\nrequired. A shunt was not placed due to inconsistent need for CSF drainage beyond a\nfew days per episode.\n\nThe serum and CSF CrAg varied considerably over this time course. The maximum serum\nCrAg titer was 1:>4096 and the minimum was 1:256. The maximum CSF CrAg titer was\n1:>2048 and the minimum was 1:8. Fluconazole levels were judged to be therapeutic\n(41.4 µg/mL serum fluconazole).\n\nIn the fourth hospitalization, a follow-up MRI of the brain demonstrated the\ndevelopment of cryptococcomas in the right posterior cerebellum and left temporal\nregion. He was declared a therapeutic failure on fluconazole. Isolates were sent for\nsensitivity testing and results showed. Isolate sensitivity did not indicate drug\nresistance to any antifungal medications. Sensitivity results revealed AmB 0.5\nµg/mL, fluconazole 4.0 µg/mL, natamycin 4.0 µg/mL, itraconazole 0.25 µg/mL,\nposaconazole 0.25 µg/mL, voriconazole 0.06 µg/mL, isavuconazole (ISA) 0.125 µg/mL.\nInduction therapy with AmB and flucytosine was reintroduced for 6 weeks.\nSubsequently, consolidation therapy with voriconazole 450 mg twice daily was\ninitiated, at calculated dosing 6 mg/kg.\n\nSalvage therapy with voriconazole, did not improve his fever, headache, or elevated\nICP, prevent hospitalizations, or reduce the CSF or blood CrAg titers. He was\nadherent to therapy, but therapeutic levels were not achieved. After 3 months on\nvoriconazole, the patient developed dysphagia that drew concern for possible onset\nof IRIS or worsening CNS cryptococcosis. Candida was not\nidentified. The dysphagia self-resolved within 2 months, requiring no further\nworkup.\n\nOn the ninth hospitalization, and 1 year into treatment, an MRI of the head, revealed\na new cryptococcoma (see Figure\n2) and evidence of CVT. Magnetic resonance venography of the brain\nrevealed a superior sagittal sinus thrombosis (see Figure 3). Superior sagittal sinus thrombosis\nwas diagnosed and treated with anticoagulation therapy18 (see Figure 4 for\ndiagnoses, hospitalizations and therapeutic regiments).\n\nFigure 2. Magnetic resonance imaging of brain axial T1-weighted postcontrast with a red\narrow showing the cryptococcoma.\n\nFigure 3. Magnetic resonance venography of brain showing a red arrow at the region of\nsignal void of the sagittal 2-dimensional echo sequence source images,\nindicating a superior sagittal sinus thrombosis.\n\nFigure 4. Diagnoses, hospitalizations, and therapeutic regiments.\n\nMost of the patient’s treatment was spent inpatient. He was started on multiple\nrounds of induction therapy, with regiment durations of 2 weeks or 6 weeks.\nTypically, he ended up in the emergency room with hospitalization for elevated ICP.\nConsolidation therapies included fluconazole and voriconazole, both of which failed,\ndespite patient adherence. The therapeutic levels of antifungal medications were\nmeasured in the serum regularly throughout treatment. Therapeutic levels were\nachieved consistently with fluconazole antifungal treatment. Voriconazole was\nconsistently identified at subtherapeutic in the serum despite patient\nadherence.\n\nIsolate sensitivity did not suggest resistance, but his worsening condition warranted\ntherapeutic modification. Antifungal therapy was switched from voriconazole to ISA\n372 mg daily. Concern for IRIS was also increasing. Antifungal and antiretroviral\ntherapies were continued in accordance to guidelines. No treatment holiday was\ntaken. Treatment efforts were focused on ICP control, anticoagulation therapy for\nCVT, and continued adherence to antifungal therapy and medications for HIV.\n\nThe patient’s cryptococcal disease significantly improved since his transition to\nISA. His headache and ICP improved. His absolute CD4+ cell count was 308 cells/µL.\nHIV-1 RNA polymerase chain reaction was not detected (<20 copies/mL: “not\ndetected”) at his 1-year follow-up. The superior sagittal sinus thrombosis also\nresolved as demonstrated by magnetic resonance venography. There have not been any\nfurther hospitalizations since ISA therapy. He is adherent to ISA maintenance\ntherapy and antiretroviral therapy 12 months after the ninth hospital discharge.\n\nDiscussion\nEight cases were found in the medical literature that recognize concomitant\ncryptococcal meningitis and CVT (Table 1). Five of these 8 cases involve\nindividuals with HIV disease. Specifically, CVT was identified in the transverse\nsinus, superior sagittal sinus, and sigmoid sinuses in these 8 cases. C\nneoformans was found in half of the recorded cases, while 3 did not\ndistinguish the species. We were unable to identify any instances of CVT involving\nC gattii. Additionally, none of these cases demonstrated the\nmultiplicity of problems, extensive hospitalizations, and specific therapy as\nreported here.\n\nTable 1. Literature Review of Cryptococcal Meningitis.\n\nStudy\tPublishing type\tCountry\tAge (years)\tFirst symptom at presentation\tThrombosis location\tIRIS\tHIV disease (CD4+ count at time of\ndiagnosis)\tCryptococcus meningitis and\nspecies\t\nThiansukhon et al19\tPoster\tThailand\t49\tHeadache\tStraight sinus\nTransverse and sigmoid venous sinuses\nbilaterally\tNo\tYes\nCD4+ count: 70 cells/mm3\tYes\nCryptococcus neoformans\t\nAlejandra et al20\tCase report\tMexico\t21\tHeadache\tLeft transverse sinus\nBilateral sigmoid sinuses\tNo\tYes\nCD4+ count: 96 cells/mm3\tYes\nNo speciation\t\nSenadim et al21\tCase report\tTurkey\t19\tHeadache\tRight transverse sinus\tNo\tNo\tYes\nCryptococcus neoformans\t\nKulkarni et al22\tCase report\tIndia\t37\tHeadache\tSuperior sagittal sinus\nRight transverse\nsinus\nProximal internal jugular vein\tNo\tYes\nCD4+ count: 24 cells/mm3\tYes\nNo speciation\t\nRen et al23\tCase report\tChina\t31\tHeadache\tBilateral transverse sinus\nSuperior sagittal\nsinus\nInferior longitudinal sinus\tNo\tNo\tYes\nNo speciation\t\nEquiza et al24\tCase report\tSpain\t45\tHeadache, dizziness, nausea\tRight transverse sinus\nRight sigmoid sinus\tNo\tYes\nUnknown\tYes\nCryptococcus neoformans\t\nMohamed et al25\tCase report\tKenya\t40\tHeadache, vomiting, blurred vision, painful Right eye\tDistal superior sagittal sinus\nLeft transverse sinus\tNo\tYes\nCD4+ count: 9 cells/mm3\tYes\nNo speciation\t\nKammeyer and Lehmann26\tCase report\tUnited States\t61\tHeadache, chills, night sweats\tLeft transverse and sigmoid sinus\tNo\tNo\tYes\nCryptococcus neoformans\t\nHeidari\n 2020\tCase report\tUnited States\t45\tHeadache\tSuperior sagittal sinus\tYes\tYes\nCD4+ count: cells/mm3\tYes\nCryptococcus gattii\t\nAbbreviation: IRIS, immune reconstitution inflammatory syndrome.\n\nA failed induction or consolidation therapy requires a modification of dose,\nduration, or change of the therapeutic agent. Relapse of signs and symptoms during\ntreatment should be carefully assessed to decipher between a failure to control\nfungal growth from drug resistance, or adherence, or IRIS. IRIS is an additional\nproblem seen in HIV and can mimic therapeutic failure. Secondary resistance to\nfluconazole is an emerging problem in some geographical locations. This was not case\nin our patient as demonstrated by the sensitivity results (AmB 0.5 µg/mL,\nfluconazole 4.0 µg/mL, natamycin 4.0 µg/mL, itraconazole 0.25 µg/mL, posaconazole\n0.25 µg/mL, voriconazole 0.06 µg/mL, isavuconazole 0.125 µg/mL). In persistent and\nrelapse infections, isolates should be submitted for sensitivity testing and\nalternative agents should be considered.1\n\nLow CD4+ counts (<200 cells/mm3), high viral load, and nonadherence to\nantiretroviral therapies are all risk factors for venous thrombosis. The most common\nrisk factor is an ongoing infection. Proinflammatory cytokines, interluekin-6 and\nTNF-α, and endothelial activation have been implicated as underlying pathogenesis.27\n\nPatients with advanced HIV disease with active C gattii meningitis\nappear to be at a higher risk for complications than persons without HIV disease.\nIndividuals with Cryptococcus and HIV disease are at substantial\nrisk for IRIS. IRIS is most probable in patients who have a very low CD4 count\n(<200 cells/mm3) when antiretroviral therapy is initiated. HIV therapy\nwas difficult in this patient because he was not adherent at both the first\ninstitution and at our institution with initial therapies. With varying timelines of\npoor adherence and monitoring of his ART medications, all may have contributed to\nthe development of IRIS. The timing of initiating antiretroviral therapy remains\nchallenging.\n\nMinor IRIS manifestations will typically resolve spontaneously in days to weeks.\nMajor IRIS complications, such as CNS inflammation with increased ICP may require corticosteroids.1 The exactness of when to initiate antiretroviral therapy in the setting of\ncryptococcus and HIV coinfection to side skirt IRIS remains indeterminate.\nRecommendations propose a wide range of 2 to 10 weeks should be undertaken to\naccommodate this uncertainty.1\n\nConclusion\nPatients with complex cryptococcal disease may have a multiplicity of complications\nthat include increased ICP, hydrocephalus, and CVT. An additional complication is\nIRIS more common in HIV patients. The clinical presentation of these symptoms may\noverlap significantly. Significant effort is required to discern the appropriate\ntherapeutic intervention to achieve resolution.\n\nAuthors’ Note: This case has been presented at the American Federation of Medical Research’s\nWestern Conference, January 2019, as well as the Infectious Disease Association\nof California’s 34th Annual Fall Symposium, November 2019.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the\nresearch, authorship, and/or publication of this article.\n\nFunding: The author(s) received no financial support for the research, authorship, and/or\npublication of this article.\n\nEthics Approval: Ethical approval to report this case was obtained from the Kern Medical\nInstitutional Review Board (Approval ID: 20026).\n\nInformed Consent: Informed consent for patient information to be published in this article was not\nobtained.\n\nORCID iD: Valerie F. 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"fulltext_license": "CC BY-NC",
"issn_linking": "2324-7096",
"issue": "8()",
"journal": "Journal of investigative medicine high impact case reports",
"keywords": "Cryptococcus gattii; IRIS; azoles; cryptococcal meningitis; isavuconazonium; superior sagittal sinus thrombus; thrombus in HIV",
"medline_ta": "J Investig Med High Impact Case Rep",
"mesh_terms": "D000935:Antifungal Agents; D002555:Cerebrospinal Fluid; D056285:Cryptococcus gattii; D015658:HIV Infections; D006801:Humans; D054019:Immune Reconstitution Inflammatory Syndrome; D008297:Male; D016919:Meningitis, Cryptococcal; D008875:Middle Aged; D009570:Nitriles; D011725:Pyridines; D054063:Superior Sagittal Sinus; D013927:Thrombosis; D014230:Triazoles",
"nlm_unique_id": "101624758",
"other_id": null,
"pages": "2324709620959880",
"pmc": null,
"pmid": "32935587",
"pubdate": "2020",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": "21291588;17921651;20651641;15067312;19806246;25210020;31863401;11346263;22016503;27025504;18783326;23874010;20047480;21488192",
"title": "A Rare Case of Cryptococcus gattii Meningitis in Advanced HIV Disease, Sagittal Thrombosis, and Immune Reconstitution Syndrome, Resolved With Isavuconazonium.",
"title_normalized": "a rare case of cryptococcus gattii meningitis in advanced hiv disease sagittal thrombosis and immune reconstitution syndrome resolved with isavuconazonium"
} | [
{
"companynumb": "US-BAXTER-2020BAX020558",
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"occurcountry": "US",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLUCONAZOLE"
},
"drugadditional": "1",
... |
{
"abstract": "Drug Rash with Eosinophilia and Systemic Symptoms (DRESS) syndrome is characterised by fever, rash, eosinophilia and organ damage that develops 2-6 weeks after the initiation of a medication. We report a case of DRESS syndrome in a 79-year-old man that developed after the introduction of rifabutin, ethambutol and clarithromycin used to treat Mycobacterium avium complex (MAC) vertebral osteomyelitis. This case highlights treatment and management challenges in a patient with known MAC vertebral osteomyelitis requiring prolonged steroids. Steroids are the mainstays of treatment for moderate to severe cases of DRESS syndrome. Initiation of steroids for the treatment of DRESS syndrome among patients with concomitant infections requires multidisciplinary collaboration for optimal management.",
"affiliations": "School of Medicine and Health Sciences, George Washington University, Washington DC, USA.;School of Medicine and Health Sciences, George Washington University, Washington DC, USA.;School of Medicine and Health Sciences, George Washington University, Washington DC, USA.;School of Medicine and Health Sciences, George Washington University, Washington DC, USA.",
"authors": "Blair|Paul W|PW|;Herrin|Douglas|D|;Abaalkhail|Nawaf|N|;Fiser|Wesley|W|",
"chemical_list": "D000900:Anti-Bacterial Agents; D017828:Rifabutin; D004977:Ethambutol; D017291:Clarithromycin; D011241:Prednisone",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1757-790X",
"issue": "2015()",
"journal": "BMJ case reports",
"keywords": null,
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000368:Aged; D000900:Anti-Bacterial Agents; D017291:Clarithromycin; D063926:Drug Hypersensitivity Syndrome; D004977:Ethambutol; D006801:Humans; D008111:Liver Function Tests; D008297:Male; D015269:Mycobacterium avium Complex; D015270:Mycobacterium avium-intracellulare Infection; D010019:Osteomyelitis; D011241:Prednisone; D017828:Rifabutin; D016896:Treatment Outcome",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "26438676",
"pubdate": "2015-10-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "20609861;23114284;18583892;23602183;21592453;21143513;23602182",
"title": "DRESS syndrome presenting after initiation of mycobacterium avium complex osteomyelitis treatment.",
"title_normalized": "dress syndrome presenting after initiation of mycobacterium avium complex osteomyelitis treatment"
} | [
{
"companynumb": "US-WATSON-2016-12253",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "RIFABUTIN"
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"drugadditional": null,
"d... |
{
"abstract": "Flecainide is recommended as a first-line antiarrhythmic drug to maintain normal sinus rhythm in patients with atrial fibrillation (AF) who have structurally normal hearts or hypertension without left ventricular hypertrophy. Flecainide is a sodium channel blocker with minimal effects expected on ventricular repolarization. We describe the case of a 32-year-old man with a structurally normal heart and persistent AF who was started on diltiazem and flecainide 50 mg twice/day approximately a year prior to presentation. Due to persistent and bothersome symptoms, his dose was increased to 150 mg twice/day, which was associated with a progressive lengthening of his corrected QT interval. On the day of presentation, he underwent an exercise test as part of his job requirements. While running, he felt lightheaded and experienced a syncopal event and cardiac arrest. An automated external defibrillator was available that displayed polymorphic ventricular tachycardia. The patient was successfully resuscitated. Although rare, this case suggests that flecainide can induce QT prolongation leading to torsades de pointes. Clinicians should be aware and consider periodic evaluations with electrocardiograms.",
"affiliations": "Department of Internal Medicine, Baylor Scott & White Healthcare, Temple, Texas; College of Medicine, Texas A&M University Health Science Center, Temple, Texas.",
"authors": "Oguayo|Kevin N|KN|;Oyetayo|Ola O|OO|;Costa|Steven M|SM|;Mixon|Timothy A|TA|",
"chemical_list": "D000889:Anti-Arrhythmia Agents; D005424:Flecainide",
"country": "United States",
"delete": false,
"doi": "10.1002/phar.1403",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "34(5)",
"journal": "Pharmacotherapy",
"keywords": "QT interval; antiarrhythmic drugs; atrial fibrillation; flecainide; torsades de pointes",
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000328:Adult; D000889:Anti-Arrhythmia Agents; D001281:Atrial Fibrillation; D047548:Defibrillators; D005424:Flecainide; D006323:Heart Arrest; D006801:Humans; D008133:Long QT Syndrome; D008297:Male; D012151:Resuscitation; D016896:Treatment Outcome",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "e30-3",
"pmc": null,
"pmid": "24510469",
"pubdate": "2014-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "An unusual case of flecainide-induced QT prolongation leading to cardiac arrest.",
"title_normalized": "an unusual case of flecainide induced qt prolongation leading to cardiac arrest"
} | [
{
"companynumb": "US-ROXANE LABORATORIES, INC.-2015-RO-00266RO",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "FLECAINIDE ACETATE"
},
"dr... |
{
"abstract": "BACKGROUND\nDrug eruptions range from transient erythema to the life threatening severe cutaneous adverse reactions (SCAR) that encompass Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms complex (DRESS).\n\n\nOBJECTIVE\nTo study the clinical and epidemiological aspects of cutaneous adverse drug reactions (CADR).\n\n\nMETHODS\nEthical clearance was obtained from the institutional ethics committee. All patients admitted in the Dermatology ward of our tertiary care hospital with CADR (those who fit in the category of probable or possible drug reaction as per WHO casuality assessment) from first September 2011 to 31(st) August 2012 were included in this cross sectional study after obtaining written informed consent. The drug reaction patterns observed in the study population were determined and the common offending drugs were identified.\n\n\nRESULTS\nIn the study, population of males outnumbered females and the majority were between 46 and 60 years of age. The commonest reaction pattern observed was SJS- TEN spectrum of illness and aromatic anticonvulsants were the common offending drugs. Prompt withdrawal of the culprit drug and administration of systemic steroids with or without I/V Ig reverted the adverse reaction in all except one.\n\n\nCONCLUSIONS\nSevere drug reactions predominated as the study population was comprised of inpatients of a tertiary referral centre. Though; previous authors had reported a mortality rate of up to 20% in DRESS, all our patients with this reaction pattern, responded well to treatment. The mortality rate among TEN cases was much lower than the previous reports. Early diagnosis, prompt withdrawal of the suspected drug, careful monitoring for development of complications and immediate intervention can improve the prognosis of CADR.",
"affiliations": "Department of Dermatology and Venereology, Govt. Medical College, Kozhikode, Kerala, India.;Department of Dermatology and Venereology, Govt. Medical College, Kozhikode, Kerala, India.;Department of Dermatology and Venereology, Govt. Medical College, Kozhikode, Kerala, India.;Department of Dermatology and Venereology, Govt. Medical College, Kozhikode, Kerala, India.;Department of Dermatology and Venereology, Govt. Medical College, Kozhikode, Kerala, India.;Department of Dermatology and Venereology, Govt. Medical College, Kozhikode, Kerala, India.",
"authors": "Sasidharanpillai|Sarita|S|;Riyaz|Najeeba|N|;Khader|Anza|A|;Rajan|Uma|U|;Binitha|Manikoth P|MP|;Sureshan|Deepthi N|DN|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0019-5154.147834",
"fulltext": "\n==== Front\nIndian J DermatolIndian J DermatolIJDIndian Journal of Dermatology0019-51541998-3611Medknow Publications & Media Pvt Ltd India IJD-60-102c10.4103/0019-5154.147834E-IJD Original ArticleSevere Cutaneous Adverse Drug Reactions: A Clinicoepidemiological Study Sasidharanpillai Sarita Riyaz Najeeba Khader Anza Rajan Uma Binitha Manikoth P Sureshan Deepthi N From the Department of Dermatology and Venereology, Govt. Medical College, Kozhikode, Kerala, IndiaAddress for correspondence: Dr. Sarita Sasidharanpillai, ‘Rohini’, Girish Nagar, Nallalom PO, Kozhikode - 673 027, Kerala, India. E-mail: saritasclt@gmail.comJan-Feb 2015 60 1 102 102 3 2013 6 2013 Copyright: © Indian Journal of Dermatology2015This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nDrug eruptions range from transient erythema to the life threatening severe cutaneous adverse reactions (SCAR) that encompass Stevens–Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), acute generalized exanthematous pustulosis (AGEP) and drug reaction with eosinophilia and systemic symptoms complex (DRESS).\n\nAims and Objectives:\nTo study the clinical and epidemiological aspects of cutaneous adverse drug reactions (CADR).\n\nMaterials and Methods:\nEthical clearance was obtained from the institutional ethics committee. All patients admitted in the Dermatology ward of our tertiary care hospital with CADR (those who fit in the category of probable or possible drug reaction as per WHO casuality assessment) from first September 2011 to 31st August 2012 were included in this cross sectional study after obtaining written informed consent. The drug reaction patterns observed in the study population were determined and the common offending drugs were identified.\n\nResults:\nIn the study, population of males outnumbered females and the majority were between 46 and 60 years of age. The commonest reaction pattern observed was SJS- TEN spectrum of illness and aromatic anticonvulsants were the common offending drugs. Prompt withdrawal of the culprit drug and administration of systemic steroids with or without I/V Ig reverted the adverse reaction in all except one.\n\nConclusion:\nSevere drug reactions predominated as the study population was comprised of inpatients of a tertiary referral centre. Though; previous authors had reported a mortality rate of up to 20% in DRESS, all our patients with this reaction pattern, responded well to treatment. The mortality rate among TEN cases was much lower than the previous reports. Early diagnosis, prompt withdrawal of the suspected drug, careful monitoring for development of complications and immediate intervention can improve the prognosis of CADR.\n\nDrug reactiondrug reaction with eosinophilia and systemic symptoms complexepidemiology\n==== Body\nWhat was known?\n\nCADR range from mild cutaneous manifestations to life threatening SCAR. Early diagnosis of CADR is necessary for the effective management.\n\nIntroduction\nDrug reactions are unwanted reactions of the body that occur following the administration of drugs and that are not characteristic of the desired pharmacodynamic effects.[1] They vary from transient erythema to severe forms (collectively designated as SCAR).[2] The pattern of drug reactions and the offending drugs show changing trends with the introduction of newer drugs. Drug reactions are most often under-reported and many questions regarding the pathogenesis are yet to be addressed. They can mimic viral exanthemes or neoplastic diseases or collagen vascular diseases. A high degree of suspicion is required to make a prompt diagnosis which is crucial in the management of CADR. In this study; we have tried to determine the different patterns of drug reactions and the offending drugs in patients who were admitted in the Dermatology ward of our institution with CADR during the one year study period.\n\nMaterials and Methods\nEthical clearance was obtained from the institutional ethics committee.\n\n\nInclusion criteria\nPatients admitted in the Dermatology ward of our tertiary care hospital during the study period (from 1st September 2011 to 31st August 2012) with CADR, were classified as probable, possible or unlikely case of drug reaction, as per WHO definitions[3]. After obtaining written informed consent, only the probable and possible cases on causality assessment were included in the study (we can’t comment whether they were certain CADR, as drug rechallenge was not performed) DRESS, SJS, TEN and AGEP were considered as SCAR as per RegiSCAR group recommendations.[1].\n\nExclusion criteria\nPatients who developed CADR following intake of homeo, ayurveda and indigenous medicines were excluded from the study.\n\nA pre-set proforma (see appendix) was used to collect patients’ details including demographic data, detailed clinical history, past history and comorbidities. To determine the culprit drug, the drug history, temporal correlation with the drug, duration of skin lesions, time interval between the drug intake and onset of rash, morphology of drug eruption, associated mucosal or systemic involvement and improvement of lesions on withdrawl of drug were carefully analysed, In patients receiving multiple drugs, the most likely offending agent was identified on the basis of the type of reaction and the latent period between drug intake and the onset of reaction and this was further confirmed by the improvement on the withdrawal of the same. Blood and urine investigations, liver function test, renal function test, random blood sugar estimation and screening for retro infection were done in all. Chest radiography and ultrasound abdomen were done in relevant cases. Different types of drug reactions manifested in the study population were studied and the culprit drugs were noted.\n\nResults\nDuring the one year study period, 43 of 106 patients (40.6%) who attended our dermatology department with CADR required hospitalization. Fourteen patients (32.6% of total admissions due to CADR) were admitted through the emergency department. Of these 14, there were 10 cases of TEN, 2 of SJS and one each of AGEP and exfoliative dermatitis. Males outnumbered females (the male to female ratio being 1.5:1). There was a male preponderance in all types of drug reactions with the exception of DRESS and erythema multiforme (EM). Majority was in the 46-60 years age group with a decline in prevalence of drug reactions in those above 60 [Table 1]. The commonest reaction pattern [Table 2] observed was SJS-TEN (5 were SJS and 12 were TEN) [Figure 1] followed by maculopapular rash [Figure 2] and DRESS [Figure 3]. Commonest drug group producing reactions were aromatic anticonvulsants (20/43, 46.5%) followed by antibiotics and NSAIDs [Table 3]. Phenytoin was the commonest offender followed by carbamazepine. In 48% of SCAR cases, the culprit drug was aromatic anticonvulsants, whereas NSAIDs and antibiotics contributed to 32% of SCAR. Compared to phenytoin, carbamazepine was more commonly associated with SCAR (five out of eleven CADR produced by phenytoin and six out of eight reactions induced by carbamazepine were SCAR). Non-SCAR reactions in the study population were commonly induced by phenytoin (6), antibiotics (5) and NSAIDs (4). Fifty percent of non-SCAR reactions were caused by NSAIDs and antibiotics. One female patient presented with multiple lesions of FDE [Figure 4].\n\nTable 1 Age distribution in drug reactions\n\nTable 2 Drug reaction patterns\n\nFigure 1 Spots of toxic epidermal necrolysis\n\nFigure 2 Erythematous macules and papules of maculopapular drug rash\n\nFigure 3 Erythema, oedema and pustulation in drug reaction with eosinophilia and systemic symptoms complex\n\nTable 3 Drugs producing adverse reactions\n\nFigure 4 Well circumscribed, hyperpigmented lesions of fixed drug eruption\n\nLatent period between the drug intake and the onset of symptoms varied from 12h to 21 days in drug reactions other than DRESS [Figure 5]. One patient who gave history of fixed eruption following etoricoxib, on re-exposure to the same drug developed similar lesion within 12 h. With antibiotics and NSAIDs, the usual time interval observed between the drug intake and the onset of adverse reaction was one to three days, whereas anticonvulsants produced reactions other than DRESS within a span of 12 to 21 days. In DRESS, this latent period varied from 21 to 90 days with an average of 37 days.\n\nFigure 5 Time interval between drug intake and onset of reaction\n\nTwelve of forty three (27.9%), developed reaction following drug intake for an infectious illness (antibiotics or NSAIDs).\n\nFrom Table 4, it is obvious that eosinophilia (eosinophil count above 450 cells/mm3) constitutional symptoms, lymphadenopathy and LFT derangement were more prevalent among severe drug reactions. All the DRESS patients in our study had systemic involvement in the form of LFT derangement. Two DRESS patients (after intake of carbamazepine and phenytoin respectively) had lung involvement in the form of pneumonitis. Though systemic involvement was more common in DRESS cases, they had relatively less severe skin and mucosal involvement (limited to scaling of lips in five patients and two patients had conjunctival congestion in addition). Facial erythema and oedema was more marked in phenytoin induced DRESS.\n\nTable 4 Extracutaneous manifestations in drug reactions\n\nThe SJS-TEN patient who had LFT derangement, manifested more severe mucocutaneous involvement. On the contrary, the patients with maculopapular drug rash and EM who developed LFT derangement had no other clinical differences, from their counterparts without liver function abnormality.\n\nComorbidities noted in our study population were hypertension (3 patients), diabtes mellitus (1 patient), interstitial nephritis (1 patient), cirrhosis liver (one patient) and coronary artery disease (1 patient). In addition one patient had multiple comorbidities (diabetes mellitus, hypertension and chronic obstructive pulmonary disease) and he succumbed to his illness. Except in the patient with coronary artery disease (who developed AGEP following intake of diltiazem prescribed for ventricular fibrillation) in all others drug reactions were precipitated by medications given for unrelated ailments. None of our patients had coexisting retro-infection or collagen vascular disease.\n\nOne patient who came to us with SJS following intake of etoricoxib gave history of reactions to multiple drugs (diclofenac, paracetamol and ketorolac) in the past. This was a 45-year old female, who was taking NSAIDs for arthritis of knee and ankle joints for the past 9 years. Three other patients in the study group gave history of drug reactions in the past and all these three developed reactions during the study period, on re-exposure to the same drug that had produced adverse reaction in the past (etoricoxib, doxycyclin and cefadroxyl respectively were the causative drugs).\n\nNone of our patients gave history of CADR in a close family member.\n\nAll our patients with drug rashes were treated with the withdrawal of the culprit drug and administration of 1-2 mg/kg body weight of prednisolone or dexamethasone equivalent. In addition, I/V Ig were given to SJS-TEN patients with severe skin and mucosal involvement. All except one patient, responded to this line of management. The lone patient who didn’t improve was a 67 year old male who suffered TEN following carbamazepine taken for post herpetic neuralgia. He had multiple comorbidities and he expired on the 6th post-admission day, thus producing a mortality rate of 8.3% (1/12) among the TEN cases of the study group.\n\nTwo of our DRESS patients, on tapering the steroids, developed rebound flare up but responded to a higher dose of steroids which was tapered more slowly. In all except these two, we were able to stop steroids within three weeks. Average duration of hospital stay was maximum for SJS-TEN patients and ranged from two to six weeks. For DRESS and AGEP this varied from one to two weeks. In all other drug reactions we were able to discharge the patients within a week. Though DRESS patients were at a higher risk for developing systemic involvement, once diagnosed we were able to manage them relatively easily (with withdrawal of the culprit drug and administration of systemic steroids).\n\nThe major complication observed in the study population was septicemia. Six of our patients developed this complication and all of them suffered from SJS-TEN spectrum of illness. One of the TEN patients, developed adult respiratory distress syndrome and required ventelatory care.\n\nDiscussion\nA significant percentage of CADR patients who attended our department required inpatient care. This could be due to the fact that patients with more severe reactions seek medical aid in a tertiary referral centre. Analysis of data revealed that most of our patients were in the 46-60 years age group, in concordance with the observations made by many previous authors.[45] This is attributed to an increased use of medicines as age advances, leading to a heightened potential for drug to drug interactions and altered drug handling by the body.[6] The sharp decline after 60 could be due to the immunodeficiency associated with old age. There are studies that have documented a higher prevalence of drug reactions in the 20-40 age group.[678] The age disparity in various studies may be due to the regional variations in health care seeking behaviour of the population.[7] As in our study; male predominance was documented in many other studies.[78] Heizerling et al.,[9] and Pudukadan et al.,[6] reported a higher prevalence among females.\n\nTime interval between the onset of drug intake and the manifestation of CADR and the pattern of reaction observed were used to determine the offending drug in patients on polypharmacy and we were able to identify the culprit drug in all our patients.\n\nTime interval between the drug intake and the onset of reaction vary with the type of CADR. It ranges from less than a day in urticaria to three weeks to 3m in DRESS. Any drug can produce maculopapular rash at any time upto three weeks after the onset of drug intake. On re-exposure to the same drug, all these reactions can develop within 24 h.\n\nAll drugs are capable of producing any type of reaction in susceptible individuals but some drugs are more likely to induce certain reaction patterns and this can also give a clue regarding the likely causative drug. Aromatic anticonvulsants, antituberculous drugs, pencillins, cephalosporins, sulfa group of drugs, allopurinol and NSAIDs are more likely to produce SJS-TEN spectrum of illness. The drugs well known to produce DRESS are aromatic anticonvulsants, lamotrigine, minocycline, salazopyrine and dapsone. Urticaria is commonly produced by pencillins, angiotensin converting enzyme inhibitors (ACE inhibitors), aspirin and other NSAIDs. FDE is commonly associated with NSAIDs, tetracyclins, doxycyclin, cotrimoxazole, pencillins, cephalosporins and phenobarbitone, Exfoliative dermatitis is known to be induced by antibiotics, NSAIDs, dapsone, anticonvulsants etc., Macrolide antibiotics, hydroxychloroquin, and diltiazem are well known to induce AGEP.[10] The female patient who presented with multiple lesions of FDE gave a history of recurrent attacks of one or two FDE lesions for the past one year. A detailed drug history revealed that she was receiving amitryptilline and NSAID for peripheral neuropathy intermittently during the above mentioned period. With the appearance of FDE, she was asked to avoid NSAID which is commonly associated with FDE and was continued on amitryptilline. We advised her to stop amitryptilline and the present episode was managed with systemic steroids. She was relieved of the lesions and has remained symptom free to this date. Repeated exposures to the causative drug can result in increase in number of FDE lesions, ultimately developing TEN. Our patient was continued on amitryptilline considering it to be an innocuous drug.\n\nOne of our patients developed SJS-TEN to antituberculous treatment (ATT), ATT was stopped and the patient was managed with I/V Ig and steroids. He responded to this management and was referred to the chest physician for further treatment of his pulmonary tuberculosis. He was treated with second line ATT regimen comprising of ethionamide, kanamycin, cycloserin, levofloxacin and para aminosalicylic acid. The patient developed a recurrence of SJS in a more severe form within a week, which was again managed with withdrawal of the drugs, systemic steroids and I/V Ig. As our patient manifested reaction to both these regimens and as INH and ethionamide are structurally related after subsidence of reaction he was restarted on first line ATT, with INH being substituted by levofloxacin and he completed the course of treatment without any further complications.\n\nIn previous studies commonest reaction pattern detected was maculopapular rash,[791112] or fixed drug eruption.[6] Our study was conducted in patients who required inpatient management in a tertiary care hospital. This could be the reason for the predominance of SCAR in our study. Again this could be the reason for anticonvulsants (known to produce more severe adverse reactions)[7] being the commonest offender in this study as against antimicrobials.[6911]\n\nEosinophilia was almost an exclusive finding of severe drug reactions, a similar observation was made by Pudukadan et al.[6]\n\nBetter prognosis observed in DRESS could be attributed to the milder skin and mucosal involvement in this reaction pattern. Our finding of relatively less severe mucocutaneous involvement in DRESS was noted by previous authors and it is proposed to be due to the expansion of regulatory T (Treg) cells in DRESS that migrate to skin and suppress the activation of effector T-cells. In SJS-TEN spectrum, it is suggested that the migration of Treg cells to skin is inhibited, thus removing their inhibitory role on T-cell inflammatory response.[13] Our observation of flare up noticed in two patients with DRESS, on tapering steroids has been well documented in literature.[1415] These patients had more severe manifestations including marked derangement of liver enzymes and pneumonitis. The causative drugs were dapsone and carbamazepine respectively.\n\nThough it is suggested that coexisting collagen vascular disorders and genetic factors can predispose to adverse drug reactions, none among the study population had coexisting collagen vascular disease or a family history of drug reaction.\n\nProlonged hospital stay in SJS-TEN was expected as all these patients had varying degrees of epidermal detachment. The same could be the reason for development of septicemia in 6 SJS-TEN cases. Though not common, ARDS has been described in SJS-TEN, as witnessed in one of our patients, which if not tackled promptly, can end up fatally. Tracheobronchial sloughing and septicemia are the common precipitating causes for ARDS in SJS-TEN. Hence tachypnoea and dyspnoea in CADR, especially SJS-TEN, should be considered as warning signs and should be dealt on an emergency basis. The mortality rate observed among TEN cases in this study was much lower than the previous reports,[12] probably due to early intervention in a referral centre.\n\nConclusion\nThe commonest reaction pattern observed in our study was SJS – TEN spectrum of disease. There was a male preponderance and the commonest age group affected was 46-60 years. Eosinophilia was a feature of more severe reactions. Early diagnosis and prompt withdrawl of the offending drug and administration of systemic steroids with or without I/V Ig can be life saving in CADR. Though DRESS was more commonly associated with constitutional symptoms and systemic involvement, more complications and prolonged morbidity were associated with SJS-TEN, probably due to widespread epidermal detachment and due to higher chance of life threatening complications like septicemia and ARDS. We need more studies on drug reactions as the common offending drugs varies with the general prescription practices in a region, which depend on the common infections and the life style diseases prevalent in that particular population.\n\nWhat is new?\n\nEarly diagnosis, prompt withdrawal of the suspected drug and administration of systemic steroids with careful monitoring of vital signs for early detection of complications and management of the same in an ICU with modern critical care facilities can improve the prognosis in SCAR.\n\nAcknowledgment\nWe are grateful to all the faculty and postgraduates in the department for their invaluable help in conducting this study.\n\nSource of support: Nil\n\nConflict of Interest: Nil.\n\nAppendix: Severe cutaneous adverse drug reactions: A clinicoepidemiological study\nCase No:\n\nName: Age: yrs. Sex: M/F\n\nOccupation: Address:\n\nPresenting complaints:\n\nDate of Admission:\n\nDate of onset of illness:\n\nDate of onset of Upper Respiratory Illness (if present)\n\nDate of onset of rash:\n\nConstitutional symptoms (If present):\n\nConjunctival congestion, Sore throat, Fever, Myalgia, Arthralgia, Cough, Diarrhoea, Abdominal pain, Yellowish discolouration of urine, Pain on micturition\n\nDistribution of rash: Face/Chest/Abdomen/Back of trunk/Upper arms/Fore arms/Thigh/Leg/Palms/Soles\n\nSite of onset of rash: Face/Chest/Abdomen/Back of trunk/Upper arms/Fore arms/Thigh/Leg/Palms/Soles\n\nRash: Pruritic/painful/asymptomatic/burning sensation\n\nEvolution of disease:\n\nMucosal involvement: oral/conjunctival/Nasal/Genital\n\nTime interval between constitutional symptoms and mucosal involvement\n\nMention the offending drug:\n\nDrug intake: Before appearance of constitutional symptoms\n\nFollowing appearance of constitutional symptoms\n\nTime interval between drug intake and appearance of symptoms:\n\nPast History:\n\nCurrent medication:\n\nHistory of drug reaction in the past:\n\nIf yes, mention the drug\n\nSpecify the type of reaction\n\nHistory of collagen vascular disease:\n\nIf yes, specify the disease\n\nPersonal history including addictions:\n\nFamily history:\n\nHistory of drug reactions in family members:\n\nFamily history of collagen vascular diseases: Yes/No\n\nIf yes, specify the disease:\n\nGeneral examination\n\nBuilt and nourishment\n\nPallor/clubbing/cyanosis/jaundice/pedal oedema/lymph node enlargement\n\nPlus Rate: Blood pressure: Respiratory rate: Temperature:\n\nDermatological examination\n\nDermatological manifestations:\n\nMorphology of rash:\n\nSites affected: Face/chest/abdomen/back of trunk/upper arms/forearms/thighs/legs/palms/soles\n\nMucosal lesions: Conjunctival congestion/Hemorrhagic crusting of lips/Erosions of buccal mucosa/Gingivitis/Erosions of tongue/Nasal erosions/Genital erosions/others\n\nScalp: Nails:\n\nExamination of systems\n\nCardio Vascular system:\n\nCentral Nervous system:\n\nRespiratory system:\n\nGastro-intestinal system: Hepatomegaly/Splenomegaly\n\nLab investigations\n\nBlood R/E\n\nHb: Tc: Dc: ESR:\n\nPlatelet count Absolute eosinophil count Peripheral smear\n\nUrine R/E\n\nAlb: Sugar: M/E\n\nLFT: RFT: Serum Electrolytes:\n\nHBsAg Anti HCV HIV Screening ANA\n\nChest X-ray PA view Ultrasound abdomen\n\nFinal diagnosis\n==== Refs\n1 Roujeau JC Allanore L Liss Y Mockenhaupt M Severe Cutaneous Adverse Reactions to Drugs (SCAR): Definitions, diagnostic criteria, genetic predisposition Dermatol Sinica 2009 27 203 9 \n2 Bilimoria FE Shah BJ Drug Reactions. IADVL Text Book of Dermatology 2008 2 3rd ed Mumbai Bhalani Publishing House 1633 86 \n3 Edwards IR Aronson JK Adverse drug reactions: Definitions, diagnosis, and management Lancet 2000 356 1255 9 11072960 \n4 Leape LL Brennan TA Laird N Lawthers AG Localio AR Barnes BA The nature of adverse events in hospitalized patients. Results of the Harvard Medical Practice study II N Eng J Med 1991 324 377 84 \n5 Hafner JW Belknap SM Squillante MD Bucheit KA Adverse drug events in emergency department patients Ann Emerg Med 2002 39 258 67 11867978 \n6 Pudukadan D Thappa DM Adverse cutaneous drug reactions: Clinical pattern and causative agents in a tertiary care centre in South India Indian J Dermatol Venereol Leprol 2004 70 20 4 17642552 \n7 Sharma VK Sethuraman G Kumar B Cutaneous adverse drug reactions: Clinical Pattern and Causative Agents – A 6 year series from Chandigarh, India J Postgrad Med 2001 47 95 9 11832597 \n8 Mehta TK Marquis L Shetty JN A study of 70 cases of drug eruptions Indian J Dermatol Venereol Leprol 1971 37 2 5 \n9 Heinzerling LM Tomsitz D Anliker MD Is drug allergy less prevalent than previously assumed? A 5-year analysis Br J Dermatol 2012 166 107 14 21916887 \n10 Breathnach SM Burns T Breathnach S Cox N Griffiths C Drug reactions Rook's Textbook of Dermatology 2010 75 8th ed UK Wiley-Blackwell 1 177 \n11 Nandha R Gupta A Hashmi A Cutaneous adverse drug reactions in a tertiary care teaching hospital: A North Indian perspective Int J Appl Basic Med Res 2011 1 50 3 23776774 \n12 Nayak S Acharjya B Adverse cutaneous drug reaction Indian J Dermatol 2008 53 2 8 19967009 \n13 Shiohara T Kano Y Takahashi R Current concepts on the diagnosis and pathogenesis of drug-induced hypersensitivity syndrome Japan Medical Association Journal 2009 52 347 52 \n14 Gentile I Talamo M Borgia G Is the drug-induced hypersensitivity syndrome (DIHS) due to human herpes virus 6 infection or to allergy-mediated viral reactivation? Report of a case and literature review BMC Infect Dis 2010 10 49 20205923 \n15 Criado PR Avancini J Santi CG Medrado AT Rodrigues CE de Carvalho JF Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS): A complex interaction of drug, viruses and the immune system Isr Med Assoc J 2012 14 577 82 23101424\n\n",
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"issue": "60(1)",
"journal": "Indian journal of dermatology",
"keywords": "Drug reaction; drug reaction with eosinophilia and systemic symptoms complex; epidemiology",
"medline_ta": "Indian J Dermatol",
"mesh_terms": null,
"nlm_unique_id": "0370750",
"other_id": null,
"pages": "102",
"pmc": null,
"pmid": "25657416",
"pubdate": "2015",
"publication_types": "D016428:Journal Article",
"references": "11072960;11832597;11867978;17642552;1824793;19967009;20205923;21916887;23101424;23776774;29154336",
"title": "Severe cutaneous adverse drug reactions: a clinicoepidemiological study.",
"title_normalized": "severe cutaneous adverse drug reactions a clinicoepidemiological study"
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"activesubstancename": "VALPROATE SODIUM"
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"abstract": "In this article, a case-based format is used to address complex clinical issues in addiction medicine. The cases were developed from the authors' practice experience, and were presented at the American College of Medical Toxicology Addiction Academy in 2015. Section I: Drug and Alcohol Dependence and Pain explores cases of patients with co-occurring pain and substance use disorders. Section II: Legal and Policy Issues in Substance Use Disorders highlights difficult legal and policy questions in addiction medicine. Section III: Special Populations and Addictive Disorders delves into the complexity of addiction in special populations (pregnant, pediatric, and geriatric patients).",
"affiliations": "Division of Addiction Medicine, Hennepin County Medical Center, 701 Park Avenue, Mail Code G5, Minneapolis, MN, 55415, USA. joan.laes@hcmed.org.;University of Rochester Medical Center & Strong Memorial Hospital, Rochester, NY, USA.",
"authors": "Laes|JoAn R|JR|;Wiegand|Timothy|T|",
"chemical_list": "D000701:Analgesics, Opioid",
"country": "United States",
"delete": false,
"doi": "10.1007/s13181-015-0520-x",
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"journal": "Journal of medical toxicology : official journal of the American College of Medical Toxicology",
"keywords": "Addiction; Chronic pain; Legal; Pregnancy; Special populations",
"medline_ta": "J Med Toxicol",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D000367:Age Factors; D000368:Aged; D000701:Analgesics, Opioid; D016739:Behavior, Addictive; D059350:Chronic Pain; D015897:Comorbidity; D055030:Drug Users; D005260:Female; D006291:Health Policy; D006299:Health Services for the Aged; D006801:Humans; D008297:Male; D008875:Middle Aged; D058850:Opiate Substitution Treatment; D028701:Patient Rights; D011247:Pregnancy; D011295:Prenatal Care; D012307:Risk Factors; D015813:Substance Abuse Detection; D016320:Substance Abuse Treatment Centers; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders; D016896:Treatment Outcome; D055815:Young Adult",
"nlm_unique_id": "101284598",
"other_id": null,
"pages": "82-94",
"pmc": null,
"pmid": "26586253",
"pubdate": "2016-03",
"publication_types": "D016428:Journal Article",
"references": "5565851;1202204;7183759;6471323;9547764;16203961;16336480;16418412;17293546;17493754;18203666;18248941;21142534;22024000;22291123;23055125;23617867;24717237;25299603;25325907;12038895;12924748",
"title": "Case Presentations from the Addiction Academy.",
"title_normalized": "case presentations from the addiction academy"
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"abstract": "Thrombocytopenia is often caused by myelosuppression during chemotherapy. However, when platelet transfusions are required, pathological conditions such as idiopathic thrombocytopenic purpura(ITP)and thrombotic thrombocytopenic purpura( TTP)also occur. We report a case of Merkel cell carcinoma complicated with severe thrombocytopenia treated with carboplatin/etoposide regimen after surgery. The patient's platelet count did not increase in spite of platelet transfusions. However, the platelet count increased after steroid treatment was chosen under the diagnosis of ITP. Subsequent examinations revealed that the patient had HLA antibody, which caused the platelet transfusion refractoriness. When the platelet count does not increase in spite of platelet transfusions during chemotherapy, the possibility that the platelet transfusion refractoriness is due to the presence of HLA antibody should be considered.",
"affiliations": "Dept. of Pharmacy, Tohoku Medical and Pharmaceutical University Hospital.",
"authors": "Saito|Yuko|Y|;Kiba|Takayoshi|T|;Takahashi|Toru|T|;Hirakawa|Hiroyuki|H|;Saito|Miho|M|;Otomo|Chiaki|C|;Sato|Miho|M|;Watanabe|Yoshiteru|Y|;Sakaguchi|Masanobu|M|;Kadota|Risako|R|;Noguchi|Naoya|N|;Suzuki|Takahiro|T|;Awataguchi|Toshikazu|T|;Shoji|Fumi|F|;Ota|Nobuo|N|",
"chemical_list": "D006680:HLA Antigens; D005047:Etoposide; D016190:Carboplatin",
"country": "Japan",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0385-0684",
"issue": "44(8)",
"journal": "Gan to kagaku ryoho. Cancer & chemotherapy",
"keywords": null,
"medline_ta": "Gan To Kagaku Ryoho",
"mesh_terms": "D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D015266:Carcinoma, Merkel Cell; D005047:Etoposide; D005260:Female; D006680:HLA Antigens; D006801:Humans; D017713:Platelet Transfusion; D012878:Skin Neoplasms; D013921:Thrombocytopenia",
"nlm_unique_id": "7810034",
"other_id": null,
"pages": "685-687",
"pmc": null,
"pmid": "28860441",
"pubdate": "2017-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Case of Merkel Cell Carcinoma Complicated with Severe Thrombocytopenia Treated with Carboplatin/Etoposide Regimen after Surgery.",
"title_normalized": "a case of merkel cell carcinoma complicated with severe thrombocytopenia treated with carboplatin etoposide regimen after surgery"
} | [
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"companynumb": "JP-TEVA-2018-JP-877215",
"fulfillexpeditecriteria": "1",
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"activesubstancename": "ETOPOSIDE"
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"abstract": "Radiation recall pneumonitis (RRP) is a poorly understood clinical syndrome in which patients develop radiation pneumonitis triggered by a systemic agent, often years after the completion of radiation therapy. Immune checkpoint blockade agents have only recently been posited as a trigger for RRP. Here, we present three cases of immunotherapy-induced RRP.\nOur first patient was diagnosed with primary lung adenocarcinoma, and 4.5 years after completing radiation therapy developed symptomatic RRP immediately following a second dose of nivolumab-containing immunotherapy regimen. Our second patient was diagnosed with primary bladder cancer metastatic to the mediastinum, which was treated twice with radiation therapy. He developed RRP in the days following his second course of ipilimumab-pembrolizumab which was months after his second course of radiation that he received. Our final patient was diagnosed with metastatic small cell lung cancer and received local consolidative radiation therapy in addition to whole-brain radiation. He developed RRP on the 11th day after concluding his 4th cycle of nivolumab-ipilimumab, approximately 7 months after having had completed chest radiation therapy.\nImmunotherapy-induced RRP is a rare diagnosis which can present more focally than traditional immunotherapy pneumonitis and which must be clinically differentiated from other local processes such as pneumonia. Further research should explore the mechanisms underlying these radiation recall reactions as many patients receive radiation and immunotherapy during the course of their cancer treatment.",
"affiliations": "Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, United States.;Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, United States.;Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, United States.;Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, United States.;Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, United States.;Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, United States.;Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, United States.;Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, United States.;Divisions of Hematology-Oncology and Bone Marrow Transplantation, Moores Cancer Center, University of California San Diego, La Jolla, CA, United States.;Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, United States.",
"authors": "Riviere|Paul|P|;Sumner|Whitney|W|;Cornell|Mariel|M|;Sandhu|Ajay|A|;Murphy|James D|JD|;Hattangadi-Gluth|Jona|J|;Bruggeman|Andrew|A|;Kim|Sangwoo S|SS|;Randall|J Michael|JM|;Sharabi|Andrew B|AB|",
"chemical_list": null,
"country": "Switzerland",
"delete": false,
"doi": "10.3389/fonc.2021.662954",
"fulltext": "\n==== Front\nFront Oncol\nFront Oncol\nFront. Oncol.\nFrontiers in Oncology\n2234-943X\nFrontiers Media S.A.\n\n10.3389/fonc.2021.662954\nOncology\nOriginal Research\nRadiation Recall Pneumonitis After Treatment With Checkpoint Blockade Immunotherapy: A Case Series and Review of Literature\nRiviere Paul 1\n\nSumner Whitney 1\n\nCornell Mariel 1\nSandhu Ajay 1\nMurphy James D. 1\nHattangadi-Gluth Jona 1\nBruggeman Andrew 1\nKim Sangwoo S. 1\n\nRandall J. Michael 2\nSharabi Andrew B. 1 *\n\n1 Department of Radiation Medicine and Applied Sciences, University of California San Diego, La Jolla, CA, United States\n2 Divisions of Hematology-Oncology and Bone Marrow Transplantation, Moores Cancer Center, University of California San Diego, La Jolla, CA, United States\nEdited by: Anne Laprie, Institut Universitaire du Cancer de Toulouse Oncopole, France\n\nReviewed by: Fiori Alite, Geisinger Commonwealth School of Medicine, United States; Zachary Scott Morris, University of Wisconsin-Madison, United States\n\n*Correspondence: Andrew B. Sharabi, Sharabi@health.ucsd.edu\nThis article was submitted to Radiation Oncology, a section of the journal Frontiers in Oncology\n\n30 4 2021\n2021\n11 66295402 2 2021\n12 4 2021\nCopyright © 2021 Riviere, Sumner, Cornell, Sandhu, Murphy, Hattangadi-Gluth, Bruggeman, Kim, Randall and Sharabi\n2021\nRiviere, Sumner, Cornell, Sandhu, Murphy, Hattangadi-Gluth, Bruggeman, Kim, Randall and Sharabi\nhttps://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nBackground\n\nRadiation recall pneumonitis (RRP) is a poorly understood clinical syndrome in which patients develop radiation pneumonitis triggered by a systemic agent, often years after the completion of radiation therapy. Immune checkpoint blockade agents have only recently been posited as a trigger for RRP. Here, we present three cases of immunotherapy-induced RRP.\n\nCase Presentation\n\nOur first patient was diagnosed with primary lung adenocarcinoma, and 4.5 years after completing radiation therapy developed symptomatic RRP immediately following a second dose of nivolumab-containing immunotherapy regimen. Our second patient was diagnosed with primary bladder cancer metastatic to the mediastinum, which was treated twice with radiation therapy. He developed RRP in the days following his second course of ipilimumab-pembrolizumab which was months after his second course of radiation that he received. Our final patient was diagnosed with metastatic small cell lung cancer and received local consolidative radiation therapy in addition to whole-brain radiation. He developed RRP on the 11th day after concluding his 4th cycle of nivolumab-ipilimumab, approximately 7 months after having had completed chest radiation therapy.\n\nConclusions\n\nImmunotherapy-induced RRP is a rare diagnosis which can present more focally than traditional immunotherapy pneumonitis and which must be clinically differentiated from other local processes such as pneumonia. Further research should explore the mechanisms underlying these radiation recall reactions as many patients receive radiation and immunotherapy during the course of their cancer treatment.\n\nradiation\nimmunotherapy\npneumonitis\nreaction\ncheckpoint\nPD-1\n==== Body\nIntroduction\n\nRadiation recall is a clinical phenomenon in which patients acutely develop signs and symptoms of inflammatory radiation toxicities or erythema within previously irradiated fields after initiation of a systemic therapy. Radiation recall typically arises after the timeframe during which any acute radiation toxicity would be expected (up to several years after completion of radiation therapy (RT)) and patients often tolerate re-challenge with the offending agent without recurrence of RRP (1). Numerous drugs have been linked to recall reactions, including cytotoxic antineoplastic medications, targeted cancer therapeutics, antibiotics, and even statins (2–4). While radiation recall has classically been described as a cutaneous reaction, more recently there has been increasing awareness of recall reactions occurring within other organ systems (2). One emerging diagnosis is radiation recall pneumonitis (RRP), a focal disease of lung parenchyma that clinically and radiographically resembles radiation pneumonitis, but which is temporally incongruent with radiation pneumonitis which typically occurs 1-3 months after conventional radiation (5). RRP has been described with chemotherapeutic agents (e.g. gemcitabine, doxorubicin, and docetaxel) (1, 6–8) and small-molecule kinase inhibitors (e.g. everolimus, sunitinib, erlotinib) (9–11). However, the literature is much sparser on RRP arising in the context of immunotherapy (12–14), with the largest case series containing only two patients (13). Here, we describe three cases of suspected immunotherapy-induced RRP treated at our institution.\n\nCase Descriptions\n\nPatient 1\n\nPatient 1 64 y/o man with a 48 pack-year cigarette smoking history presented to an outside hospital with a chronic cough in 2012, which was refractory to antibiotic therapy. Imaging revealed an approximately 3.7x2.3 cm right-sided mass in the minor fissure with associated hypermetabolic hilar and mediastinal lymphadenopathy, as well as an ipsilateral pleural effusion which was pathologically negative. Biopsy via EUS diagnosed poorly differentiated adenocarcinoma, TTF-1 positive, CK 7, Napsin A positive, CK 20 negative, CK 5 negative, CD45 negative, EGFR wild-type, ALK wild-type, ROS1 wild-type. Staging imaging showed a right paratracheal lymph node measuring 3.2 cm, a subcarinal lymph node measuring 3.3 cm, and a right hilar lymph node 5.5 cm in maximal dimension, but no evidence of distant metastatic disease; he was thus diagnosed with a T2N2 stage IIIb non-small cell lung adenocarcinoma, per AJCC 7 criteria. He completed 4 cycles of carboplatin with pemetrexed, followed by concurrent cisplatin and radiation therapy (intensity-modulated RT (IMRT) 59.4 Gy in 33 fractions) completed 2013, with good radiographic response. Surveillance imaging detected multiple new parenchymal lung lesions, the largest of which was 1.1cm in the left upper lobe, as well as precarinal mediastinal adenopathy measuring 1.3x1.8cm. He was started on first line systemic therapy for advanced disease with pemetrexed, carboplatin, and bevacizumab. After progressing with bilateral pulmonary nodules on imaging he was enrolled on clinical trials, and in the ensuing years received: single-agent pembrolizumab (partial response, treated 11 months); single-agent nivolumab (progressed, treated 10 weeks); single-agent gemcitabine (partial response, treated 6 months); a second course of single-agent pembrolizumab (progressed, treated 1 month); single-agent docetaxel (partial response but discontinued due to toxicity, treated 5 months); and single-agent atezolizumab (progressed, treated 2 months). Throughout these courses of therapy, he developed metastatic disease to the left kidney, vertebral body, right sided ribs, and bilateral lung parenchyma.\n\nIn early 2018, he enrolled on a novel open-label immunotherapy trial, consisting of nivolumab combined with an experimental HDAC inhibitor. He received the first dose on 3/2018, and developed a cough approximately 2 weeks later, days following his second dose of the immunotherapy combination. After 2 weeks of symptomatic cough, on 5/2018 he started a course of empiric levofloxacin with no improvement. He completed his second cycle of therapy despite the cough becoming increasingly productive and having an increased home oxygen requirement. 2 weeks later, a CT of the chest with contrast revealed pneumonitis changes correlating to the previous IMRT fields ( Figure 1 ), and was diagnosed with RRP. Cycle 3 was deferred and he started a tapered course of oral prednisone, 60 mg daily with excellent clinical response. After recovering, he tolerated a re-trial of monotherapy nivolumab (omitting the experimental agent) without a recurrent RRP. He has since received two courses of palliative radiation for chest wall lesions without complications.\n\nFigure 1 Patient 1's initial treatment plan, post treatment CT, CT at time of presentation with radiation recall, and CT following course of steroids with interval improvement.\n\nPatient 2\n\nPatient 2 originally presented to an outside hospital in 2015 complaining of 2 years of gross hematuria that had progressed to blood clots in his urine. At that time, he was 63 years old with a 20 pack-years cigarette smoking history, and had no other known risk factors for urogenital malignancies. He was diagnosed with a T2G3 urothelial cancer of the bladder dome with extensive invasion in the muscularis propria via transurethral resection of bladder tumor (TURBT). In mid 2015, and underwent a restaging TURBT which re-demonstrated high-grade urothelial carcinoma invading the muscularis propria, and CT chest revealed an anterior mediastinal mass that was positive for metastatic urothelial cancer. He completed frontline therapy with cisplatin and gemcitabine in 1/2016 (cisplatin exchanged for carboplatin after acute kidney injury during cycle 3), after which he received palliative-intent RT with 30 Gy in 10 fractions to the mediastinal mass, completed 4/2016. He then was treated with an experimental immunotherapeutic agent on trial combined with durvalumab and has a durable response over 3.5 years. He was noted to progress in his mediastinum and this site was retreated using SBRT to 25Gy in 5 fractions, completed in mid 2019. This was followed by monotherapy pembrolizumab as a bridge to a clinical trial for which he was ultimately deemed ineligible, and in late 2019, ipilimumab was added to his pembrolizumab regimen. 3 days following his second cycle of pembrolizumab-ipilimumab, he presented to the emergency room complaining of abdominal and flank pain. He was found to have peritonitis from his necrotic primary tumor, as well as radiographic evidence of RRP of the left lung ( Figure 2 ). However, the patient reported no symptoms associated with this, and was breathing normally on room air. Unfortunately, his clinical status rapidly declined, and he expired 12 days later in the hospital.\n\nFigure 2 Patient 2's treatment plan, post treatment CT, CT at time of presentation with radiation recall, and CT following course of steroids with interval improvement.\n\nPatient 3\n\nPatient 3 presented in 2017 at age 52 with headaches, and was subsequently diagnosed with lung cancer metastatic to the brain. He was found to have small-cell lung cancer from a left upper lobe primary tumor and underwent surgical resection of a 4.1 cm. metastasis in the left cerebellum via posterior fossa craniectomy. He completed a cycle of cisplatin/etoposide while hospitalized, and then underwent whole-brain radiation therapy to 37.5 Gy in 15 fractions (completed mid 2017), followed by 4 additional cycles cisplatin and etoposide (completed 2 months later), which was followed by consolidative conformal RT to the primary tumor and mediastinum to 30 Gy in 10 fractions, completed in mid 2017. The patient subsequently developed 4 new brain metastases, which were treated with SRS in late 2017, followed by ipilimumab with nivolumab.\n\nSeven months after completing thoracic RT, 11 days after receiving his 4th cycle infusion of nivolumab/ipilimumab, the patient developed acutely worsening left-sided chest pain, most severe upon inspiration and with no associated cough or fevers. He showed no infectious signs or symptoms, and was oxygenating well on room air. A CT scan of the thorax revealed evolving left lung fibrosis consistent with a recall reaction ( Figure 3 ). Infectious workup was unrevealing, and the patient responded rapidly to a tapered course of oral prednisone 50 mg daily. Upon resolution of his symptoms his medical oncologists elected to halt systemic therapies without a re-challenge. To date he has received ablative radiotherapy to the left adrenal gland and SRS twice to new brain metastases without complication.\n\nFigure 3 Patient 3's treatment plan, post treatment CT, CT at time of presentation with radiation recall, and CT following course of steroids with interval improvement.\n\nConclusions\n\nImmunotherapy-related pneumonitis is a well-documented (15, 16) adverse effect of immune checkpoint therapies. However, while prior RT may increase incidence of low grade pneumonitis in patients treated with these drugs (15, 17), radiologic manifestations of immunotherapy-related pneumonitis typically do not overlap with high-dose treatment fields (17), suggesting that RRP is indeed a distinct clinical entity. The pathophysiology of radiation recall remains an area of active investigation; authors have hypothesized radiation-induced: (1) sublethal stem cell damage/reprograming, in which surviving local stem cells lose future proliferative ability or develop aberrant inflammatory responses to systemic agents (2) hypersensitivity reaction in which radiation might lower the inflammatory response threshold, causing localized idiosyncratic drug reactions (3) changes to vascular permeability/proliferation causing local accumulation of systemic agents (i.e. pharmacokinetic effects), and (4) DNA damage and oxidative stress causing keratinocyte necrosis/depletion, amongst others (1, 6, 12, 18). Immunotherapy-mediated RRP implies that direct cytotoxic drugs may not be required to induce recall reactions. Additionally, the tolerance of some patients to re-challenge with checkpoint inhibitor therapies suggests that RRP is not simply the result of additive toxicities from these two therapies. These findings have led some to argue that recall reactions are non-immune inflammatory idiosyncratic drug hypersensitivities caused by RT-induced reprogramming of the inflammatory pathway in treated tissues (2). To date, however, there is no established mechanism for radiation recall.\n\nThree recent publications have described a total of 4 cases of patients with primary lung cancers developing RRP following therapy with nivolumab (3 patients) or pembrolizumab (1 patient). In one case (14), a patient developed RRP both at the site of RT for her primary lung adenocarcinoma, and at the site of prior RT for breast cancer on the contralateral lung. Similarly to our patients, all of these patients were successfully treated with oral steroids, and one patient was reported to have tolerated a re-challenge with nivolumab without recurrence of RRP.\n\nThis is the largest single-institution immunotherapy-related RRP case series. Upon presentation with RRP, these patients had very focal/asymmetric findings (inconsistent with immunotherapy-related pneumonitis) corresponding closely with the distribution of prior radiation arising acutely post treatment with the offending agent(s), and radiographic (and symptomatic for patients 1 and 3) signs showed marked improvement following treatment with steroids. Dose in the regions demonstrating exudative changes during the recall pneumonitis ranged from 12.5 to 80 Gy ( Table 1 ). Interestingly, all of our patients developed symptoms while on dual-agent immunotherapy (one of whom was receiving a novel experimental immunotherapeutic on a clinical trial); patients 1 and 2 had both tolerated immunotherapy(ies) (patient 1: nivolumab and pembrolizumab, patient 2: and an experimental agent with durvalumab, as well as pembrolizumab) prior to the treatment course that is believed to have triggered the RRP. Similarly to the literature on radiation recall reactions more generally, the only patient (patient 1) to trial a re-challenge of immunotherapy did so without a recurrence of RRP. If future studies find that patients on dual-agent immunotherapy have a higher propensity towards RRP, an interesting question remains of whether this is a synergistic toxic reaction or simply an additive effect with each agent contributing a minute increased probability of a recall reaction.\n\nTable 1 Dosimetric parameters including Max, Mean, V5, V10 radiation doses to the lung and heart in treated patients.\n\n\tBilateral Lung Max Dose (tGy)\tBilateral Lung Mean Dose (tGy)\tRight Lung Mean Dose (tGy)\tLeft Lung Mean Dose (tGy)\tLung VS (%)\tLung V20 (%)\tHeart Mean Dose (cGy)\t\nPatient 1\t8100\t1803\t2452\t1303\t86.4\t34.4\t2440\t\nPatient 2\t5845\t1134\t1014\t1280\t69.5\t10.7\t819\t\nPatient 3\t3327\t795\t447\t1293\t31.1\t20.8\t631\t\n\nThere are several limitations to this case series: our patients presented with a variety of primary cancers at different stages, and received distinct systemic therapies and sequencing of radiation therapy regimens. Patient 2, for example, received radiation therapy in two stages, first with palliative intent and subsequently for consolidation as his goals of care evolved. This limits this study to hypothesis generation, and increasing awareness of the potential of recall reactions in patients treated with immunotherapeutics. Additionally, with only 3 patients, it is difficult to identify if there is a temporal relationship between radiation dose and the grade of RRP. Furthermore, there remains the possibility that these reactions may represent a ‘recall like-reaction’ due to overlapping toxicity and increased risk of pneumonitis from immunotherapy and radiation therapy, or where immunotherapy could be impacting the timing or induction of a conventional radiation pneumonitis. Nevertheless, these cases serve to highlight the potential for radiation recall reactions in the setting of immunotherapy.\n\nAs immunotherapeutics have advanced to clinical and community practice, there has been continued monitoring of their toxicities and adverse effects (19), particularly with rare outcomes unlikely to manifest in smaller and controlled clinical trial populations. In each case presented here, patients developed acute radiographic changes consistent with pneumonitis within prior radiation fields months or years after having concluded treatment. In summary, these cases together with other cases from the literature suggest that radiation recall reactions and radiation recall pneumonitis can be associated with immunotherapies. Monitoring for recall pneumonitis and further investigation of the mechanisms underlying radiation recall reactions is warranted.\n\nData Availability Statement\n\nThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.\n\nEthics Statement\n\nPatients were enrolled on UCSD IRB approved studies and provided informed consent for use of data and publication.\n\nAuthor Contributions\n\nPR, WS, MC, SK, and ABS contributed to conception and design of the study. AS, JM, JH-G, AB, and JR managed and treated patients involved in this study. PR, WS, and MC performed analysis of patient data. PR wrote the first draft of the manuscript. PR, WS, and AS wrote sections of the manuscript. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis work was supported in part by 1KL2TR001444 and a grant from the San Diego Center for Precision Immunotherapy (SDCPI).\n\nConflict of Interest\n\nAS reports research funding and honoraria from Pfizer and Varian Medical Systems, and consultant fees from AstraZeneca and Merck. ABS is the scientific founder and has an equity interest in Toragen Inc. outside the submitted work. The terms of this arrangement have been reviewed and approved by the University of California, San Diego in accordance with its conflict of interest policies.\n\nThe remaining 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\nAbbreviations\n\nRRP, radiation recall pneumonitis; RT, radiation therapy; IMRT, intensity-modulated radiation therapy; TURBT, transurethral resection of bladder tumor.\n==== Refs\nReferences\n\n1 Burris HA 3rd Hurtig J . Radiation Recall With Anticancer Agents. Oncologist (2010) 15 :1227–37. 10.1634/theoncologist.2009-0090\n2 Azria D Magne N Zouhair A Castadot P Culine S Ychou M . Radiation Recall: A Well Recognized But Neglected Phenomenon. Cancer Treat Rev (2005) 31 :555–70. 10.1016/j.ctrv.2005.07.008\n3 Cho S Breedlove JJ Gunning ST . Radiation Recall Reaction Induced by Levofloxacin. J Drugs Dermatol (2008) 7 :64–7.\n4 Mussani F Skotnicki S . Recall Dermatitis to Metronidazole. J Cutan Med Surg (2015) 19 :326–7. 10.2310/7750.2014.14135\n5 Bledsoe TJ Nath SK Decker RH . Radiation Pneumonitis. Clin Chest Med (2017) 38 :201–8. 10.1016/j.ccm.2016.12.004\n6 Ding X Ji W Li J Zhang X Wang L . Radiation Recall Pneumonitis Induced by Chemotherapy After Thoracic Radiotherapy for Lung Cancer. Radiat Oncol (2011) 6 :24. 10.1186/1748-717X-6-24 21375774\n7 Schwarte S Wagner K Karstens JH Bremer M . Radiation Recall Pneumonitis Induced by Gemcitabine. Strahlenther Onkol (2007) 183 :215–7. 10.1007/s00066-007-1688-z\n8 Jeter MD Janne P Brooks S Burstein H Wen P Fuchs C . Gemcitabine-Induced Radiation Recall. Int J Radiat Oncol Biol Phys (2002) 53 :394–400. 10.1016/s0360-3016(02)02773-6 12023144\n9 Clark D Gauchan D Ramaekers R Norvell M Copur MS . Radiation Recall Pneumonitis During Systemic Treatment With Everolimus. Oncol Res (2014) 22 :321–4. 10.3727/096504015X14400775740416\n10 Onal C Abali H Koc Z Kara S . Radiation Recall Pneumonitis Caused by Erlotinib After Palliative Definitive Radiotherapy. Onkologie (2012) 35 :191–4. 10.1159/000337616\n11 Seidel C Janssen S Karstens J.H Welte T Morgan M Ganser A . Recall Pneumonitis During Systemic Treatment With Sunitinib. Ann Oncol (2010) 21 :2119–20. 10.1093/annonc/mdq444\n12 McGovern K Ghaly M Esposito M Barnaby K Seetharamu N . Radiation Recall Pneumonitis in the Setting of Immunotherapy and Radiation: A Focused Review. Future Sci OA (2019) 5 :FSO378. 10.2144/fsoa-2018-0123 31245041\n13 Shibaki R Akamatsu H Fujimoto M Koh Y Yamamoto N . Nivolumab Induced Radiation Recall Pneumonitis After Two Years of Radiotherapy. Ann Oncol (2017) 28 :1404–5. 10.1093/annonc/mdx115\n14 Thoré P Godbert B Petit I Chaouat A . Radiation Recall Pneumonitis in a Patient Treated by Nivolumab for Non-Small Cell Lung Cancer, No Relapse With Rechallenge. Eur J Oncol (2018) 23 :224–7.\n15 Sul J Blumenthal G Jiang X He K Keegan P Pazdur R . Fda Approval Summary: Pembrolizumab for the Treatment of Patients With Metastatic non-Small Cell Lung Cancer Whose Tumors Express Programmed Death-Ligand 1. Oncologist (2016) 21 :643–50. 10.1634/theoncologist.2015-0498\n16 Suresh K Owen D Bazzi L Jackson W Ten Haken R.K. Cuneo K . Pneumonitis in Non-Small Cell Lung Cancer Patients Receiving Immune Checkpoint Immunotherapy: Incidence and Risk Factors. J Thorac Oncol (2018) 13 :1930–9. 10.1016/j.jtho.2018.08.2035\n17 Voong KR Hazell S. Z. Fu W Hu C Lin CT Ding K . Relationship Between Prior Radiotherapy and Checkpoint-Inhibitor Pneumonitis in Patients With Advanced Non-Small-Cell Lung Cancer. Clin Lung Cancer (2019) 20 :e470–9. 10.1016/j.cllc.2019.02.018\n18 Smith KJ Germain M Skelton H . Histopathologic Features Seen With Radiation Recall or Enhancement Eruptions. J Cutaneous Med Surgery: Incorporating Med Surg Dermatol (2002) 6 :535–40. 10.1007/s10227-001-0156-0\n19 Shepshelovich D Tibau A Goldvaser H Molto C Ocana A Seruga B . Postmarketing Modifications of Drug Labels for Cancer Drugs Approved by the US Food and Drug Administration Between 2006 and 2016 With and Without Supporting Randomized Controlled Trials. J Clin Oncol (2018) 36 :1798–804. 10.1200/JCO.2017.77.5593\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2234-943X",
"issue": "11()",
"journal": "Frontiers in oncology",
"keywords": "PD-1 ; checkpoint; immunotherapy; pneumonitis; radiation; reaction",
"medline_ta": "Front Oncol",
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"pmid": "33996587",
"pubdate": "2021",
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"title": "Radiation Recall Pneumonitis After Treatment With Checkpoint Blockade Immunotherapy: A Case Series and Review of Literature.",
"title_normalized": "radiation recall pneumonitis after treatment with checkpoint blockade immunotherapy a case series and review of literature"
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"abstract": "BACKGROUND\nDonepezil is an acetylcholinesterase inhibitor used to improve cognition and delay disease progression in dementia patients by increasing acetylcholine levels. This drug may potentially interact with neuromuscular blocking agents (NMBAs) that act on muscular acetylcholine receptors during general anesthesia. Herein, we present a case of inadequate neuromuscular blockade with rocuronium, a nondepolarizing NMBA, in a dementia patient who had taken donepezil.\n\n\nMETHODS\nA 71-year-old man was scheduled for laparoscopic gastrectomy. He had been taking donepezil 5 mg for dementia. General anesthesia was induced with propofol and remifentanil. The depth of neuromuscular blockade was monitored by train-of-four (TOF) stimulation. After the administration of rocuronium, the TOF ratio decreased at an unusually slow rate, and a TOF count of 0 was detected 7 min later. After intubation, a TOF count of 1 was detected within 1 min, and a TOF ratio of 12% was detected within 2 min. The TOF count remained at 4 even with an additional bolus and continuous infusion of rocuronium, suggesting resistance to this NMBA. Instead of propofol, an inhalation anesthetic was administered alongside another NMBA (cisatracurium). Then, the quality of neuromuscular blockade improved, and the TOF count remained at 0-1 for the next 70 min. No further problems were encountered with respect to surgery or anesthesia.\n\n\nCONCLUSIONS\nDonepezil may be responsible for inadequate neuromuscular blockade during anesthesia, especially when total intravenous anesthesia is used.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 61469, South Korea.;Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 61469, South Korea.;Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 61469, South Korea.;Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 61469, South Korea.;Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 61469, South Korea.;Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 61469, South Korea. aneshead@gmail.com.",
"authors": "Jang|Eun-A|EA|;Kim|Tae-Young|TY|;Jung|Eu-Gene|EG|;Jeong|Seongtae|S|;Bae|Hong-Beom|HB|;Lee|Seongheon|S|",
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"doi": "10.12998/wjcc.v8.i21.5341",
"fulltext": "\n==== Front\nWorld J Clin Cases\nWJCC\nWorld Journal of Clinical Cases\n2307-8960 Baishideng Publishing Group Inc \n\n33269268\njWJCC.v8.i21.pg5341\n10.12998/wjcc.v8.i21.5341\nCase Report\nDonepezil-related inadequate neuromuscular blockade during laparoscopic surgery: A case report\nJang Eun-A Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 61469, South Korea\n Kim Tae-Young Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 61469, South Korea\n Jung Eu-Gene Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 61469, South Korea\n Jeong Seongtae Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 61469, South Korea\n Bae Hong-Beom Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 61469, South Korea\n Lee Seongheon Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, Gwangju 61469, South Korea. aneshead@gmail.com\n Author contributions: Jang EA and Lee S wrote the manuscript; Kim TY and Jung EG performed literature analysis; Jeong S was the anesthesiologist in charge of the patient; Bae HB revised the manuscript for important intellectual content; all authors approved the final version of the manuscript to be submitted.\n\nCorresponding author: Seongheon Lee, MD, PhD, Assistant Professor, Department of Anesthesiology and Pain Medicine, Chonnam National University Medical School, Chonnam National University Hospital, 160, Baekseo-ro, Dong-gu, Gwangju 61469, South Korea. aneshead@gmail.com\n\n\n6 11 2020 \n6 11 2020 \n8 21 5341 5346\n12 5 2020 27 9 2020 12 10 2020 ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.2020This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial.BACKGROUND\nDonepezil is an acetylcholinesterase inhibitor used to improve cognition and delay disease progression in dementia patients by increasing acetylcholine levels. This drug may potentially interact with neuromuscular blocking agents (NMBAs) that act on muscular acetylcholine receptors during general anesthesia. Herein, we present a case of inadequate neuromuscular blockade with rocuronium, a nondepolarizing NMBA, in a dementia patient who had taken donepezil.\n\nCASE SUMMARY\nA 71-year-old man was scheduled for laparoscopic gastrectomy. He had been taking donepezil 5 mg for dementia. General anesthesia was induced with propofol and remifentanil. The depth of neuromuscular blockade was monitored by train-of-four (TOF) stimulation. After the administration of rocuronium, the TOF ratio decreased at an unusually slow rate, and a TOF count of 0 was detected 7 min later. After intubation, a TOF count of 1 was detected within 1 min, and a TOF ratio of 12% was detected within 2 min. The TOF count remained at 4 even with an additional bolus and continuous infusion of rocuronium, suggesting resistance to this NMBA. Instead of propofol, an inhalation anesthetic was administered alongside another NMBA (cisatracurium). Then, the quality of neuromuscular blockade improved, and the TOF count remained at 0-1 for the next 70 min. No further problems were encountered with respect to surgery or anesthesia.\n\nCONCLUSION\nDonepezil may be responsible for inadequate neuromuscular blockade during anesthesia, especially when total intravenous anesthesia is used.\n\nDonepezilDementiaGeneral anesthesiaRocuroniumNeuromuscular blocking agentsCase report\n==== Body\nCore Tip: In the present case of a 71-year-old patient taking donepezil for dementia, we collected peripheral nerve stimulation data that showed objective evidence of inadequate neuromuscular blockade during total intravenous anesthesia. The goal of this case report is to draw attention to the need to carefully review potential drug interactions between donepezil and neuromuscular blocking agents during general anesthesia. As the number of elderly patients with dementia is increasing and total intravenous anesthesia has become more popular, there is a possibility that this drug interaction may be observed more frequently in the future.\n\nINTRODUCTION\nAs a result of an increasing life expectancy, it is likely that anesthesiologists will encounter an increasing number of elderly patients with dementia in the operating room. As most types of dementia are associated with profound cholinergic deficits, acetylcholinesterase inhibitors have been used to improve cognition and delay disease progression in dementia patients by increasing cerebral acetylcholine levels[1]. Due to this mechanism, these anti-dementia drugs may potentially interact with neuromuscular blocking agents (NMBAs), which act on muscular nicotinic acetylcholine receptors during general anesthesia. Donepezil is an acetylcholinesterase inhibitor approved by the United States Food and Drug Administration for the treatment of Alzheimer’s disease. A few case reports have described donepezil-related resistance to nondepolarizing NMBAs, rocuronium and atracurium, through subjective observations of train-of-four (TOF) stimulation or respiratory effort[2-5]. Herein, we present a case of inadequate neuromuscular blockade with rocuronium during total intravenous anesthesia (TIVA) with propofol-remifentanil in a dementia patient who had taken donepezil. Furthermore, we demonstrate the objective time course of TOF responses. In this case, adequate neuromuscular blockade was achieved with the subsequent administration of an inhalational anesthetic (desflurane) and another NMBA (cisatracurium). Written informed consent was obtained from the patient for the publication of this case.\n\nCASE PRESENTATION\nChief complaints\nA 71-year-old man (55 kg, 149 cm) was admitted to the hospital for total laparoscopic distal gastrectomy under general anesthesia. During surgery, insufficient muscle relaxation was reported repeatedly by surgical team. \n\nHistory of present illness\nGeneral anesthesia was induced and maintained with 2% propofol and remifentanil using target-controlled infusion. When the patient became unconscious, TOF stimulation of the right ulnar nerve was initiated using a peripheral nerve stimulator (NMT module of the Carescape monitor B850; GE Healthcare, Madison, WI, United States). The initial TOF ratio was 0.98, and the patient then received a bolus injection of rocuronium 50 mg (0.9 mg/kg). According to routine practice, we waited to perform intubation until a TOF count of 0 was observed. The TOF ratio decreased at an unusually slow rate, and a TOF count of 0 was detected approximately 7 min after the administration of rocuronium (Figure 1). After successful endotracheal intubation, however, a TOF count of 1 was detected within 1 min, and a TOF ratio of 12% was detected within 2 min. Rocuronium 5 mg was then injected followed by a continuous infusion at a rate of 9 µg/kg/min for deep neuromuscular blockade (post-tetanic count of 1-2). However, a TOF count of 4 (TOF ratio < 10%) was continuously recorded and visually detected. The surgical team noted insufficient muscle relaxation 20 min after the start of the laparoscopic procedure.\n\nFigure 1 \nProgress of the train-of-four ratios and counts from the start of total intravenous anesthesia with propofol and remifentanil. After a bolus injection of rocuronium 50 mg (0.9 mg/kg), the train-of-four (TOF) ratio decreased at an unusually slow rate. When a TOF count of 0 was detected approximately 7 min later, endotracheal intubation was performed. A TOF count of 1 was detected within 1 min, and a TOF ratio of 12% was detected within 2 min. A TOF count of 4 was continuously detected even with an additional bolus and continuous infusion of rocuronium. A TOF count of 0 was achieved after the conversion of total intravenous anesthesia to inhalation anesthesia with cisatracurium 6 mg. Solid black lines represent TOF count (0-4); red dots represent TOF ratio (%). Roc: Rocuronium; Cis: Cisatracurium; TOF: Train-of-four; OP: Operation.\n\nHistory of past illness\nThe patient had previously been diagnosed with dementia and mild parkinsonism with tremor and had been taking donepezil 5 mg, quetiapine 25 mg, and pregabalin 75 mg twice a day for 16 mo. He had been taking anti-hypertensive medication for 11 years and had undergone diaphragm surgery in our hospital 7 and 10 years prior. During these two surgeries, he required rocuronium 50 mg during 195 min of balanced anesthesia with sevoflurane-remifentanil and rocuronium 60 mg during 225 min of TIVA with propofol-remifentanil. No specific events or comments regarding insufficient muscle relaxation were identified from a review of his anesthesia records of previous surgeries. \n\nPersonal and family history\nThe patient had no history of smoking or alcohol abuse. He had no family history of cancer or any other hereditary diseases.\n\nPhysical examination\nDuring general anesthesia, vascular access for intravenous anesthetics and NMBAs was well secured, and the patient’s vital signs and state entropy (Entropy module of the Carescape monitor B850; GE Healthcare, Madison, WI, United States) were within the normal ranges, which indicated adequate depth of anesthesia. Using forced-air warming blankets, the central core temperature and skin temperature over the adductor pollicis muscle were maintained above 35.5 °C and 32 °C, respectively. The preoperative physical examination was unremarkable.\n\nLaboratory examinations\nThe results of preoperative laboratory tests and electrocardiography were normal.\n\nImaging examinations\nThe preoperative chest X-ray showed elevation of the left diaphragm, which was considered evidence of previous diaphragm surgeries.\n\nFINAL DIAGNOSIS\nThe etiology was considered donepezil-related resistance to nondepolarizing NMBAs based on donepezil’s mechanism and previous case reports.\n\nTREATMENT\nAn additional bolus injection of rocuronium 10 mg (0.18 mg/kg) from different batches of drug product was administered, but the TOF count remained at 1-2 for the next 15 min, and the surgical team requested additional relaxation for optimal surgical conditions. We decided to use an inhalational anesthetic (desflurane) instead of propofol. Therefore, we administered desflurane at an end-tidal concentration of 4-6 vol% while stopping the infusion of propofol and rocuronium. We also administered a bolus dose of cisatracurium 6 mg (0.1 mg/kg) instead of rocuronium.\n\nOUTCOME AND FOLLOW-UP\nAdequate neuromuscular blockade was achieved with the subsequent administration of desflurane and cisatracurium. The TOF count remained at 0-1 for the next 70 min without further complaints from the surgical team. At the end of surgery, the TOF ratio was 0.78, and spontaneous respiratory efforts returned soon after all anesthetic drugs were stopped. Residual neuromuscular blockade was reversed with neostigmine 2.5 mg and glycopyrrolate 0.4 mg. When the TOF ratio increased to 0.91 and consciousness returned, extubation was performed successfully. There were no significant problems with the patient’s vital signs in the operating room or recovery room. The patient was transferred to the ward 1 h after the end of surgery. He was discharged from the hospital after 9 d without any complications.\n\nDISCUSSION\nSurgical patients sometimes exhibit resistance to nondepolarizing NMBAs during anesthesia. This manifests as an increased NMBA dose required to abolish the twitch response, a prolonged time to maximum effect, and a shortened duration of neuromuscular blockade after the administration of a bolus[6], as seen in this case.\n\nResistance to NMBAs has been reported in patients with burns[7,8] and cerebral palsy[9], immobilized patients[10], and patients taking anticonvulsants[11,12]. However, all of these conditions were excluded in this patient. Moreover, no specific problems were described in his anesthesia records from two diaphragm surgeries performed 7 and 10 years prior. During these two surgeries, he required rocuronium 50 mg during 195 min and rocuronium 60 mg during 225 min. In the present case, however, the dose of rocuronium administered during the first 60 min of anesthesia (83 mg) was higher than that administered during two previous surgeries. Therefore, individual variability in NMBA sensitivity may not explain the inadequate neuromuscular blockade observed in this case.\n\nWe suspected the existence of a drug-drug interaction between the NMBA and the patient’s current medications. Donepezil was considered to be the drug most likely to be responsible for the observed inadequate neuromuscular blockade, as it is an acetylcholinesterase inhibitor and thus theoretically antagonizes the effects of nondepolarizing NMBAs. We also identified four case reports (two in English) of donepezil-related resistance to nondepolarizing NMBAs. Baruah et al[2] reported that four twitches were continuously observed in response to TOF stimulation after the administration of a single intubating dose of atracurium 30 mg and a supplemental dose of 10 mg in an Alzheimer’s disease patient who had been taking donepezil for 14 mo. Bhardwaj et al[3] reported the case of an Alzheimer’s disease patient who had been taking donepezil (5 mg daily) for 4 mo. Spontaneous respiratory efforts reappeared while attempting intubation after the administration of a single intubation dose of rocuronium 0.6 mg/kg, and repeated administrations of rocuronium and vecuronium could not inhibit the return of spontaneous respiratory efforts. Inadequate neuromuscular blockade with atracurium or rocuronium in Alzheimer’s disease patients taking donepezil (10 mg daily) was also described in the abstracts of two non-English articles[4,5]. In addition, donepezil is known to produce prolonged neuromuscular blockade with depolarizing NMBAs such as succinylcholine[5,13].\n\nDonepezil is a new generation of acetylcholinesterase inhibitors that are considered the first-choice drugs for the pharmacological treatment of dementia, usually of the Alzheimer type[14]. This therapy targets elevated acetylcholine levels in the brain. However, acetylcholine levels at the neuromuscular junction may also increase, resulting in potential interactions between donepezil and NMBAs. The manufacturer of this drug and a few previous articles have recommended that donepezil should be discontinued 2-4 wk before elective surgery due to its long half-life (70 h in heathy volunteers and even longer in elderly patients)[2,13,15]. However, this long withdrawal period may cause irreversible cognitive decline such that cognitive function becomes even worse than that before treatment was initiated[16]. To date, there are no clear guidelines on whether this drug should be discontinued before elective surgery.\n\nIn this case, inadequate neuromuscular blockade was noted even at doses higher than those indicated for the patient's weight. The quality of neuromuscular blockade improved when desflurane inhalation was initiated and a single bolus of cisatracurium was administered. Inhalation anesthetics such as desflurane and sevoflurane cause a slight reduction in neuromuscular transmission and enhance the neuromuscular blocking effects of nondepolarizing NMBAs[17,18]. Therefore, the improved muscle relaxation might be associated with the use of desflurane. \n\nMeanwhile, we could not exclude the possibility that cisatracurium might also have contributed to the observed improvement of neuromuscular blockade. Although cisatracurium is a commonly used, intermediate duration, nondepolarizing NMBA just like as rocuronium, the chemical structures of cisatracurium and rocuronium are quite different (benzylisoquinolinium vs steroidal). Mixtures of structurally different NMBAs are considered to produce a synergistic response[19,20]. Thus, the additional administration of cisatracurium might have enhanced the quality of neuromuscular blockade synergistically. In addition, further studies are required to investigate whether cisatracurium has a relatively weak interaction with donepezil.\n\nCONCLUSION\nAs the number of elderly patients with dementia is increasing, it is essential that anesthesiologists carefully review the current medications of these patients prior to surgery. In situations when an acetylcholinesterase inhibitor is not discontinued sufficiently long before surgery, the use of a peripheral nerve stimulator and inhalation anesthetics may help achieve adequate neuromuscular blockade for surgery and avoid residual neuromuscular blockade after surgery.\n\nInformed consent statement: Written informed consent was obtained from the patient for the publication of this case.\n\nConflict-of-interest statement: The authors have no funding and conflicts of interest to disclose.\n\nCARE Checklist (2016) statement: The authors have read the CARE Checklist (2016), and the manuscript was prepared and revised according to the CARE Checklist (2016).\n\nManuscript source: Unsolicited manuscript\n\nPeer-review started: May 12, 2020\n\nFirst decision: September 14, 2020\n\nArticle in press: October 12, 2020\n\nSpecialty type: Medicine, research and experimental\n\nCountry/Territory of origin: South Korea\n\nPeer-review report’s scientific quality classification\n\nGrade A (Excellent): 0\n\nGrade B (Very good): B\n\nGrade C (Good): C\n\nGrade D (Fair): 0\n\nGrade E (Poor): 0\n\nP-Reviewer: Higa K S-Editor: Gao CC L-Editor: A P-Editor: Xing YX\n==== Refs\n1 Noufi P Khoury R Jeyakumar S Grossberg GT Use of Cholinesterase Inhibitors in Non-Alzheimer's Dementias Drugs Aging 2019 36 719 731 31201687 \n2 Baruah J Easby J Kessell G Effects of acetylcholinesterase inhibitor therapy for Alzheimer's disease on neuromuscular block Br J Anaesth 2008 100 420 18276655 \n3 Bhardwaj A Dharmavaram S Wadhawan S Sethi A Bhadoria P Donepezil: A cause of inadequate muscle relaxation and delayed neuromuscular recovery J Anaesthesiol Clin Pharmacol 2011 27 247 248 21772691 \n4 Pautola L Reinikainen M [Interaction of donepezil with rocuronium] Duodecim 2012 128 1031 1032 22724318 \n5 Sánchez Morillo J Demartini Ferrari A Roca de Togores López A [Interaction of donepezil and muscular blockers in Alzheimer's disease] Rev Esp Anestesiol Reanim 2003 50 97 100 12712872 \n6 Jung KT An TH Updated review of resistance to neuromuscular blocking agents Anesth Pain Med 2018 13 122 127 \n7 Martyn JA Goudsouzian NG Chang Y Szyfelbein SK Schwartz AE Patel SS Neuromuscular effects of mivacurium in 2- to 12-yr-old children with burn injury Anesthesiology 2000 92 31 37 10638896 \n8 Han T Kim H Bae J Kim K Martyn JA Neuromuscular pharmacodynamics of rocuronium in patients with major burns Anesth Analg 2004 99 386 392, table of contents 15271712 \n9 Moorthy SS Krishna G Dierdorf SF Resistance to vecuronium in patients with cerebral palsy Anesth Analg 1991 73 275 277 1678256 \n10 Hepağuşlar H Uyar M Uğur G Balcioğlu T Resistance to vecuronium after immobilization Paediatr Anaesth 1999 9 94 95 \n11 Soriano SG Sullivan LJ Venkatakrishnan K Greenblatt DJ Martyn JA Pharmacokinetics and pharmacodynamics of vecuronium in children receiving phenytoin or carbamazepine for chronic anticonvulsant therapy Br J Anaesth 2001 86 223 229 11573664 \n12 Gray HS Slater RM Pollard BJ The effect of acutely administered phenytoin on vecuronium-induced neuromuscular blockade Anaesthesia 1989 44 379 381 2568098 \n13 Crowe S Collins L Suxamethonium and donepezil: a cause of prolonged paralysis Anesthesiology 2003 98 574 575 12552219 \n14 Birks JS Harvey RJ Donepezil for dementia due to Alzheimer's disease Cochrane Database Syst Rev 2018 6 CD001190 29923184 \n15 Dooley M Lamb HM Donepezil: a review of its use in Alzheimer's disease Drugs Aging 2000 16 199 226 10803860 \n16 Alcorn S Foo I Perioperative management of patients with dementia BJA Education 2016 17 94 98 \n17 Kelly RE Lien CA Savarese JJ Belmont MR Hartman GS Russo JR Hollmann C Depression of neuromuscular function in a patient during desflurane anesthesia Anesth Analg 1993 76 868 871 8466031 \n18 Rupp SM Miller RD Gencarelli PJ Vecuronium-induced neuromuscular blockade during enflurane, isoflurane, and halothane anesthesia in humans Anesthesiology 1984 60 102 105 6141748 \n19 Naguib M Samarkandi AH Ammar A Elfaqih SR Al-Zahrani S Turkistani A Comparative clinical pharmacology of rocuronium, cisatracurium, and their combination Anesthesiology 1998 89 1116 1124 9821999 \n20 Paul M Kindler CH Fokt RM Dipp NC Yost CS Isobolographic analysis of non-depolarising muscle relaxant interactions at their receptor site Eur J Pharmacol 2002 438 35 43 11906708\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2307-8960",
"issue": "8(21)",
"journal": "World journal of clinical cases",
"keywords": "Case report; Dementia; Donepezil; General anesthesia; Neuromuscular blocking agents; Rocuronium",
"medline_ta": "World J Clin Cases",
"mesh_terms": null,
"nlm_unique_id": "101618806",
"other_id": null,
"pages": "5341-5346",
"pmc": null,
"pmid": "33269268",
"pubdate": "2020-11-06",
"publication_types": "D002363:Case Reports",
"references": "6141748;15271712;11573664;10803860;2568098;21772691;1678256;11906708;9821999;18276655;10638896;12552219;31201687;22724318;29923184;12712872;8466031;10712725",
"title": "Donepezil-related inadequate neuromuscular blockade during laparoscopic surgery: A case report.",
"title_normalized": "donepezil related inadequate neuromuscular blockade during laparoscopic surgery a case report"
} | [
{
"companynumb": "KR-INDICUS PHARMA-000736",
"fulfillexpeditecriteria": "1",
"occurcountry": "KR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ROCURONIUM BROMIDE"
},
"drugadditional": "1",
... |
{
"abstract": "We report a case of severe Citrobacter koseri folliculitis of the face in a boy with acne. A 15-year-old boy affected by acne was admitted because of a rash located on the face. Dermatological examination revealed two large plaques, with numerous pustules, eschars and crusts, located bilaterally and symmetrically on the cheeks. Three bacteriological examinations were positive for C. koseri. The patient was successfully treated with i.m. ceftriaxone. C. koseri is a Gram-negative, aerobic, mobile, nonsporulating bacillus belonging to the Enterobacteriaceae family. It can cause meningitis, central nervous system abscess and sepsis, almost exclusively in infants and immunocompromised hosts. Respiratory tract and urinary infections have been reported in elderly people. Furthermore, rare cases of skin infections have been described.",
"affiliations": "Department of Pathophysiology and Transplantation, Institute for Treatment and Research Cà Granda Ospedale Maggiore Policlinico Foundation, Università degli Studi di Milano, Via Pace 9, 20122, Milan, Italy. danny2003@libero.it.;Department of Pathophysiology and Transplantation, Institute for Treatment and Research Cà Granda Ospedale Maggiore Policlinico Foundation, Università degli Studi di Milano, Via Pace 9, 20122, Milan, Italy.;Department of Pathophysiology and Transplantation, Institute for Treatment and Research Cà Granda Ospedale Maggiore Policlinico Foundation, Università degli Studi di Milano, Via Pace 9, 20122, Milan, Italy.",
"authors": "Raia|D D|DD|;Barbareschi|M|M|;Veraldi|S|S|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone",
"country": "Germany",
"delete": false,
"doi": "10.1007/s15010-015-0734-5",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0300-8126",
"issue": "43(5)",
"journal": "Infection",
"keywords": "Acne; Acne fulminans; Citrobacter koseri; Folliculitis",
"medline_ta": "Infection",
"mesh_terms": "D000293:Adolescent; D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D041041:Citrobacter koseri; D004756:Enterobacteriaceae Infections; D005145:Face; D005499:Folliculitis; D006801:Humans; D008297:Male; D016896:Treatment Outcome",
"nlm_unique_id": "0365307",
"other_id": null,
"pages": "595-7",
"pmc": null,
"pmid": "25630477",
"pubdate": "2015-10",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "10321942;12680804;12041821;2760119;2921299;3899035;10871958;6763304;6511332;15454901;20107742;9538959;21673472;9585893;18682995;10064257",
"title": "Citrobacter koseri folliculitis of the face.",
"title_normalized": "citrobacter koseri folliculitis of the face"
} | [
{
"companynumb": "IT-TEVA-603543ISR",
"fulfillexpeditecriteria": "1",
"occurcountry": "IT",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CLARITHROMYCIN"
},
"drugadditional": null,
... |
{
"abstract": "BACKGROUND\nAlpha lipoic acid is a powerful antioxidant widely used for the supplementary treatment of diabetic neuropathy. Intoxication with alpha lipoic acid is very rare. There is no reported dose of safety in children.\n\n\nMETHODS\nA 14-month-old previously healthy girl was referred to our hospital with the diagnosis of drug intoxication. She was admitted to the emergency department with lethargy and continuing involuntary movements for several hours after she had ingested an unknown amount of alpha lipoic acid. On admission she was lethargic and had myoclonic seizures involving all extremities. She had no fever and laboratory examinations were normal except for mild metabolic acidosis. The seizures were unresponsive to bolus midazolam, phenytoin infusion and levetiracetam infusion. She was taken to the pediatric intensive care unit with the diagnosis of status epilepticus. After failure of the treatment with midazolam infusion she was intubated and thiopental sodium infusion was started. Her myoclonic seizures were controlled with thiopental sodium infusion. After 48 h intubation and mechanical ventilation thiopental sodium was gradually reduced and then stopped. Following the withdraw of thiopental sodium, she was seizure free on her discharge on the 8th day.\n\n\nCONCLUSIONS\nAlpha lipoic acid and derivatives cause side effects in children like refractory convulsions. They are frequently rendered as vitamins by diabetic patients and are left at places where children can easily access them. Therefore, when faced with refractory convulsions in children who have had no disease before, intoxication by medicaments with alpha lipoic acid should be taken into consideration.",
"affiliations": "Department of Pediatrics, Adana Numune Training and Research Hospital, Adana, Turkey. Electronic address: orkuntolunay@yahoo.co.uk.;Department of Pediatric Neurology, Adana Numune Training and Research Hospital, Adana, Turkey.;Department of Pediatric Neurology, Adana Numune Training and Research Hospital, Adana, Turkey.;Department of Pediatrics, Adana Numune Training and Research Hospital, Adana, Turkey.;Department of Pediatrics, Adana Numune Training and Research Hospital, Adana, Turkey.;Department of Pediatric infection, Adana Numune Training and Research Hospital, Adana, Turkey.",
"authors": "Tolunay|Orkun|O|;Çelik|Tamer|T|;Kömür|Mustafa|M|;Gezgin|Ali Emre|AE|;Kaya|Musa Soner|MS|;Çelik|Ümit|Ü|",
"chemical_list": "D000927:Anticonvulsants; D000077287:Levetiracetam; D008063:Thioctic Acid; D013874:Thiopental; D008874:Midazolam; D010889:Piracetam",
"country": "England",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1090-3798",
"issue": "19(6)",
"journal": "European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society",
"keywords": "Alpha lipoic acid; Infant; Intoxication; Status epilepticus",
"medline_ta": "Eur J Paediatr Neurol",
"mesh_terms": "D000927:Anticonvulsants; D004831:Epilepsies, Myoclonic; D005260:Female; D006801:Humans; D007223:Infant; D000077287:Levetiracetam; D008874:Midazolam; D010889:Piracetam; D012121:Respiration, Artificial; D012640:Seizures; D013226:Status Epilepticus; D008063:Thioctic Acid; D013874:Thiopental",
"nlm_unique_id": "9715169",
"other_id": null,
"pages": "730-2",
"pmc": null,
"pmid": "26216607",
"pubdate": "2015-11",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A rare cause of status epilepticus; alpha lipoic acid intoxication, case report and review of the literature.",
"title_normalized": "a rare cause of status epilepticus alpha lipoic acid intoxication case report and review of the literature"
} | [
{
"companynumb": "TR-SUN PHARMACEUTICAL INDUSTRIES LTD-2015R1-101172",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "LEVETIRACETAM"
},
"d... |
{
"abstract": "BACKGROUND\nEndosonography is being implemented rapidly in pulmonary medicine for the diagnosis and staging of lung cancer, the assessment of sarcoidosis, and the assessment of mediastinal lesions. Although serious adverse events (SAEs) have been described, safety data outside cohort studies are scarce.\n\n\nOBJECTIVE\nTo assess the SAE and mortality rate of EUS-guided FNA (EUS-FNA) and endobronchial ultrasound guided transbronchial needle aspiration (EBUS-TBNA) for mediastinal and/or hilar analysis.\n\n\nMETHODS\nNationwide, retrospective survey by using questionnaires.\n\n\nMETHODS\nAll hospitals in the Netherlands.\n\n\nMETHODS\nAll patients undergoing EUS-FNA and EBUS-TBNA for intrathoracic analysis in the period 1999 to 2011.\n\n\nMETHODS\nEUS-FNA and EBUS-TBNA.\n\n\nMETHODS\nOccurrence of fatal outcomes and SAEs. Detailed information was obtained for each reported case, and all cases were reviewed independently by 2 investigators, including identification of risk factors.\n\n\nRESULTS\nAll 89 hospitals (100%) responded. An estimated 14,075 EUS-FNA and 2675 EBUS procedures were performed. Seven patients died after endosonography (5 EUS-FNA, 2 EBUS [mortality rate 0.04%]). All fatalities occurred in patients of poor performance status (American Society of Anesthesiologists Physical Status Classification System score of III/IV). Twenty-five SAEs were reported (22 EUS-FNA, 3 EBUS [SAE rate of 0.15%; EUS-FNA 0.16%, EBUS 0.11%]). SAEs were mostly (64%) of infectious origin. No specific risk factors for infectious adverse events could be identified.\n\n\nCONCLUSIONS\nRetrospective study, possible recall bias, overrepresentation of EUS-FNA cases.\n\n\nCONCLUSIONS\nEndosonography appears to be a safe technique for the analysis of mediastinal and/or hilar lesions. Poor performance status is a risk factor for fatal outcomes. Mediastinitis and/or mediastinal abscess formation is rare but is a potential and dangerous adverse event of endosonography.",
"affiliations": "Department of Respiratory Medicine, Leiden University Medical Center, Leiden, the Netherlands.;Department of Respiratory Medicine, Leiden University Medical Center, Leiden, the Netherlands; Department of Respiratory Medicine, Academic Medical Center, Amsterdam, the Netherlands.",
"authors": "von Bartheld|Martin B|MB|;Annema|Jouke T|JT|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0016-5107",
"issue": "82(6)",
"journal": "Gastrointestinal endoscopy",
"keywords": null,
"medline_ta": "Gastrointest Endosc",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D061765:Endoscopic Ultrasound-Guided Fine Needle Aspiration; D005260:Female; D019538:Health Care Surveys; D006801:Humans; D008169:Lung Abscess; D008171:Lung Diseases; D008297:Male; D008480:Mediastinitis; D008875:Middle Aged; D009426:Netherlands; D017063:Outcome Assessment, Health Care; D012189:Retrospective Studies; D011795:Surveys and Questionnaires",
"nlm_unique_id": "0010505",
"other_id": null,
"pages": "1009-15",
"pmc": null,
"pmid": "25979815",
"pubdate": "2015-12",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Endosonography-related mortality and morbidity for pulmonary indications: a nationwide survey in the Netherlands.",
"title_normalized": "endosonography related mortality and morbidity for pulmonary indications a nationwide survey in the netherlands"
} | [
{
"companynumb": "NL-SA-2016SA014143",
"fulfillexpeditecriteria": "1",
"occurcountry": "NL",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CIPROFLOXACIN"
},
"drugadditional": null,
... |
{
"abstract": "The number of new psychoactive substances (NPS) has increased significantly, especially within the last 5 years. The EMCDDA conducts risks assessments of such substances, especially in relation to serious adverse events. Examination of the individual health risks of a substance is a fundamental requirement of the process. Based on a number of considerations, the Toxicological Significance Score has been developed to support the risk assessment of NPS by allowing the role of a substance in deaths to be better assessed and classified.",
"affiliations": "Alere Forensics, Malvern Hills Science Park, Worcestershire, UK.;European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Lisbon, Portugal.;European Monitoring Centre for Drugs and Drug Addiction (EMCDDA), Lisbon, Portugal.",
"authors": "Elliott|Simon|S|http://orcid.org/0000-0001-5219-1687;Sedefov|Roumen|R|;Evans-Brown|Michael|M|",
"chemical_list": "D013287:Illicit Drugs; D011619:Psychotropic Drugs",
"country": "England",
"delete": false,
"doi": "10.1002/dta.2225",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1942-7603",
"issue": "10(1)",
"journal": "Drug testing and analysis",
"keywords": null,
"medline_ta": "Drug Test Anal",
"mesh_terms": "D062787:Drug Overdose; D005060:Europe; D006801:Humans; D013287:Illicit Drugs; D011619:Psychotropic Drugs; D018570:Risk Assessment; D019966:Substance-Related Disorders",
"nlm_unique_id": "101483449",
"other_id": null,
"pages": "120-126",
"pmc": null,
"pmid": "28635164",
"pubdate": "2018-01",
"publication_types": "D016428:Journal Article; D016454:Review",
"references": null,
"title": "Assessing the toxicological significance of new psychoactive substances in fatalities.",
"title_normalized": "assessing the toxicological significance of new psychoactive substances in fatalities"
} | [
{
"companynumb": "GB-DRREDDYS-GER/UKI/17/0095057",
"fulfillexpeditecriteria": "1",
"occurcountry": "GB",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "MORPHINE"
},
"drugadditional": null,
... |
{
"abstract": "Medical errors are crucial factors influencing hospital mortality. We present a case of 79-year-old female, who was admitted to the hospital due to complications associated with advanced cancer disease. After several days of hospitalization, the woman died as a result of cancer as well as severe drugs intoxication. The investigation showed extremely high concentrations of chlorprothixen and tramadol in the. blood of the patient. This paper describes a number of medical errors made by hospital staff, of which the most significant was an inappropriate drugs policy.",
"affiliations": null,
"authors": "Wiergowski|Marek|M|;Schetz|Daria|D|;Jankowski|Zbigniew|Z|;Sumińska-Zuminska|Barbara|B|;Sein Anand|Jacek|J|",
"chemical_list": "D014147:Tramadol; D002749:Chlorprothixene",
"country": "Poland",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0033-2240",
"issue": "72(9)",
"journal": "Przeglad lekarski",
"keywords": null,
"medline_ta": "Przegl Lek",
"mesh_terms": "D000368:Aged; D002749:Chlorprothixene; D064420:Drug-Related Side Effects and Adverse Reactions; D017809:Fatal Outcome; D005260:Female; D006760:Hospitalization; D006801:Humans; D009369:Neoplasms; D014147:Tramadol",
"nlm_unique_id": "19840720R",
"other_id": null,
"pages": "485-7",
"pmc": null,
"pmid": "26827574",
"pubdate": "2015",
"publication_types": "D002363:Case Reports; D004740:English Abstract; D016428:Journal Article",
"references": null,
"title": "Intoxication of female patient with generalised cancer in hospital--a case report.",
"title_normalized": "intoxication of female patient with generalised cancer in hospital a case report"
} | [
{
"companynumb": "PL-MYLANLABS-2016M1019426",
"fulfillexpeditecriteria": "1",
"occurcountry": "PL",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "TRAMADOL"
},
"drugadditional": null,
... |
{
"abstract": "A 39-year-old man received a diagnosis of unresectable multiple liver metastases from multiple colorectal cancers with familial adenomatous polyposis. After construction of an ileostomy, modified FOLFOX6 (mFOLFOX6) with panitumumab was administrated because rectal cancer and sigmoid colon cancer are KRAS wild type. The 13 courses of chemotherapy resulted in a marked reduction in the size of liver metastases and sigmoid colon cancer. Consequently, curative resection with total colectomy, ileal pouch anal anastomosis, and liver metastasis resection with radiofrequency ablation was performed. Progression of KRAS wild-type rectal cancer after chemotherapy suggested that each clone from rectal and sigmoid colon cancer might have a different sensitivity to epidermal growth factor receptor antibody. Immunohistochemical analysis revealed loss of PTEN expression in rectal cancer compared with liver metastases from sigmoid colon cancer, showing that the difference of mFOLFOX6 with panitumumab might be related to activation of the PI3K-AKT pathway.",
"affiliations": "Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Graduate School of Medicine, Mie University, Mie, Japan.",
"authors": "Toiyama|Yuji|Y|;Inoue|Yasuhiro|Y|;Kitajima|Takahito|T|;Okigami|Masato|M|;Kawamura|Mikio|M|;Kawamoto|Aya|A|;Okugawa|Yoshinaga|Y|;Hiro|Jyunichiro|J|;Tanaka|Koji|K|;Mohri|Yasuhiko|Y|;Kusunoki|Masato|M|",
"chemical_list": "D000911:Antibodies, Monoclonal; D009944:Organoplatinum Compounds; D000077544:Panitumumab; D002955:Leucovorin; D005472:Fluorouracil",
"country": "Italy",
"delete": false,
"doi": "10.9738/INTSURG-D-13-00125.1",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0020-8868",
"issue": "99(6)",
"journal": "International surgery",
"keywords": "Colorectal cancer; Familial adenomatous polyposis; Liver metastases; Panitumumab; mFOLFOX6",
"medline_ta": "Int Surg",
"mesh_terms": "D000328:Adult; D000714:Anastomosis, Surgical; D000911:Antibodies, Monoclonal; D000971:Antineoplastic Combined Chemotherapy Protocols; D017115:Catheter Ablation; D003082:Colectomy; D039021:Colonic Pouches; D015179:Colorectal Neoplasms; D003131:Combined Modality Therapy; D005472:Fluorouracil; D006801:Humans; D002955:Leucovorin; D008113:Liver Neoplasms; D008297:Male; D009944:Organoplatinum Compounds; D000077544:Panitumumab; D016896:Treatment Outcome",
"nlm_unique_id": "0043524",
"other_id": null,
"pages": "795-801",
"pmc": null,
"pmid": "25437589",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "12907904;22446022;16618717;16782909;18316791;18946061;19001320;18669866;19114683;19223544;19339720;20333385;20921465;21165994;21641636;9278662",
"title": "Conversion Therapy Using mFOLFOX6 With Panitumumab for Unresectable Liver Metastases From Multiple Colorectal Cancers With Familial Adenomatous Polyposis.",
"title_normalized": "conversion therapy using mfolfox6 with panitumumab for unresectable liver metastases from multiple colorectal cancers with familial adenomatous polyposis"
} | [
{
"companynumb": "JP-AMGEN-JPNSP2014102787",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": null,
"activesubstance": {
"activesubstancename": "LEVOLEUCOVORIN CALCIUM"
},
"drugadditional": ... |
{
"abstract": "Pramipexole is a dopaminergic pharmacologic agent with reported adverse effects that include hypersexuality, shift in sexual interests, pathological gambling, compulsive shopping, and binge eating. Pramipexole is indicated in the treatment of Parkinson's disease and restless leg syndrome and has been used as adjunctive or add-on treatment in major depressive disorder. This report describes the successful treatment of a series of 4 adult men who presented with concerns about problematic sexual interests and behaviors that began after treatment with pramipexole related to Parkinson's disease or restless leg syndrome.",
"affiliations": "Sexual Behaviours Clinic, Integrated Forensic Program, Royal Ottawa Mental Health Centre, Ottawa, Ontario, Canada.;Sexual Behaviours Clinic, Integrated Forensic Program, Royal Ottawa Mental Health Centre, Ottawa, Ontario, Canada.;Department of Psychology and Department of Criminology, University of Ottawa, Ottawa, Ontario, Canada.;Department of Psychiatry and Behavioural Neurosciences, McMaster University, Hamilton, Ontario, Canada.;Sexual Behaviours Clinic, Integrated Forensic Program, Royal Ottawa Mental Health Centre, Ottawa, Ontario, Canada.",
"authors": "Murphy|Lisa|L|;Ly|Thanh|T|;DiMario|Keana|K|;Mihowich|Terry|T|;Fedoroff|J Paul|JP|",
"chemical_list": "D018491:Dopamine Agonists; D000077487:Pramipexole",
"country": "United States",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2155-7780",
"issue": "23(1)",
"journal": "The primary care companion for CNS disorders",
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"abstract": "We herein report a patient with breast cancer who developed dermatomyositis (DM) immediately after mastectomy. She had a history of severe drug eruption during neoadjuvant chemotherapy six months previously. Within a month after the operation, myalgia and rash, including Gottron's papules, developed, and skeletal-muscle enzymes elevated, so she was diagnosed with probable DM according to the Bohan and Peter criteria. In many neoplastic DM cases, the course of the disease parallels the course of the malignancy. Possible mechanisms were suggested to explain the development of DM in the present case and offer new insight into autoimmune diseases.",
"affiliations": "Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.;Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan.",
"authors": "Otsuka|Yuki|Y|;Watanabe|Haruki|H|;Kano|Yuzuki|Y|;Tatebe|Noriko|N|;Sunahori-Watanabe|Katsue|K|;Kawabata|Tomoko|T|;Sada|Ken-Ei|KE|;Wada|Jun|J|",
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"fulltext": "\n==== Front\nIntern MedIntern. MedInternal Medicine0918-29181349-7235The Japanese Society of Internal Medicine 2924976610.2169/internalmedicine.9194-17Case ReportOccurrence of Dermatomyositis Immediately after Mastectomy Subsequent to Severe Chemotherapeutic Drug Eruption Otsuka Yuki 12Watanabe Haruki 1Kano Yuzuki 1Tatebe Noriko 1Sunahori-Watanabe Katsue 1Kawabata Tomoko 1Sada Ken-ei 1Wada Jun 1\n1 Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Japan\n2 Okayama University Medical School, JapanCorrespondence to Dr. Haruki Watanabe, harukiw@okayama-u.ac.jp\n\n15 12 2017 56 24 3379 3383 22 3 2017 24 4 2017 Copyright © 2017 by The Japanese Society of Internal Medicine2017The Internal Medicine is an Open Access article distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).We herein report a patient with breast cancer who developed dermatomyositis (DM) immediately after mastectomy. She had a history of severe drug eruption during neoadjuvant chemotherapy six months previously. Within a month after the operation, myalgia and rash, including Gottron's papules, developed, and skeletal-muscle enzymes elevated, so she was diagnosed with probable DM according to the Bohan and Peter criteria. In many neoplastic DM cases, the course of the disease parallels the course of the malignancy. Possible mechanisms were suggested to explain the development of DM in the present case and offer new insight into autoimmune diseases. \n\nparaneoplastic dermatomyositissurgerychemotherapysevere drug eruption\n==== Body\nIntroduction\nDermatomyositis (DM) is a rare idiopathic autoimmune disorder with an annual incidence of approximately 1/100,000, and approximately 10% of patients with DM have an associated malignancy (1,2). Breast cancer accounts for approximately 20% of malignancies seen in DM patients with malignancy (3). The malignancy usually appeared within 1 year after the diagnosis of DM, and the standardized incidence ratio of malignancy among DM patients was reported to be 17.29 in the first year (4). However, the development of DM after the diagnosis or treatment of malignancy has not been fully evaluated. The molecular mechanisms by which malignancy induces inflammatory myositis is unclear, but several autoantibodies have been detected in DM patients with malignancy (5).\n\nStevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are known manifestations of severe drug eruption (6-8), and previous reports have suggested that severe drug eruptions provoke autoimmune disease (9-13).\n\nWe herein report a patient with breast cancer who developed a severe drug eruption during neoadjuvant chemotherapy and subsequently developed DM just after mastectomy.\n\nCase Report\nA 61-year-old Japanese woman was diagnosed with stage IIIC invasive ductal breast carcinoma and started neoadjuvant chemotherapy with doxorubicin (DXR) and cyclophosphamide (CYC) (anthracycline/CYC [AC]) in October 2015. During the first course of chemotherapy, she developed erythema on the right shoulder and chest wall, which spread after the second course was started (Fig. 1). Although atypical lymphocytes appeared (2.5%), herpes virus infection was excluded by the Tzanck test, and a dermatologist clinically diagnosed a severe drug eruption similar to SJS caused by AC chemotherapy. Mucous membrane involvement was absent. Prednisolone (PSL) was started at 30 mg/day and then tapered and discontinued 1 month later. She was also treated with weekly paclitaxel instead of AC chemotherapy. Although she developed acute pharyngitis in February, the scheduled 12 courses of chemotherapy was completed, and mastectomy and axillary node dissection were performed in March 2016 (Fig. 2). After the operation, flurbiprofen, pentazocine, loxoprofen, and rebamipide were administered temporarily; however, no other drugs such as antibiotics were used.\n\nFigure 1. Erythema after anthracycline/cyclophosphamide chemotherapy. Millet-sized blisters developed on the trunk with itching.\n\nFigure 2. Clinical course. Acute pharyngitis developed in February and was treated with antibiotics. Unfortunately, CK had never been evaluated before the development of DM. A/C: adriamycin/cyclophosphamide, CK: creatine kinase, CRP: C-reactive protein, DM: dermatomyositis, LD: lactate dehydrogenase, PSL: prednisolone, PTX: paclitaxel\n\nAt the beginning of April, anorexia, malaise, and fatigability developed and worsened daily. Her eyelids became edematous, and she developed slight myalgia; therefore, she visited our hospital. She had a rash on the face, chest, and abdominal wall. No muscle weakness or tenderness was observed, but a laboratory examination revealed a significantly increased creatine kinase (CK) level (1,299 U/L). Drug-induced rash was suspected, and loxoprofen was discontinued, but her cutaneous symptoms worsened; erythema and itching spread to the head, upper back, and extremities, and blisters appeared on the forearm. Furthermore, her proximal myalgia worsened, so she was referred to our department and admitted a week later. She had never been diagnosed with dyslipidemia or taken statins.\n\nOn admission, swelling erythemas were found on her eyelids, erythematous papules on the dorsum of the metacarpophalangeal joints, and a flat red rash over the back of the elbows; these rashes are compatible with heliotrope erythema, Gottron's papules, and Gottron's sign (Fig. 3). Furthermore, periungual erythema was found with widespread erythema and facial edema (Fig. 3). The blisters were observed on both forearms, and a shawl sign was also observed (Fig. 3). Manual muscle testing showed deltoid and quadriceps weakness, and magnetic resonance imaging showed the enhancement of the deltoid muscle and rotator cuff (Fig. 4). She did not have dysphasia. Laboratory examinations revealed elevated CK (1,181 U/L), myoglobin (854 ng/mL), lactate dehydrogenase (427 U/L), and aspartate transaminase (70 U/L) levels. There was no thyroid dysfunction, and interstitial lung disease was absent. Electromyography and a muscle biopsy were not performed. The histological findings of the blisters was consistent with DM, but myositis-related autoantibodies were undetectable (Table).\n\nFigure 3. Rash at the time of admission. A) Heliotrope erythema with facial edema. B) Shawl sign. C) Gottron’s sign on the elbow. D) Gottron’s papules. E) A blister on the forearm.\n\nFigure 4. Magnetic resonance imaging of the right shoulder. (A) Widespread enhancement of the rotator cuff muscles and deltoid muscle (arrow). (B) Tendon rupture of the supraspinatus muscle (arrow).\n\nTable. List of Undetected Myositis-associated Autoantibodies.\n\nANA, anti-Jo-1 antibody, anti-aminoacyl-tRNA synthetase antibody, anti-PL-7 antibody, anti-PL-12 antibody, anti-OJ antibody, anti-EJ antibody, anti-Mi-2 antibody, anti-Ku antibody, anti-signal recognition particle antibody, anti-PM-Scl antibody, anti-Ro52 antibody, anti-KS antibody, anti-melanoma differentiation-associated gene 5 antibody, anti-transcription intermediary factor (TIF)-1γ antibody, anti-TIF-1α antibody, and anti-NXP-2 antibody\t\nA diagnosis of DM was made according to the Bohan and Peter criteria (14). After the initiation of 1 mg/kg/day of PSL, her symptoms, including erythema and muscular weakness, quickly improved, and the serum CK level also decreased. PSL was tapered, and she was discharged at the end of May 2016 (Fig. 2). Because her breast cancer was classified as stage IIIC, adjuvant radiotherapy was required but was not performed due to the skin symptoms. Neither recurrence nor metastasis was detected on computed tomography at the end of April.\n\nDiscussion\nWe encountered a case of DM that developed immediately after breast cancer surgery in a patient with a history of severe drug eruption during neoadjuvant chemotherapy. The development of DM after the diagnosis of malignancy is relatively uncommon (15,16), and the development of DM after the surgical treatment of breast cancer has only been reported once previously, in a case of primary limited systemic sclerosis [calcinosis, Raynaud phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasis (CREST) syndrome] (17). The clinical course of DM is usually correlated with the course of the underlying malignancy (16,18,19). To explain the unexpected onset in our case, three mechanisms of pathogenesis are proposed: operative stress, chemotherapy, and severe drug eruption.\n\nThe first possible factor related to the development of DM was operative stress. Our patient had never had muscle symptoms before mastectomy, and the symptoms arose after the surgery. Interestingly, a recent study revealed that 15% of patients with Guillain-Barré syndrome, which is also attributed to an autoimmune reaction, underwent a surgical procedure within eight weeks prior to symptom onset (20). Previous reports showed that innate immunity was activated by damage-associated molecular pattern molecules from the injured tissues, resulting in the expression of inflammatory cytokines (21-23). Another report showed that excessive inflammation suppressed cellular immunity and down-regulated Th1 cells (24). As the predominance of Th2 cells in DM patients is well-known (25), operative stress may cause DM through robust inflammation and the subsequent imbalance of Th1/Th2 immunity.\n\nThe second possible factor is chemotherapy. Generally, chemotherapy induces immunosuppression and relieves autoimmune disease. However, several case reports have found that chemotherapy induced or exacerbated paraneoplastic DM (26,27). They concluded a short duration from chemotherapy to DM onset might explain the relationship (26,27). Although the precise mechanism is unknown, chemotherapy may cause exposure of tumor cell antigens and induce autoimmunity.\n\nThe third possible factor is drug eruption. A recent study revealed that autoantibodies against cytoskeletal linker protein were detected in the serum of SJS/TEN patients in the early stage as a consequence of epidermal damage (9). Drug hypersensitivity syndrome/drug reaction with eosinophilia and systemic symptoms, another type of dug eruption, has also been reported to be associated with multiple autoimmune sequelae, including thyroid disease, type 1 diabetes mellitus, and autoantibody productions, suggesting that autoimmune responses occur after severe drug eruptions (10,11). In these cases of severe drug eruption, herpes viruses are activated after the eruption (28). Virus infection is generally associated with autoimmune diseases (28) and has also been proposed as a cause of the production of myositis-specific antibodies (29). Interestingly, drug eruption was reported in 22% of Japanese patients with adult-onset Still's disease, and antibodies against various viruses were found in 47% of those patients (30). Thus, severe drug eruption might induce autoimmunity via viral reactivation. Indeed, atypical lymphocytes were detected in the present case. It is possible that DM had already developed at the onset of the first drug eruption but remained undetected because a histological evaluation was not performed at that time and was masked by PSL treatment and/or chemotherapy.\n\nWe herein reported a novel case of DM that developed immediately after excision of breast cancer in a patient with a history of severe eruption caused by chemotherapy. Surgery, chemotherapy, and drug eruptions are not specific for breast cancer; therefore, our hypothesis can be applied to all types of malignancy-related DM. Considering possible mechanisms to explain the development of DM in the present case may offer new insight into autoimmune diseases and help clarify the pathogenesis.\n\n\nWritten informed consent for this case report was obtained from the patient.\n\n\nAuthor's disclosure of potential Conflicts of Interest (COI).\n\nJun Wada: Honoraria, Astellas, Boehringer IngeIheim, Novaris and Tanabe Mitsubishi.\n\nAcknowledgement\nWe are grateful to Dr. Tsuneyo Mimori of Kyoto University for analyzing the autoantibodies using the immunoprecipitation assay, Dr. Hiroko Fukamatsu at the Dermatology Department of Okayama University Graduate School of Medicine Dentistry and Pharmaceutical Sciences for taking pictures of the rash, and all medical staff members in our department.\n==== Refs\n1. Lakhanpal S , Bunch TW , Ilstrup DM , Melton LJ \nPolymyositis-dermatomyositis and malignant lesions: does an association exist? \nMayo Clin Proc \n61 : 645 -653 , 1986 .3724244 \n2. Chen YJ , Wu CY , Huang YL , Wang CB , Shen JL , Chang YT \nCancer risks of dermatomyositis and polymyositis: a nationwide cohort study in Taiwan . Arthritis Res Ther \n12 : R70 , 2010 .20398365 \n3. Fang YF , Wu YJ , Kuo CF , Luo SF , Yu KH \nMalignancy in dermatomyositis and polymyositis: analysis of 192 patients . Clin Rheumatol \n35 : 1977 -1984 , 2016 .27210465 \n4. Qiang JK , Kim WB , Baibergenova A , Alhusayen R \nRisk of malignancy in dermatomyositis and polymyositis: a systematic review and meta-analysis . J Cutan Med Surg \n21 : 131 -136 , 2016 .27534779 \n5. Fujimoto M , Watanabe R , Ishitsuka Y , Okiyama N \nRecent advances in dermatomyositis-specific autoantibodies . Curr Opin Rheumatol \n28 : 636 -644 , 2016 .27533321 \n6. Mockenhaupt M , Viboud C , Dunant A , et al \nStevens-Johnson syndrome and toxic epidermal necrolysis: assessment of medication risks with emphasis on recently marketed drugs. The EuroSCAR-study . J Invest Dermatol \n128 : 35 -44 , 2008 .17805350 \n7. Halevy S , Ghislain PD , Mockenhaupt M , et al \nAllopurinol is the most common cause of Stevens-Johnson syndrome and toxic epidermal necrolysis in Europe and Israel . J Am Acad Dermatol \n58 : 25 -32 , 2008 .17919772 \n8. Roujeau JC , Kelly JP , Naldi L , et al \nMedication use and the risk of Stevens-Johnson syndrome or toxic epidermal necrolysis . N Engl J Med \n333 : 1600 -1607 , 1995 .7477195 \n9. Takehara A , Aoyama Y , Kurosawa M , et al \nLongitudinal analysis of antibody profiles against plakins in severe drug eruptions: emphasis on correlation with tissue damage in drug-induced hypersensitivity syndrome and drug reaction with eosinophilia and systemic symptoms . Br J Dermatol \n175 : 944 -952 , 2016 .27087170 \n10. Ushigome Y , Kano Y , Ishida T , Hirahara K , Shiohara T \nShort- and long-term outcomes of 34 patients with drug-induced hypersensitivity syndrome in a single institution . J Am Acad Dermatol \n68 : 721 -728 , 2013 .23182063 \n11. Brown RJ , Rother KI , Artman H , et al \nMinocycline-induced drug hypersensitivity syndrome followed by multiple autoimmune sequelae . Arch Dermatol \n145 : 63 -66 , 2009 .19153345 \n12. Chen YC , Chang CY , Cho YT , Chiu HC , Chu CY \nLong-term sequelae of drug reaction with eosinophilia and systemic symptoms: a retrospective cohort study from Taiwan . J Am Acad Dermatol \n68 : 459 -465 , 2013 .22959230 \n13. Takahashi R , Kano Y , Yamazaki Y , Kimishima M , Mizukawa Y , Shiohara T \nDefective regulatory T cells in patients with severe drug eruptions: timing of the dysfunction is associated with the pathological phenotype and outcome . J Immunol \n182 : 8071 -8079 , 2009 .19494333 \n14. Bohan A , Peter JB \nPolymyositis and dermatomyositis (first of two parts) . N Engl J Med \n292 : 344 -347 , 1975 .1090839 \n15. Zampieri S , Valente M , Adami N , et al \nPolymyositis, dermatomyositis and malignancy: a further intriguing link . Autoimmun Rev \n9 : 449 -453 , 2010 .20026430 \n16. Andras C , Ponyi A , Constantin T , et al \nDermatomyositis and polymyositis associated with malignancy: a 21-year retrospective study . J Rheumatol \n35 : 438 -444 , 2008 .18203322 \n17. Abraham Z , Rozenbaum M , Glück Z , Feuerman EJ \nFulminant dermatomyositis after removal of a cancer . J Dermatol \n19 : 424 -427 , 1992 .1401500 \n18. Racanelli V , Prete M , Minoia C , Favoino E , Perosa F \nRheumatic disorders as paraneoplastic syndromes . Autoimmun Rev \n7 : 352 -358 , 2008 .18486921 \n19. Song YJ , Wu YF , Fan T \nDermatosis as the initial manifestation of malignant breast tumors: retrospective analysis of 4 cases . Breast Care (Basel) \n5 : 174 -176 , 2010 .21049066 \n20. Nagarajan E , Rubin M , Wijdicks EFM , Hocker SE \nGuillain-Barré syndrome after surgical procedures. Predisposing factors and outcome . Neurol Clin Pract \n2017 (Epub ahead of print).\n21. Martin P , Leibovich SJ \nInflammatory cells during wound repair: the good, the bad and the ugly . Trends Cell Biol \n15 : 599 -607 , 2005 .16202600 \n22. Manson J , Thiemermann C , Brohi K \nTrauma alarmins as activators of damage-induced inflammation . Br J Surg \n99 (Suppl 1 ): 12 -20 , 2012 .22441851 \n23. Shaw TJ , Martin P \nWound repair at a glance . J Cell Sci \n122 : 3209 -3213 , 2009 .19726630 \n24. Shakhar G , Ben-Eliyahu S \nPotential prophylactic measures against postoperative immunosuppression: could they reduce recurrence rates in oncological patients? \nAnn Surg Oncol \n10 : 972 -992 , 2003 .14527919 \n25. Ishii W , Matsuda M , Shimojima Y , Itoh S , Sumida T , Ikeda S \nFlow cytometric analysis of lymphocyte subpopulations and TH1/TH2 balance in patients with polymyositis and dermatomyositis . Intern Med \n47 : 1593 -1599 , 2008 .18797118 \n26. Chen FW , Zhou X , Egbert BM , Swetter SM , Sarin KY \nDermatomyositis associated with capecitabine in the setting of malignancy . J Am Acad Dermatol \n70 : e47 -e48 , 2014 .24438983 \n27. Akiyama C , Osada A , Sou K , et al \nA case of dermatomyositis triggered by tegafur . Acta Derm Venereol \n77 : 490 , 1997 .9394998 \n28. Michels AW , Ostrov DA \nNew approaches for predicting T cell-mediated drug reactions: A role for inducible and potentially preventable autoimmunity . J Allergy Clin Immunol \n136 : 252 -257 , 2015 .26254052 \n29. Mathews MB , Bernstein RM \nMyositis autoantibody inhibits histidyl-tRNA synthetase: a model for autoimmunity . Nature \n304 : 177 -179 , 1983 .6866113 \n30. Ohta A , Yamaguchi M , Tsunematsu T , et al \nAdult Still's disease: a multicenter survey of Japanese patients . J Rheumatol \n17 : 1058 -1063 , 1990 .2213780\n\n",
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"issue": "56(24)",
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"keywords": "chemotherapy; paraneoplastic dermatomyositis; severe drug eruption; surgery",
"medline_ta": "Intern Med",
"mesh_terms": "D000970:Antineoplastic Agents; D044466:Asians; D001943:Breast Neoplasms; D003882:Dermatomyositis; D003875:Drug Eruptions; D005260:Female; D006801:Humans; D008408:Mastectomy; D008875:Middle Aged; D016896:Treatment Outcome",
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"title": "Occurrence of Dermatomyositis Immediately after Mastectomy Subsequent to Severe Chemotherapeutic Drug Eruption.",
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"affiliations": "Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Diagnostic Imaging, St. Jude Children's Research Hospital, Memphis, Tennessee.;Histology Laboratory, West Cancer Center, Collierville, Tennessee.;Department of Pediatric Hematology/Oncology, Our Lady of the Lake Children's Hospital, Baton Rouge, Louisiana.;Department of Gastroenterology, Le Bonheur Children's Hospital, Memphis, Tennessee.;Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.;Department of Bone Marrow Transplantation and Cellular Therapy, St. Jude Children's Research Hospital, Memphis, Tennessee.",
"authors": "Epperly|Rebecca|R|https://orcid.org/0000-0002-8998-0732;Santiago|Teresa|T|https://orcid.org/0000-0002-2838-3619;Morin|Cara E|CE|https://orcid.org/0000-0003-1953-4486;Patton|Kurt|K|;Deyo|Jeff|J|;Eshun|John|J|;Triplett|Brandon|B|https://orcid.org/0000-0001-8220-9980;Sharma|Akshay|A|https://orcid.org/0000-0003-3281-2081",
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"abstract": "Adult immune thrombocytopenia (ITP) commonly relapses after stopping treatments. This may be preventable by low-dose steroids. In this multicenter study, adult patients with ITP who had been responding to corticosteroids were randomized with the 2 strata of newly diagnosed and relapsed ITP to prednisolone 7.5 mg/d or observation for 6 months. Relapses were defined by a platelet count below 30 × 109/L and/or clinical bleeding. There were 75 patients evaluable for the efficacy and 77 for safety. The recurrent ITP comprised 57.3%. During the median follow-up of 42 weeks, there were 20.5% (8/39) and 25% (9/36) of recurrences in the prednisolone and control groups ( P = .643), with the hazard ratio (HR) of 0.75 ( P = .549). The significant factor that could predict recurrences was relapsed ITP with the HR of 2.79 (95% confidence interval, 1.02-7.64, P = .037). Prednisolone showed a trend toward a benefit in the relapsed subgroup ( P = .070). Adverse events were not different ( P = .540) and mostly mild. In conclusion, prednisolone maintenance could not prolong relapse-free survival. Relapsed patients deserve further investigations for preventive measures.",
"affiliations": "1 Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.;1 Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.;3 Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.;1 Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.;1 Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand.",
"authors": "Pirunsarn|Arunrat|A|;Kijrattanakul|Pitiphong|P|;Chamnanchanunt|Supat|S|;Polprasert|Chantana|C|;Rojnuckarin|Ponlapat|P|http://orcid.org/0000-0001-7912-1996",
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"fulltext": "\n==== Front\nClin Appl Thromb HemostClin. Appl. Thromb. HemostCATspcatClinical and Applied Thrombosis/Hemostasis1076-02961938-2723SAGE Publications Sage CA: Los Angeles, CA 2961486510.1177/107602961876484310.1177_1076029618764843Original ArticlesA Randomized Multicenter Trial Comparing Low-Dose Prednisolone Versus Observation for Prevention of Recurrences in Adult Immune Thrombocytopenia Pirunsarn Arunrat MD12Kijrattanakul Pitiphong MD1Chamnanchanunt Supat MD3Polprasert Chantana MD1http://orcid.org/0000-0001-7912-1996Rojnuckarin Ponlapat MD, PhD1\n1 Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok, Thailand\n2 Buddhasothorn Hospital, Amphoe Mueang, Chachoengsao, Thailand\n3 Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol University, Bangkok, ThailandPonlapat Rojnuckarin, Department of Medicine, Faculty of Medicine, Chulalongkorn University and King Chulalongkorn Memorial Hospital, Bangkok 10330, Thailand. Emails: rojnuckarinp@gmail.com; ponlapat.r@chula.ac.th03 4 2018 9 2018 24 6 867 873 © The Author(s) 20182018SAGE Publications Inc. unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Adult immune thrombocytopenia (ITP) commonly relapses after stopping treatments. This may be preventable by low-dose steroids. In this multicenter study, adult patients with ITP who had been responding to corticosteroids were randomized with the 2 strata of newly diagnosed and relapsed ITP to prednisolone 7.5 mg/d or observation for 6 months. Relapses were defined by a platelet count below 30 × 109/L and/or clinical bleeding. There were 75 patients evaluable for the efficacy and 77 for safety. The recurrent ITP comprised 57.3%. During the median follow-up of 42 weeks, there were 20.5% (8/39) and 25% (9/36) of recurrences in the prednisolone and control groups (P = .643), with the hazard ratio (HR) of 0.75 (P = .549). The significant factor that could predict recurrences was relapsed ITP with the HR of 2.79 (95% confidence interval, 1.02-7.64, P = .037). Prednisolone showed a trend toward a benefit in the relapsed subgroup (P = .070). Adverse events were not different (P = .540) and mostly mild. In conclusion, prednisolone maintenance could not prolong relapse-free survival. Relapsed patients deserve further investigations for preventive measures.\n\nimmune thrombocytopeniarecurrenceprednisolonerandomized trialThai Society of HematologyMulticenter Research Grant\n==== Body\nIntroduction\nImmune thrombocytopenia (ITP) is a common bleeding disorder caused by production of autoantibodies targeting platelet glycoproteins. These opsonized platelets are then destroyed in the spleen and/or liver. In addition, a platelet production defect also plays an important role in the disease pathogenesis.1 Severe thrombocytopenia may result in massive or vital organ hemorrhages that are potentially fatal. On the other hand, immunosuppressive therapy, especially high-dose corticosteroids, predisposes patients to infections which may also be lethal. In addition, there are other steroid adverse events, such as diabetes mellitus, peptic ulcer, osteoporosis, bone avascular necrosis, glaucoma, and cataract. Therefore, physicians managing ITP must weigh the benefits against the risks of the administered treatments and the disease itself.\n\nInternational consensus guidelines suggest starting treatment for adult ITP only when platelet counts fall below 30 × 109/L and/or there is clinically relevant bleeding.2,3 Corticosteroids, either prednisolone (1 mg/kg/d) or high-dose dexamethasone (40 mg/d for 4 days), have been the recommended first-line therapy yielding a very good response rate of 70% to 90%.4 Due to adverse effects of long-term steroids, the treatment needs to be tapered and finally stopped. A guideline suggests a gradual reduction in steroid dosages rather than abrupt termination3, but the most appropriate steroid tapering schedule is still undefined as randomized trials are lacking. After stopping medications, the majority of ITP recurs,4–7 with an estimated disease-free rate of only 15% at 10 years.4 A strategy to prevent ITP relapses is, therefore, required. Nevertheless, long-term side effects and costs of the preventive measures are to be concerned.\n\nCurrently, the approved long-term extended therapy for chronic ITP is thrombopoietin receptor agonists as the medications are relatively safe.3,8,9 However, the drugs are approved only for steroid-refractory ITP and the costs of drugs are very high especially for potentially lifelong uses. Additionally, there may be an increased risk for thromboembolism10 and theoretical hazards of myelofibrosis and leukemic transformation as there is a long-standing MPL/JAK/STAT pathway hyperactivation similar to myeloproliferative neoplasm.\n\nAs the toxicity of high-dose steroid is well known, lower doses of prednisolone may be more tolerable. Regarding the efficacy, one randomized trial demonstrated that prednisolone at 0.25 mg/kg/d was as effective as the standard dose prednisolone for the treatment of acute ITP.11 The efficacy of lower doses of steroid is unknown. Because some patients have ITP relapses when prednisolone is discontinued, it is a common practice in our country to maintain a very low dose (≤10 mg/d) of prednisolone for a long period of time. There has been no previous randomized trial studying steroid maintenance therapy. Therefore, we aimed to determine the efficacy and safety of a physiological dose of prednisolone in preventing ITP recurrences in patients who had been responding to steroids.\n\nMaterials and Methods\nClinical Settings\nThis is a randomized multicenter open-label trial. The 4 actively contributing centers were 3 medical school-affiliated hospitals (King Chulalongkorn Memorial Hospital, Hospital for Tropical Diseases, and HRH Princess Maha Chakri Sirindhorn Medical Center) and 1 provincial hospital (Buddhasothorn Hospital). This study was approved by each hospital’s ethics committee. The study was registered in the Thai Clinical Trial Registry: TCTR20140213002\n\nPatients\nThe inclusion criteria were the adult patients with primary ITP (age ≥18 years) who had been treated with corticosteroids, either prednisolone at 1 mg/kg/d or 4-day high-dose dexamethasone followed by lower doses of prednisolone,12 and showed responses according to the international working group criteria (platelet count ≥30 × 109/L at least twice and no clinical bleeding).13 The prednisolone doses were subsequently tapered according to the primary physicians. When prednisolone doses were reduced to 10 mg/d, or less, for at least 2 weeks and platelet counts were still ≥30 × 109/L, the patients were asked to participate in the trial. There must have been no other concomitant ITP treatment for at least 4 weeks before enrollment.\n\nThe exclusion criteria were the diagnosis of secondary ITP and causes of which were HIV infection, hepatitis C infection, malignancy, or other autoimmune diseases. Patients with steroid contraindications, which were an active infection, uncontrolled diabetes mellitus, uncontrolled hypertension, active peptic ulcer, glaucoma, cataract, osteoporosis, psychosis, or avascular osteonecrosis, were not included. Finally, post-splenectomized patients were also excluded. Informed consent was received from all enrolled patients.\n\nInterventions\nThe enrolled patients were stratified into newly diagnosed and relapsed ITP before randomized by opening one of the 2 sets of randomly arranged concealed envelopes indicating either steroid or observation. One of the investigators (A.P.) was responsible for the randomization process.\n\nThe treatment group received 7.5 mg/d prednisolone for 6 months. Subsequently, steroids were reduced until stopped in 2 months and patients were followed for 2 more months to the total of 10 months. In the control group, prednisolone doses were immediately tapered to stop within 2 months and they were followed up to the total of 10 months. After the study completion, patients at King Chulalongkorn Memorial Hospital were followed for complete blood count (CBC) and bleeding symptoms every 3 to 6 months as long as they were willing to.\n\nBaseline data included bleeding symptoms, CBC, blood smear, serum creatinine, liver function test, fasting plasma glucose, serum lipid profile, stool examination for parasites, and chest X-ray. The patients were evaluated at least every 2 months for signs and symptoms of bleeding by the clinical hemorrhagic score,14 CBC, and any adverse events. Blood chemistry was tested again at month 4 of follow-up. The primary end point was the ITP relapses as defined by platelet counts <30 × 109/L or bleeding symptoms with the clinical hemorrhagic score ≥2.\n\nSample Size Calculation\nThe reported ITP relapse rates are greatly variable among series.5–7,15–17 For the sample size calculation, a recurrent rate without treatment was estimated as two-thirds (66%) of the patients. There has been no previous report on the effects of low-dose corticosteroid maintenance. However, we thought that the treatment should be able to decrease relapses by half (to 33%) to be clinically significant. With the α and β errors of 0.05 and 0.20, respectively, the yielded sample size was 70. Approximately 15% more patients were enrolled for possible cases of loss to follow-up.\n\nStatistical Analysis\nThe continuous data were expressed as means (standard deviations, SD) or medians with interquartile ranges (IQR) as appropriate. The unpaired t test was used to compare means, and the χ2 test was used for proportions for univariate analysis. The factors that showed P values of .1 or lower were subjected to a multivariate analysis. Survival curves were generated by the Kaplan-Meier method for depictions, and hazard ratios (HRs) were calculated using Cox regression analysis. All analyses were performed using SPSS software for Windows (version 16.0). A P value <.05 was considered as statistical significance.\n\nResults\nBaseline Data\nThere were 86 patients screened for the study, and 81 cases were included. The CONSORT (Consolidated Standards of Reporting Trials) diagram is shown in Figure 1. There were 41 patients randomized to the prednisolone group and 40 to the control group. Three cases (1 in the prednisolone group and 2 cases in the control group) were lost to follow-up just after the first visits, and therefore, efficacy and safety outcomes could not be evaluated. In addition, 2 patients in the control group withdrew consent. One of these patients could not come for further follow-up after month 2 visit. The other patient in the control group developed fatigue and weight loss after discontinuing prednisolone and requested to resume prednisolone at month 6. One patient in the treatment group developed tuberculosis of the spine 2 months before the scheduled termination and the physician decided to discontinue prednisolone. None of these patients had ITP relapse at their last follow-up visits. The latter 2 patients who were switched the treatment arms due to adverse events (1 from each group) were also included in the safety study with the total number of 77 patients.\n\nFigure 1. CONSORT (Consolidated Standards of Reporting Trials) flow diagram of the study.\n\nThere were a total of 75 patients who received the interventions as planned and were evaluable for the efficacy. Fifty-eight (77.3%) of them were female, and the average age was 40.5 (14.9) years. The recurrent cases comprised 57.3% and the remaining was at the first diagnosis. Thirty-six and 39 patients were randomized to the control and prednisolone groups, respectively. The median platelet count at the onset was 7 × 109/L (IQR: 4 × 109/L to 17 × 109/L). The sites of bleeding at ITP presentations were the skin (n = 61), mouth (n = 32), heavy menstruation (n = 11), urinary tract (n = 4), gastrointestinal tract (n = 2), nose (n = 2), and central nervous system (n = 1). There were 38 patients who had multiple sites of bleeding and 2 cases without bleeding symptoms despite severe thrombocytopenia. They were initially treated with either high-dose dexamethasone followed by prednisolone (38.7%) or prednisolone from the beginning (61.3%). The median duration of corticosteroid before entering the study was 132 days, with the IQR of 90 to 187 days. The mean cumulative prednisolone-equivalent dose received was 2997 (1368) mg. There were 29 (38.7%) patients who were treated at the provincial hospital.\n\nUpon entering the study, 85.3% achieved complete response (CR; platelet count ≥100 × 109/L)13 to corticosteroids. The mean (SD) platelet count at entering the study was 199 × 109/L (92 × 109/L), ranging from 30 to 455 × 109/L. The baseline characteristics of patients were comparable between groups, as shown in Table 1. The observation group tended to be older than the prednisolone group. No other ITP treatment was allowed at least 4 weeks before entering the study.\n\nTable 1. Baseline Characteristics of the Patients.a\n\n\n\n\tObservation (n = 36)\tPrednisolone (n = 39)\t\nP Value\t\nAge (years)b\n\t43.7 (16.4)\t37.5 (12.9)\t.073\t\nFemale\t28 (77.8%)\t30 (76.9%)\t.930\t\nNewly diagnosed cases\t22 (61.1%)\t21 (53.8%)\t.525\t\nComorbidity\t18 (50%)\t15 (38.5%)\t.315\t\nPlatelet count at the onset (×109/L)c\n\t6.0 (IQR: 2.0-14.8)\t10.5 (IQR: 4.0-21.0)\t.216\t\nDexamethasone as the initial treatment\t14 (38.9%)\t15 (38.5%)\t.970\t\nCumulative steroid doses before entry (mg)c,d\n\t3177 (1522)\t2830 (1204)\t.276\t\nTreatment duration before entry (days)c\n\t147 (IQR: 99-220)\t112 (IQR: 84-158)\t.116\t\nPlatelet count at entry (×109/L)b\n\t206.6 (89.2)\t191.6 (95.2)\t.484\t\n\nan = 75.\n\n\nbMean (standard deviation, SD).\n\n\ncMedian and interquartile range (IQR).\n\n\ndPrednisolone-equivalent dose.\n\nEfficacy Analysis\nDuring the study period of 10 months, there was no statistical difference in ITP relapses between the 2 groups. There were 9 (25.0%) and 8 (20.5%) recurrences in the control and prednisolone groups, respectively (P = .643). There was also no difference in platelet counts at any time points between the 2 groups (data not shown). The Kaplan-Meier curve is shown in Figure 2, and the HR revealed no statistical difference in relapse-free survival. The prednisolone group showed no apparent different relapse rates among the 6 months of prednisolone, 2 months of steroid tapering, and final 2 months of no prednisolone (Figure 2). In cases that achieved CR, the losses of CR occurred in 43.3% versus 47.1% in observation versus prednisolone groups, respectively.\n\nFigure 2. The relapse-free survival comparing control (observation) versus prednisolone (7.5 mg/d).\n\nTwenty-seven patients (10 and 17 in observation and prednisolone groups, respectively) were followed further without corticosteroids beyond the study period of 10 months. The whole group was re-analyzed at a mean follow-up period of 90.5 weeks. There were 12 (33.3%) and 14 (35.9%) relapses in the control and prednisolone groups, respectively (P = .816), with the HR of 1.00 (95% confidence interval [CI], 0.46-2.19, P = .993).\n\nSafety Analysis\nThere were 77 patients who were evaluated for safety. There was no mortality or a grade 4 adverse event in this study. The frequencies of adverse events were not different (Table 2). However, 2 serious adverse events occurred in the prednisolone group. One patient had acute kidney injury on top underlying chronic renal disease requiring admission. The kidney function finally recovered to the baseline without a change in prednisolone dosage. The other patient had tuberculous spondylitis requiring hospitalization, and prednisolone was discontinued. In the control group, there was 1 serious adverse event from avascular necrosis of hip that required decompression surgery. In addition, 1 patient in the control needed an emergency department visit for dyspepsia and recovered after treatment for peptic ulcer without hospital admission.\n\nTable 2. Adverse Events During the Study Period.a\n\n\n\n\tObservation (n = 37)\tPrednisolone (n = 40)\t\nCases With Any Adverse Event(s)\t16 (43.2%)\t20 (50%)\t\nGrade\t1\t2\t3\t1\t2\t3\t\nElevated transaminases\t3 (8.1%)\t1b (2.7%)\t0\t3c (7.5%)\t0\t0\t\nHyperglycemia\t5d (13.5%)\t0\t0\t7e (17.5%)\t0\t0\t\nBone avascular necrosis\t0\t1f,g (2.7%)\t0\t0\t1h (2.5%)\t0\t\nAcute on top chronic renal failure\t0\t0\t0\t0\t0\t1g (2.5%)\t\nTuberculous spondylitis\t0\t0\t0\t0\t0\t1g (2.5%)\t\nFatigue\t0\t1i (2.7%)\t0\t0\t0\t0\t\nHypercholesterolemia\t1j (2.7%)\t0\t0\t1j (2.5%)\t0\t0\t\nDizziness/vertigo\t1 (2.7%)\t0\t0\t1 (2.5%)\t0\t0\t\nWeight gain\t1 (2.7%)\t0\t0\t1 (2.5%)\t0\t0\t\nDyspepsia\t1 (2.7%)\t1k (2.7%)\t0\t1 (2.5%)\t0\t0\t\nConstipation\t0\t1 (2.7%)\t0\t0\t0\t0\t\nKnee pain\t0\t0\t0\t1 (2.5%)\t0\t0\t\nSkin rash\t0\t0\t0\t0\t1 (2.5%)\t0\t\nPostherpetic neuralgia\t0\t0\t0\t1 (2.5%)\t0\t0\t\nUpper respiratory tract infection\t0\t0\t0\t1 (2.5%)\t0\t0\t\n\nBlastocystis hominis infection\t0\t0\t0\t1 (2.5%)\t0\t0\t\n\nan = 77.\n\n\nbWorkup studies revealed fatty liver.\n\n\ncOne of them had elevated liver enzymes at baseline.\n\n\ndThree of them had hyperglycemia before entering the study.\n\n\neFour of them had hyperglycemia before entering the study.\n\n\nfThe patient needed decompression surgery.\n\n\ngSerious adverse events required admissions.\n\n\nhThe patient received conservative treatments.\n\n\niThe patient wanted to resume prednisolone.\n\n\njThey had a history of dyslipidemia.\n\n\nkOne patient needed to come to the emergency department.\n\nPredictors of Relapses\nFactors possibly associated with ITP relapses were explored by univariate analysis. Age, sex, presence of comorbidity, platelet count at the ITP onset, initial treatment (dexamethasone vs prednisolone), treatment centers (provincial vs university hospitals), duration of corticosteroids before entering the study, total cumulative doses of steroids at entry, platelet count on enrollment, CR upon entry, and prednisolone maintenance were not significantly associated with recurrences.\n\nNotably, the relapsed ITP was more likely to relapse with the HR of 2.79 (95% CI: 1.02-7.64). The relapsed versus newly diagnosed cases had the recurrent rates of 34.4% versus 14.0% at 10 months (P = .037) and 56.2% versus 18.6% (P = .001) at the mean follow-up of 90.5 weeks, respectively. The probability of recurrences in newly diagnosed versus relapsed cases is shown in Figure 3.\n\nFigure 3. The relapse-free survival comparing the newly diagnosed versus relapsed mmune thrombocytopenia (ITP).\n\nThere were 45 patients who still had response at the median follow-up time of 90.5 months. The mean age was 40.9 years and 73.5% were female. The mean baseline platelet count was 11.3 × 109/L. Dexamethasone was used in 40.8% with 89.8% CR, and the mean cumulative steroid dose was 3112 (1346) mg prednisolone. These characteristics were similar to the whole group of patients.\n\nSubgroup Analysis\nIn a subgroup analysis of the newly diagnosed ITP, there was no significant difference in the relapse rate between the prednisolone and control groups (Figure 4A). However, the relapsed ITP subgroup (N = 32) showed a trend toward reduction in ITP recurrences in the prednisolone arm (Figure 4B).\n\nFigure 4. Subgroup analyses. A, The relapse-free survival comparing control (observation) versus prednisolone (7.5 mg/d) in cases with newly diagnosed ITP. B, The relapse-free survival comparing control (observation) versus prednisolone (7.5 mg/d) in cases with relapsed immune thrombocytopenia (ITP).\n\nDiscussion\nThis study cannot demonstrate a clinical benefit of low-dose prednisolone maintenance in preventing relapses of steroid-responsive ITP. Additionally, an analysis including the patients who were followed up for longer durations showed that both arms had similar relapse rates.\n\nThe recurrent rate of 22.7% (17/75) during our study period was relatively lower than those of previous reports.5,6,13,15 This may be because approximately 40% of patients were newly diagnosed ITP, which had a lower risk of relapses compared with chronic or persistent ITP.13 In addition, our patients had been followed for a relatively short time, while previous studies that showed the sustained response rates of only 15% to 30% observed their patients for 4 to 10 years.6,13,15 The survival curve of our patients (Figure 2) does not show a plateau suggesting that future relapses are probable. Hence, 34.7% (26/17) of our patients had recurrences at the median follow-up time of 90.5 weeks. Furthermore, participants in this study were selected because they all responded well to corticosteroids, not general ITP cases. Our data are consistent with a recent registry study that showed a 1-year relapse rate of 16.3%, as 92% of their patients initially responded to first-line therapy.16\n\n\nOur data suggest also that after the first episode of ITP, steroid can be safely discontinued. The durations of corticosteroid treatment were relatively long in this study mainly because platelet counts dropped during steroid tapering and the physicians decided to increase or maintain the steroid doses. The data suggest that this dose and duration of steroid (cumulative prednisolone dose of 3 g in approximately 4 months) is sufficient. Further extension of the steroid course is unlikely to be much helpful.\n\nThe treatment with a physiological dose of prednisolone for 6 months was relatively well tolerated and the frequency of adverse events was not significantly different from the observation. These events might be related to high-dose steroids received before entering the trial, such as 1 patient who developed avascular necrosis of the hip in the control arm. Two serious adverse events were difficult to be ascertained if they were related to such a low dose of prednisolone. However, subclinical corticosteroid toxicities, such as a decrease in bone mineral density or hypothalamic–pituitary–adrenal suppression, were not investigated in this study. Patients in both groups were encouraged to take calcium and vitamin D supplement to preserve bone density. One patient who needed to resume prednisolone in the control group probably had adrenal suppression due to previous exposure to high-dose corticosteroids.\n\nThis clinical trial identified the presence of previous episodes of ITP as a strong predictor of recurrences. This characteristic was prespecified and, therefore, balanced between the 2 treatment arms. In approximately 2 years, the newly diagnosed ITP had a relapse rate of only 18.6% compared with over 50% in previously relapsed cases. The information may be useful as one of the factors decide whether or not to stop ITP therapy. This is consistent with the observations that the long remission is less likely for ITP duration of more than 1 year.13,18 However, the prognostic significance of a relapse after remission has not been previously reported.\n\nFuture research is needed to find a better strategy in the relapse group. Low-dose prednisolone maintenance may be helpful in these cases (Figure 3), but a larger sample size is required to prove this hypothesis.\n\nThe sample size of this study was not large enough to detect a small effect, if there is any, of the intervention. However, long-term prednisolone is potentially harmful and high efficacy is necessary to offset the potential side effects. There were 4 patients (3 in the control group and 1 in the prednisolone group) who were not followed up completely and were excluded from the analysis. If we assume that all 3 controls relapsed and 1 prednisolone case did not recur, there is still no statistical difference in the recurrent rates (P = .274), suggesting that our conclusion is valid. Therefore, this study does not support the long-term prednisolone uses in ITP.\n\nIn conclusion, a physiological dose of prednisolone for 6 months could not significantly prevent ITP relapses. Notably, previous ITP episodes can predict ITP recurrences. This subgroup deserves further investigations for an appropriate measure to prevent relapses.\n\nDeclaration of Conflicting Interests: The author(s) declared no potential conflict of interest with respect to the research, authorship, and/or publication of this article.\n\nFunding: The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: The study was supported by the Multicenter Research Grant from the Thai Society of Hematology (TSH).\n\nORCID iD: Ponlapat Rojnuckarin, \nhttp://orcid.org/0000-0001-7912-1996\n==== Refs\nReferences\n1 \nStasi R Evangelista ML Stipa E Buccisano F Venditti A Amadori S \nIdiopathic thrombocytopenic purpura: current concepts in pathophysiology and management . Thromb Haemost . 2008 ;99 (1 ):4 –13 .18217129 \n2 \nBritish Committee for Standards in Haematology General Haematology Task Force . 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Br J Haematol . 2007 ;138 (2 ):245 –248 .17542983 \n15 \nDiFino SM Lachant NA Kirshner JJ Gottlieb AJ \nAdult idiopathic thrombocytopenic purpura . Clinical findings and response to therapy . Am J Med . 1980 ;69 (3 ):430 –442 .6998293 \n16 \nMoulis G Germain J Comont T \nNewly diagnosed immune thrombocytopenia adults: clinical epidemiology, exposure to treatments, and evolution. Results of the CARMEN multicenter prospective cohort . Am J Hematol . 2017 ;92 (6 ):493 –500 .28240787 \n17 \nPalau J Sancho E Herrera M \nCharacteristics and management of primary and other immune thrombocytopenias: Spanish registry study . Hematology . 2007 ;22 (8 ):484 –492 .\n18 \nKhellaf M Charles-Nelson A Fain O \nSafety and efficacy of rituximab in adult immune thrombocytopenia: results from a prospective registry including 248 patients . Blood . 2014 ;124 (22 ):3228 –3236 .25293768\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1076-0296",
"issue": "24(6)",
"journal": "Clinical and applied thrombosis/hemostasis : official journal of the International Academy of Clinical and Applied Thrombosis/Hemostasis",
"keywords": "immune thrombocytopenia; prednisolone; randomized trial; recurrence",
"medline_ta": "Clin Appl Thromb Hemost",
"mesh_terms": "D000293:Adolescent; D000328:Adult; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D010976:Platelet Count; D011239:Prednisolone; D016553:Purpura, Thrombocytopenic, Idiopathic; D012008:Recurrence; D015996:Survival Rate",
"nlm_unique_id": "9508125",
"other_id": null,
"pages": "867-873",
"pmc": null,
"pmid": "29614865",
"pubdate": "2018-09",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D016448:Multicenter Study; D064888:Observational Study; D016449:Randomized Controlled Trial",
"references": "12588344;17542983;18217129;19005182;19548911;19846889;21325604;23169778;23927437;2451549;25293768;26051432;28240787;28415913;6998293;7733121;8039754;8704187",
"title": "A Randomized Multicenter Trial Comparing Low-Dose Prednisolone Versus Observation for Prevention of Recurrences in Adult Immune Thrombocytopenia.",
"title_normalized": "a randomized multicenter trial comparing low dose prednisolone versus observation for prevention of recurrences in adult immune thrombocytopenia"
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"abstract": "No publications have reported on osteomalacia in patients receiving intermittent cyclical therapy with etidronate (a bisphosphonate) and undergoing long-term hemodialysis (HD).\n\n\n\nWe report on a 46-year-old Japanese man admitted to our hospital for further examination of left forearm pain. Maintenance HD was started at age 24 years, and the man had been on HD since then. At age 38 years, surgical parathyroidectomy was performed for secondary hyperparathyroidism; iliac crest bone biopsy performed at the same time showed osteitis fibrosa. The active vitamin D3 preparation calcitriol was started, and intermittent cyclical etidronate therapy was introduced 2 years later for osteoporosis. At age 45 years, the patient stopped taking calcitriol because of hypercalcemia but continued with etidronate. At age 46 years, a pseudofracture with a Looser zone occurred in the left ulna, and left femur bone biopsy revealed osteomalacia. Etidronate was discontinued, and calcitriol was restarted; open reduction and internal fixation with an angular stability plate were performed. Union of the bone was achieved 10 months after the operation. At age 49 years, a lumber bone biopsy confirmed improved bone morphometry.\n\n\n\nWe believe that intermittent cyclical etidronate therapy without administration of active vitamin D3 during long-term HD might have induced osteomalacia, resulting in the ulna insufficiency fracture. Therefore, we propose that administration of active vitamin D3 is essential to prevent osteomalacia in patients on long-term HD who are receiving bisphosphonates and have potential vitamin D3 deficiency.",
"affiliations": "Department of Orthopaedic Surgery, Toranomon Hospital Kajigaya, 1-3-1 Kajigaya, Takatsu, Kawasaki, Tokyo, Kanagawa, 212-0015, Japan. hm0523jp@yahoo.co.jp.;Department of Orthopaedic Surgery, Toranomon Hospital Kajigaya, 1-3-1 Kajigaya, Takatsu, Kawasaki, Tokyo, Kanagawa, 212-0015, Japan.;Department of Orthopaedic Surgery, Toranomon Hospital Kajigaya, 1-3-1 Kajigaya, Takatsu, Kawasaki, Tokyo, Kanagawa, 212-0015, Japan.;Department of Orthopaedic Surgery, Toranomon Hospital Kajigaya, 1-3-1 Kajigaya, Takatsu, Kawasaki, Tokyo, Kanagawa, 212-0015, Japan.;Department of Orthopaedic Surgery, Toranomon Hospital Kajigaya, 1-3-1 Kajigaya, Takatsu, Kawasaki, Tokyo, Kanagawa, 212-0015, Japan.;Department of Orthopaedic Surgery, Toranomon Hospital Kajigaya, 1-3-1 Kajigaya, Takatsu, Kawasaki, Tokyo, Kanagawa, 212-0015, Japan.;Department of Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Tokyo, Kanagawa, 212-0015, Japan.;Department of Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Tokyo, Kanagawa, 212-0015, Japan.;Department of Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Tokyo, Kanagawa, 212-0015, Japan. ubara@toranomon.gr.jp.",
"authors": "Hatano|Masaki|M|0000-0002-7096-5604;Kitajima|Izuru|I|;Yamamoto|Seizo|S|;Nakamura|Masaki|M|;Isawa|Kazuya|K|;Hirota|Yutaka|Y|;Hoshino|Junichi|J|;Sawa|Naoki|N|;Ubara|Yoshifumi|Y|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s12882-021-02509-5",
"fulltext": "\n==== Front\nBMC Nephrol\nBMC Nephrol\nBMC Nephrology\n1471-2369\nBioMed Central London\n\n2509\n10.1186/s12882-021-02509-5\nCase Report\nCase report: Osteomalacia due to bisphosphonate treatment in a patient on hemodialysis\nhttp://orcid.org/0000-0002-7096-5604\nHatano Masaki hm0523jp@yahoo.co.jp\n\n1\nKitajima Izuru 1\nYamamoto Seizo 1\nNakamura Masaki 1\nIsawa Kazuya 1\nHirota Yutaka 1\nHoshino Junichi 23\nSawa Naoki 23\nUbara Yoshifumi ubara@toranomon.gr.jp\n\n23\n1 grid.410813.f 0000 0004 1764 6940 Department of Orthopaedic Surgery, Toranomon Hospital Kajigaya, 1-3-1 Kajigaya, Takatsu, Kawasaki, Tokyo, Kanagawa 212-0015 Japan\n2 grid.410813.f 0000 0004 1764 6940 Department of Nephrology Center, Toranomon Hospital Kajigaya, 1-3-1, Takatsu, Kawasaki, Tokyo, Kanagawa 212-0015 Japan\n3 grid.410813.f 0000 0004 1764 6940 Okinaka Memorial Institute for Medical Research, Toranomon Hospital, Tokyo, Japan\n3 9 2021\n3 9 2021\n2021\n22 29817 11 2020\n20 8 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\nNo publications have reported on osteomalacia in patients receiving intermittent cyclical therapy with etidronate (a bisphosphonate) and undergoing long-term hemodialysis (HD).\n\nCase presentation\n\nWe report on a 46-year-old Japanese man admitted to our hospital for further examination of left forearm pain. Maintenance HD was started at age 24 years, and the man had been on HD since then. At age 38 years, surgical parathyroidectomy was performed for secondary hyperparathyroidism; iliac crest bone biopsy performed at the same time showed osteitis fibrosa. The active vitamin D3 preparation calcitriol was started, and intermittent cyclical etidronate therapy was introduced 2 years later for osteoporosis. At age 45 years, the patient stopped taking calcitriol because of hypercalcemia but continued with etidronate. At age 46 years, a pseudofracture with a Looser zone occurred in the left ulna, and left femur bone biopsy revealed osteomalacia. Etidronate was discontinued, and calcitriol was restarted; open reduction and internal fixation with an angular stability plate were performed. Union of the bone was achieved 10 months after the operation. At age 49 years, a lumber bone biopsy confirmed improved bone morphometry.\n\nConclusions\n\nWe believe that intermittent cyclical etidronate therapy without administration of active vitamin D3 during long-term HD might have induced osteomalacia, resulting in the ulna insufficiency fracture. Therefore, we propose that administration of active vitamin D3 is essential to prevent osteomalacia in patients on long-term HD who are receiving bisphosphonates and have potential vitamin D3 deficiency.\n\nKeywords\n\nBisphosphonate\nBone histomorphometry\nEtidronate\nHemodialysis\nOsteomalacia\nCase report\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nMineral abnormalities related to renal osteodystrophy (ROD) are common in patients with chronic kidney disease (CKD) [1]. The gold standard for the diagnosis and specific classification of ROD is bone biopsy with bone histomorphometry [2]. A bone biopsy is recommended if results will guide treatment decisions, and is therefore advised in cases of unexplained fractures and bone pain, and may be considered prior to PTX or starting anti-resorptive treatment. However, a bone biopsy is not well suited to monitor treatment response in cases of frequent changes, as bone is a slow-reacting tissue.\n\nBisphosphonates (BPs) are bone antiresorptive agents that are widely used to treat postmenopausal or glucocorticoid-induced osteoporosis. The current Kidney Disease: Improving Global Outcomes (KDIGO) recommendations limit their use in patients with renal impairment because of concerns about worsening renal function, bone mineralization defects, and osteomalacia. However, the pathogenesis of osteomalacia due to BPs in HD patients remains unclear. Currently, no publications report on osteomalacia due to BPs in patients on long-term HD. Here, we describe a patient on long-term HD who received intermittent cyclical etidronate therapy after parathyroidectomy (PTX) and developed osteomalacia after discontinuing active vitamin D3 derivative.\n\nCase presentation\n\nA 46-year-old Japanese man on HD for 22 years was admitted to our hospital for further examination of left forearm pain. Maintenance dialysis was started at age 24 years after bilateral nephrectomy for hemorrhagic angiomyolipoma related to tuberous sclerosis. At age 38 years, the patient developed severe bone pain without any precipitating cause, and bilateral Achilles tendon rupture was noted (Fig. 1A). Because secondary hyperparathyroidism (with an intact parathyroid hormone [PTH] level of 1630 pg/mL) resistant to conservative treatment was considered a causative factor, surgical PTX was performed with autotransplantation into the subcutaneous tissue of the non-shunt side forearm. The iliac crest bone was biopsied at the same time and bone histomorphometric analysis was performed at the Ito Bone Science Institute, Niigata, Japan. Tetracycline double labeling was also performed with doxycycline at 200 mg daily (with a schedule of 3 days on, 12 days off, 3 days on, 13 days off). Osteitis fibrosa was diagnosed, with a fibrous tissue volume to total volume (Fb.V/TV) of 9.1% (> 0.5% required for diagnosis) and an osteoid volume to bone volume (OV/BV) of 13.0% (< 15% required for diagnosis according to the Sherrard et al. classification of ROD) [3]. Double labelling by tetracycline showed a bone formation rate per unit of bone volume (BFR/BV) of 120.2% per year, indicating a high bone turnover. Bone is resorped by osteoclasts and formed by osteoblasts, and normally these 2 processes progress at the same time and rate; in our patient, the higher bone turnover resulted in woven bone characterized by haphazardly organized collagen fibers (Fig. 2A). Fig. 1 (A) 1 Sagittal t1 magnetic resonance imaging (MRI) shows complete Achilles tendon tear (yellow arrow); 2 Sagittal t1 MRI shows Normal achilles tendon (blue arrow). (B) 1 Anteroposterior and lateral radiograph of the left ulna shows left ulna pseudofracture (white arrows); 2 Sagittal T1 and T2 weighted images in MRI show low band in the bone; 3 Successful bone union. (C) Bone scintigraphy revealed multifocal lesions, including multiple ribs, costochondral junctions, costovertebral junctions, and both posterior iliac bones\n\nFig. 2 (A) Natural light and fluorescent microscopic analysis of the iliac bone section (1st bone biopsy). Bone resorption by osteoclasts and bone formation by osteoblasts progress at the same time, and woven bone was formed characterized by haphazardly organized collagen fibers. (B) Natural light and fluorescent microscopic analysis of the femoral cortical bone near a cancellous bone section (2nd bone biopsy). An increase in the amount of osteoid was observed, along with increased thickness of osteoid seam width and a low calcification area on the bone surface and in the bone. (C) Analysis of the lumbar spine bone section (3rd bone biopsy). Both remodeling and minimodeling were observed. The majority of trabecular bone was occupied by 2 types of new lamellar bone formation: remodeling, which is characterized by new bone formation by osteoblasts after bone resorption by osteoclasts, and minimodeling, which is characterized by a lack of precedent bone erosion by osteoclasts\n\nAfter PTX, the intact PTH level was less than 100 pg/mL, so the patient was prescribed calcium lactate (3.0 g/d) and active vitamin D3 (calcitriol, 0.5 μg/d) to treat hungry bone syndrome. The bilateral Achilles tendon rupture healed. Two years after the surgical procedure, low bone mineral density was diagnosed (T-score of − 3.1 measured by dual energy X-ray absorptiometry [DEXA]) and intermittent cyclical etidronate therapy (200 mg/d for 2 weeks every 4 months) was started; calcitriol was continued. At age 45 years, calcitriol was stopped because of hypercalcemia, and at age 46 years the patient developed left forearm pain for no obvious reason that worsened by the day. One week later, a radiograph showed a pseudofracture with a Looser zone in a proximal portion of left ulna; the pseudofracture manifested as a 3 mm-wide radiolucent band perpendicular to the bone surface (Fig. 1B). Therefore, the patient was admitted to our hospital for surgical treatment.\n\nOn admission, the patient was 174.0 cm tall and weighed 79.5 kg. Blood levels (Table 1) were as follows: the patient had PTH in target range, with normal calcium, high phosphate levels and lower 1.25-dihydroxy vitamin D3. Table 1 Laboratory Data. BAP: bone alkaline phosphatase, IGF-1: Insulin-like growth factor 1, NM: no measurement, PTH: parathyroid hormone, PTX: parathyroidectomy\n\nBone scintigraphy with 99mTc-labeled methylene diphosphonate showed intense uptake in multifocal regions, including multiple ribs, costochondral junctions, costovertebral junctions, and both posterior iliac bones, as well as in the affected left ulna; these findings are characteristic of osteomalacia (Fig. 1C).\n\nOpen reduction and fixation with an angular stability plate and left total knee arthroplasty were performed. At the same time, left femur bone biopsy was performed to identify the pathogenesis of the ulna pseudofracture. Bone histomorphometric analysis was performed at the Ito Bone Science Institute (Niigata, Japan). Tetracycline double labeling was not performed.\n\nCancellous bone was assessed by bone histomorphometry (Table 2). The trabecular bone volume (BV/TV) was within the age-matched reference range according to the report by Reccker et al. [4]; however, the trabecular thickness (Tb.Th) was lower than at the first bone biopsy (93.4 μm). All osteoid markers were increased compared with the first bone biopsy, parameters of bone resorption were decreased (Fig. 2B). Osteomalacia was diagnosed according to Sherrard’s classification of ROD [3] because the Fb.V/TV was 0.1% (< 0.5% required for diagnosis) and the OV/BV was 40.7% (> 15% required for diagnosis). The number of osteoclasts (N.Oc/BS) was decreased to 0.148 N/mm, and the number osteoblasts surface (Ob.S/BS) was 12.3%. Table 2 First, second, and third histomorphometric analysis of the iliac crest\n\nA deficiency in 1,25-dihydroxyvitamin D was found, and we assumed that this deficiency, combined with administration of etidronate in a condition of lower PTH levels after PTX, might have contributed to mineralization disturbance-related osteomalacia and resulted in the formation of multiple pseudofractures, including a Looser zone because bone disease manifested 1 year after calcitriol was stopped. Therefore, calcitriol was restarted at a dose of 0.5 μg/d and etidronate was discontinued. Ten months later, the Looser zone had disappeared and bone union was achieved (Fig. 1B).\n\nAt age 49 years, a surgical procedure was performed for lumbar destructive spondyloarthropathy related to beta 2 microglobulin amyloidosis resulting from long-term HD, and a lumber bone biopsy was performed at the same time. Bone histomorphometric analysis was again performed at the Ito Bone Science Institute (Niigata, Japan). Tetracycline double labeling was not performed.\n\nAt the third bone histomorphometric analysis, all osteoid markers had improved compared with the second biopsy. The abnormal woven bone seen at the first biopsy and abnormal osteoid seen at the second biopsy had disappeared. Normal levels of osteoblasts and osteoclasts were noted. The majority of trabecular bone was occupied by lamellar bone, which is obtained by well-balanced bone remodeling and indicates new bone formation by osteoblasts arising after bone resorption by osteoclasts. In addition, new bone had been formed by minimodeling, which is characterized by a lack of precedent bone erosion by osteoclasts (Fig. 2C) [5].\n\nBone mineral density (BMD) assessed by DEXA at the lumbar spine and the forearm were improved (Table 3). Table 3 Bone mineral density data. PTX: parathyroidectomy, Spine AP: Spine anterior-posterior, Spine LAT: Spine lateral\n\nDiscussion and conclusions\n\nThese findings indicated that active vitamin D3 replacement induced normal bone formation even though PTH levels were lower after PTX [6].\n\nChronic kidney disease mineral and bone disorder (CKD-MBD) is a complex disorder of bone and mineral metabolism. Stress fractures are known to be caused by ROD associated with bone fragility and long-term HD [7, 8]. Therefore, ROD must be evaluated and diagnosed: According to histologic features of biopsied bone, ROD is classified as osteitis fibrosa, osteomalacia, and mixed, mild, and adynamic disease [3]. Generally, BMD is widely used to evaluate osteoporosis; however, it does not predict the type of ROD or accurately evaluate bone fragility in HD patients [9]. KDIGO recommends that bone biopsy should be considered if it will inform treatment decisions [10]. The decision to treat with either antiresorptive or anabolic agents needs to be based on the level of kidney function, bone turnover, and mineralization.\n\nBPs are potent inhibitors of osteoclast-mediated bone resorption. They are widely used to treat postmenopausal or glucocorticoid-induced osteoporosis, but little evidence is available on their effectiveness and safety in patients on HD. Previous studies reported that BPs were a potential treatment for renal osteodystrophy, particularly in patients with high bone turnover or hypercalcemia related to increased release of calcium from bone [11, 12], and that they may be beneficial in HD patients [13, 14].\n\nBPs are classified into 2 groups with different molecular modes of action: non–nitrogen-containing BPs and nitrogen-containing BPs. Etidronate is a non–nitrogen-containing BP. BPs have several severe adverse effects, including acute renal failure, worsening renal function, reduced bone mineralization, and osteomalacia. The pathophysiological mechanisms by which BPs cause osteomalacia are still unknown. So far, studies have reported that etidronate and clodronate, another non–nitrogen-containing BP, may inhibit bone mineralization [15–17]. Reports on osteomalacia or mineralization defects associated with etidronate therapy were described in patients with Paget’s disease who received continuous etidronate therapy at high doses (17–20 mg/kg/d). High doses and continuous therapy with etidronate might induce mineralization defects, although no serious adverse effects were reported with intermittent cyclical etidronate therapy for postmenopausal osteoporosis [18].\n\nOsteomalacia is a bone disease characterized by low bone turnover, defective mineralization, and accumulation of unmineralized osteoid. Traditionally, ROD-related osteomalacia was caused by aluminum toxicity (aluminum inhibits bone mineralization in case of vitamin D deficiency) [3], and osteomalacia caused by iron deposition was frequently found from 1970 to 1990. Hypocalcemia, hypophosphatemia, hypovitaminosis D, toxic effects of drugs are common in patients with CKD [19, 20]; however, few studies reported finding osteomalacia due to vitamin D deficiency in HD patients [8, 21, 22]. In addition, the effects of vitamin D deficiency in HD patients remain to be clarified.\n\nOur patient started intermittent cyclical etidronate therapy after surgical PTX for severe secondary hyperparathyroidism. After PTX, our patient took the active vitamin D3 preparation calcitriol because of hungry bone syndrome [23]. However, 7 years after PTX calcitriol was discontinued because of hypercalcemia. One year later, the ulna pseudofracture occurred and osteomalacia was diagnosed. In this case, intermittent cyclical etidronate therapy combined with vitamin D deficiency and HD might have contributed to bone demineralization.\n\nSecondary hyperparathyroidism is a common problem in long-term HD patients. Despite considerable advances in medical therapy for secondary hyperparathyroidism, PTX remains an important therapeutic tool for treating refractory hyperparathyroidism. Surgical PTX is better at preventing recurrence than other surgical therapies [24]. On the other hand, PTX can easily induce hypocalcemia and adynamic bone disease [25, 26], and even now no appropriate pharmacotherapy exists for low PTH levels after surgical PTX. Minimodeling was reported to be closely related to new bone formation in patients with hypoparathyroidism [5].\n\nThis study has limitation. Thus patient’s underlying tuberous scleros may be contributed to the bone abnormalities, because tuberous sclerosis can cause bone cysts or sclerotic lesions.\n\nIn conclusion, the first biopsy in our patient showed that osteitis fibrosa related to hyperparathroidism contributed to the Achilles tendon ruptures. The second biopsy showed that osteomalacia contributed to the pseudofracture of the ulna, seen as a Looser zone; the osteomalacia was related to continuation of etidronate and 1,25-dihydroxyvitamin D deficiency resulting from discontinuation of calcitriol in a condition of low serum levels of PTH after PTX. The third biopsy showed that resumption of calcitriol and discontinuation of etidronate improved the bone disease, despite continued low levels of PTH. This case indicates that when BPs are started in long-term HD patients with a potential vitamin D deficiency administration of active vitamin D3 is essential to prevent osteomalacia via mineralization disturbances.\n\nAbbreviations\n\nALP Alkaline phosphatase\n\nBAP bone alkaline phosphatase\n\nBFR/BV bone formation rate per unit of bone volume\n\nBMD bone mineral density\n\nBPs bisphosphonates\n\nBV/TV trabecular bone volume to total volume\n\nCKD chronic kidney disease\n\nCKD-MBD chronic kidney disease mineral and bone disorder\n\nDEXA dual energy X-ray absorptiometry\n\nES/BS eroded surface to bone surface\n\nFb.V/TV fibrous tissue volume to total volume\n\nHD hemodialysis\n\nKDIGO Kidney Disease: Improving Global Outcomes\n\nN.Oc/BS number of osteoclasts to bone surface\n\nOb.S/BS osteoblasts surface to bone surface\n\nOS/BS osteoid surface to bone surface\n\nO.Th osteoid thickness\n\nOV/BV osteoid volume to bone volume\n\nOV/TV osteoid volume to tissue volume\n\nPTH parathyroid hormone\n\nPTX parathyroidectomy\n\nROD renal osteodystrophy\n\nTb.Th trabecular thickness\n\nTh.W trabecular unit wall thickness\n\nWe wish to thank Mrs. Akemi Ito (Ito Bone Science Institute, Niigata, Japan) for performing the bone histomorphometric analyses.\n\nAuthors’ contributions\n\nMH, IK, SY, MN, KI, YH, JH, NS and YU were involved in study design and data interpretation. MH, IK, SY, MN, KI, YH, JH, NS and YU were involved in the data analysis. All authors critically revised the report, commented on drafts of the manuscript, and approved the final report.\n\nFunding\n\nNo funding was obtained for this study.\n\nAvailability of data and materials\n\nAll data generated or analysed during this study are included in this published article.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot Applicable.\n\nConsent for publication\n\nWritten informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor of this journal.\n\nCompeting interests\n\nThe authors declare no competing financial interests and no conflicts of interest.\n\nPublisher’s Note\n\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\n==== Refs\nReferences\n\n1. 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Jean G Terrat JC Vanel T Hurot JM Lorriaux C Mayor B Chazot C Daily oral 25-hydroxycholecalciferol supplementation for vitamin D deficiency in haemodialysis patients: effects on mineral metabolism and bone markers Nephrol Dial Transplant 2008 23 11 3670 3676 10.1093/ndt/gfn339 18579534\n21. Mac-Way F Azzouz L Noel C Lafage-Proust MH Osteomalacia induced by vitamin D deficiency in hemodialysis patients: the crucial role of vitamin D correction J Bone Miner Metab 2014 32 2 215 219 10.1007/s00774-013-0480-7 23794122\n22. Hernandez JD Wesseling K Boechat MI Gales B Salusky IB Osteomalacia in a hemodialysis patient receiving an active vitamin D sterol Nat Clin Pract Nephrol 2007 3 4 227 232 10.1038/ncpneph0443 17389892\n23. Rodríguez-Ortiz ME Pendón-Ruiz de Mier MV Rodríguez M Parathyroidectomy in dialysis patients: indications, methods, and consequences Semin Dial 2019 32 5 444 451 10.1111/sdi.12772 30656752\n24. Schneider R Slater EP Karakas E Bartsch DK Schlosser K Initial parathyroid surgery in 606 patients with renal hyperparathyroidism World J Surg 2012 36 2 318 326 10.1007/s00268-011-1392-0 22202993\n25. Lorenz K Ukkat J Sekulla C Gimm O Brauckhoff M Dralle H Total parathyroidectomy without autotransplantation for renal hyperparathyroidism: experience with a qPTH-controlled protocol World J Surg 2006 30 5 743 751 10.1007/s00268-005-0379-0 16680589\n26. Saunders RN Karoo R Metcalfe MS Nicholson ML Four gland parathyroidectomy without Reimplantation in patients with chronic renal failure Postgrad Med J 2005 81 954 255 258 10.1136/pgmj.2004.026450 15811891\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1471-2369",
"issue": "22(1)",
"journal": "BMC nephrology",
"keywords": "Bisphosphonate; Bone histomorphometry; Case report; Etidronate; Hemodialysis; Osteomalacia",
"medline_ta": "BMC Nephrol",
"mesh_terms": null,
"nlm_unique_id": "100967793",
"other_id": null,
"pages": "298",
"pmc": null,
"pmid": "34479496",
"pubdate": "2021-09-03",
"publication_types": "D016428:Journal Article",
"references": "16680589;3085789;11887832;1295713;2146521;3213608;23794122;8556838;28941764;26321176;15811891;22202993;30656752;17389892;10883448;25503527;18579534;11496050;8441240;17687259;2113611;19644521;16014063;23207124;16641930;28964571",
"title": "Case report: Osteomalacia due to bisphosphonate treatment in a patient on hemodialysis.",
"title_normalized": "case report osteomalacia due to bisphosphonate treatment in a patient on hemodialysis"
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"abstract": "A 56-year-old woman with rheumatoid arthritis who had been taking methotrexate (MTX) for six years visited our hospital with dyspnea and dizziness. Abdominal ultrasonography revealed mild splenomegaly. Laboratory examinations showed a marked elevation in soluble interleukin-2 receptor and lactate dehydrogenase levels. These abnormalities revealed a spontaneous regression after MTX discontinuation, however, they worsened again four months later. Skin biopsies revealed a diagnosis of intravascular large B-cell lymphoma (IVLBCL), and we diagnosed MTX-associated IVLBCL (MTX-IVLBCL) based on its characteristic course. Despite the recurrence of IVLBCL, it showed a good response to chemotherapy. MTX-IVLBCL should therefore be treated with consideration since it has different characteristics from that of de novo IVLBCL.",
"affiliations": "Department of Hematology, Imakiire General Hospital, Japan.;Department of Hematology, Imakiire General Hospital, Japan.;Department of Hematology, Imakiire General Hospital, Japan.",
"authors": "Tabuchi|Tomohisa|T|;Inoue|Hirosaka|H|;Obama|Kosuke|K|",
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"fulltext": "\n==== Front\nIntern Med\nIntern Med\nInternal Medicine\n0918-2918\n1349-7235\nThe Japanese Society of Internal Medicine\n\n34176840\n10.2169/internalmedicine.7531-21\nCase Report\nDevelopment of Intravascular Large B-cell Lymphoma during Methotrexate Treatment for Rheumatoid Arthritis\nTabuchi Tomohisa 1\nInoue Hirosaka 1\nObama Kosuke 1\n1 Department of Hematology, Imakiire General Hospital, Japan\nCorrespondence to Dr. Tomohisa Tabuchi, tmhstabuchi@gmail.com\n\n26 6 2021\n1 1 2022\n61 1 8790\n11 3 2021\n9 5 2021\nCopyright © 2022 by The Japanese Society of Internal Medicine\nhttps://creativecommons.org/licenses/by-nc-nd/4.0/ The Internal Medicine is an Open Access journal distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view the details of this license, please visit (https://creativecommons.org/licenses/by-nc-nd/4.0/).\nA 56-year-old woman with rheumatoid arthritis who had been taking methotrexate (MTX) for six years visited our hospital with dyspnea and dizziness. Abdominal ultrasonography revealed mild splenomegaly. Laboratory examinations showed a marked elevation in soluble interleukin-2 receptor and lactate dehydrogenase levels. These abnormalities revealed a spontaneous regression after MTX discontinuation, however, they worsened again four months later. Skin biopsies revealed a diagnosis of intravascular large B-cell lymphoma (IVLBCL), and we diagnosed MTX-associated IVLBCL (MTX-IVLBCL) based on its characteristic course. Despite the recurrence of IVLBCL, it showed a good response to chemotherapy. MTX-IVLBCL should therefore be treated with consideration since it has different characteristics from that of de novo IVLBCL.\n\nrheumatoid arthritis\nmethotrexate\nlymphoproliferative disorder\nintravascular lymphoma\nimmunological surveillance\n==== Body\npmcIntroduction\n\nMethotrexate (MTX) has been widely used in recent years as a key drug in the treatment of rheumatoid arthritis (RA). Patients with RA are known to be at a high risk for complications associated with lymphoproliferative disorder (LPD) (1). A case of spontaneous regression of LPD after MTX discontinuation was reported in 1993, and the involvement of MTX in the development of LPD was thus proposed (2). MTX-associated LPD (MTX-LPD) is now classified as one of the iatrogenic immunodeficiency-associated LPDs (OIIA-LPDs), in the current WHO classification revised fourth edition (3). Although the epidemiological background of the disease is still unclear, the incidence of lymphoma in patients with RA is significantly higher in Japan, and MTX has been shown to be a risk factor for the disease (4).\n\nIn this study, we report a case of intravascular large B-cell lymphoma (IVLBCL) development during MTX therapy for RA. Since it had a unique clinical course, it was considered to be MTX-LPD and the patient responded well to chemotherapeutic treatment. IVLBCL such as MTX-LPD is extremely rare, and its clinical features are not well known. We herein report the details of the case and discuss the clinical features of MTX-associated IVLBCL (MTX-IVLBCL) in light of previous reviews (5-9).\n\nCase Report\n\nA 56-year-old woman with RA, who had been treated with MTX for six years, visited our hospital complaining of dyspnea and dizziness. There was no fever, skin rash, or superficial lymphadenopathy. Initial laboratory examinations showed a red blood cell count of 360×106 cells/μL, hemoglobin concentration of 10.8 g/dL, lactate dehydrogenase (LDH) level of 1,314 U/L, and soluble interleukin-2 receptor (sIL-2R) level of 2,570 U/mL (normal range, 157-474 U/mL). Abdominal ultrasonography revealed mild splenomegaly. Her symptoms and laboratory findings normalized after the discontinuation of MTX, and her lymphocyte count was increased from 510 cells/μL to 1,200 cells/μL. We diagnosed MTX-LPD based on the clinical course.\n\nFour months later, at three months after the start of treatment with iguratimod (IGU), her lymphocyte count decreased to 630 cells/μL, and serum levels of LDH and sIL-2R were elevated to 953 U/L and 1,720 U/mL, respectively. However, no fever, dyspnea, skin rash, or superficial lymphadenopathy were observed. Laboratory test showed no pancytopenia. Computed tomography (CT) showed mesenteric lymphadenopathy and splenomegaly, and positron emission tomography (PET) scan showed an increased accumulation in the mesenteric lymph nodes and a diffuse accumulation in both lungs. Bone marrow aspiration revealed no malignancy or hemophagocytosis. Skin specimens randomly collected from the upper arm, abdomen, and thigh revealed large atypical lymphoid cell proliferation within the vessel. The atypical lymphoid cells were positive for CD20, CD79a, CD5, Ki-67, Bcl-6, and MUM1, but negative for CD3, CD10, and Epstein-Barr virus encoded small RNA (EBER) in situ hybridization (Fig. 1). The serum Epstein-Barr virus deoxyribonucleic acid (EBV-DNA) quantitative test was under detection sensitivity. Mesenteric lymph node involvement is atypical, but based on these findings, the patient was diagnosed with IVLBCL. Magnetic resonance imaging of the head showed no abnormal signals, and cerebrospinal fluid cytology showed no atypical lymphoid cells.\n\nFigure 1. Pathological findings of a skin biopsy. (a, b) Large atypical lymphoid cells had proliferated in the small vessels. Immunohistochemical staining showed the cells to be positive for CD20 (c) and negative for Epstein-Barr virus encoded small RNA in situ hybridization (d).\n\nAlthough we stopped IGU, her lymphocyte count did not recover, and the elevation in LDH and sIL-2R levels progressed. She received a total of six courses of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy, two courses of rituximab and high-dose MTX (R-HDMTX) therapy, four rounds of intrathecal MTX, cytarabine, and prednisolone infusions. Her laboratory findings thereafter normalized, and mesenteric lymphadenopathy and both lung diffuse accumulation had disappeared (Fig. 2). She has now been in complete remission (CR) for over 12 months since the onset of MTX-LPD.\n\nFigure 2. Clinical course of the patient. ALC: absolute lymphocyte count, IGU: iguratimod, IT: intrathecal methotrexate, cytarabine, and dexamethasone, LDH: lactate dehydrogenase, R-CHOP: rituximab, doxorubicin, cyclophosphamide, vincristine, and predonisolone, R-HDMTX: rituximab, high-dose methotrexate, sIL-2R: soluble interleukin-2 receptor\n\nDiscussion\n\nThis is a case of IVLBCL that spontaneously regressed after MTX withdrawal, but later relapsed during treatment with disease-modifying anti-rheumatic drugs, and responded well to chemotherapy. Based on the characteristic course of the disease, it was assumed that it had a pathogenesis of MTX-LPD.\n\nAlthough a tissue biopsy could not be performed because the patient did not have superficial lymphadenopathy at the initial diagnosis and the disease resolved quickly after MTX withdrawal, a clinical diagnosis of MTX-LPD was made based on the course of the disease. A CT scan at the time of recurrence showed mesenteric lymphadenopathy, but no other lymphadenopathy, and since the patient had mild splenomegaly, a random skin biopsy was performed at an early stage considering the possibility of IVLBCL, and specimens revealed large atypical B-lymphoid cell proliferation within the vessel. CT showed no abnormal findings in both lungs, but a PET scan showed a diffuse accumulation in both lungs, a finding suggestive of IVLBCL (10). Although the presence of lymphadenopathy is atypical, there are reports of lymphadenopathy in about 10% of IVLBCL (11), and we therefore finally diagnosed IVLBCL.\n\nLPDs occurring in patients treated with immunosuppressive drugs are defined as OIIA-LPDs in the WHO classification revised fourth edition (3). Among these, the LPD that occurs in patients with RA treated with MTX is referred to as MTX-LPD. Since the report of MTX-associated IVLBCL in 2015, six cases, including this case, have been reported (5-9); their clinical characteristics are summarized in Table. Of these six cases, spontaneous regression with MTX cessation was observed in four cases, which was strongly suggestive of an MTX association. A relapse after MTX discontinuation was observed in three of four cases (case 2 relapsed 14 months after MTX discontinuation). These three patients responded well to chemotherapeutic treatment despite the recurrence of IVLBCL.\n\nTable. MTX-associated IVLBCL in Literature.\n\nCase No.\tAge/\nSex\tSymptoms\tCNS infiltration\tBM infiltration\tHPS\tEBV infection\tMTX duration\tMTX stop response\tChemotherapy\tChemo response\tRef\t\n1\t50/F\tFever,\nleg pain\t(+)\t(+)\t(-)\t(-)\t3 Y\tRegression\tR-CHOP\nIT\tCR\t(5)\t\n2\t70/F\tFever, dyspnea\t(-)\t(-)\t(-)\t(-)\t7 Y\tRegression\t\t\t(6)\t\n3\t76/M\tFever, dyspnea\t(-)\t(-)\t(-)\t(-)\t10 Y\tRegression →Relapse\tR-THP-COP\nIT\nHDMTX\tCR\t(7)\t\n4\t56/F\tDyspnea, dizziness\t(-)\t(-)\t(-)\t(-)\t6 Y\tRegression →Relapse\tR-CHOP\nR-HDMTX\nIT\tCR\tThis case\t\n5\t75/F\tFever, malaise\t(+)\t(+)\t(-)\t(-)\t2 M\tPersistent\tR-hyper-CVAD/ MA\tCR\t(8)\t\n6\t59/M\tFever, dyspnea, skin rash\t(+)\t(+)\t(+)\t(+)\t13 Y\tPersistent\tR-CHOP\tPD\t(9)\t\nCNS: central nervous system, BM: bone marrow, HPS: hemophagocytic syndrome, EBV: Epstein–Barr Virus, MTX: methotrexate, R-CHOP: rituximab, doxorubicin, cyclophosphamide, vincristine, and prednisolone, IT: intrathecal injection of anticancer drugs, CVAD/MA: cyclophosphamide, vincristine, doxorubicin, and dexamethasone/methotrexate and cytarabine, HDMTX: high-dose methotrexate, CR: complete remission, PD: progression disease, IVLBCL: intravascular large B-cell lymphoma\n\nAll reports of MTX-IVLBCL were from Japan, suggesting an association with the patient's ethnic background. IVLBCL is generally known to have a wide variety of clinical manifestations. The Asian variant, which is more common in East Asia, including Japan, is characterized by frequent bone marrow infiltration and hemophagocytic syndrome (HPS) (12). In these six cases, bone marrow involvement was found in three cases, but only one of them showed HPS. This case of HPS was associated with EBV and had a poor outcome. Although immunosuppressive drugs such as MTX may modify the clinical features, it is assumed that the pathogenesis may be essentially different from that of de novo IVLBCL (in terms of overall survival, five of six patients, including two patients with central nervous system involvement, are still alive and in complete remission). This favorable outcome therefore suggests that MTX-IVLBCL is a different concept from de novo IVLBCL.\n\nIn this case, lymphocyte recovery was observed after a spontaneous regression of MTX-LPD, and lymphocytopenia was observed again after a relapse of MTX-LPD. The spontaneous regression of MTX-LPD has been reported to be associated with lymphocyte recovery (13,14), and this case also suggested an association between lymphocyte suppression and LPD. MTX inhibits cell proliferation and differentiation by inhibiting nucleic acid synthesis, and directly or indirectly regulates inflammatory cell functions through a number of mechanisms, including the induction of adenosine production (15). However, it is unlikely to induce a mutation in lymphocytes (16). Considering the unique clinical course of MTX-LPD, MTX may play a role in the development of LPD through a decrease in cell-mediated immunity associated with suppression of lymphocyte function. Four cases with a spontaneous regression were negative for EBV infection. It has been reported that the spontaneous regression of MTX-LPD correlates with the recovery of Th1 cells and effector memory CD8+ T cells regardless of EBV infection; an immune response to unknown LPD-related antigens was thought to be involved in MTX-LPD (17). IVLBCL with such a background of impaired immunological surveillance may not have a well-developed mechanism of tumorigenesis compared to de novo IVLBCL, which may be associated with both a spontaneous regression and favorable outcomes.\n\nIf the development of IVLBCL is suspected during MTX administration for RA, then an early diagnosis and early discontinuation of MTX and follow-up of lymphocyte counts are required. MTX-IVLBCL may often relapse after a spontaneous regression, but there may be a good response to chemotherapeutic treatment. MTX-IVLBCL is likely to be a disease with different characteristics from de novo IVLBCL, and the treatment strategies need to take this unique background into account.\n\nThe authors state that they have no Conflict of Interest (COI).\n==== Refs\n1. Hashimoto A , Chiba N , Tsuno H , et al . Incidence of malignancy and the risk of lymphoma in Japanese patients with rheumatoid arthritis compared to the general population. J Rheumatol 42 : 564-571, 2015.25593236\n2. Kamel OW , Van de RM , Weiss LM , et al . Brief report: reversible lymphomas associated with Epstein-Barr virus occurring during methotrexate therapy for rheumatoid arthritis and dermatomyositis. N Engl J Med 328 : 1317-1321, 1993.8385742\n3. Gaulard P , Swerdlow SH , Harris NL , Sundstrom C , Jaffe ES . Other iatrogenic immunodeficiency-associated lymphoproliferative disorders. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th ed. Swerdlow SH, Campo E, Harris NL, et al , Eds. IARC Press, Lyon, 2017: 462-464.\n4. Honda S , Sakai R , Inoue E , et al . Association of methotrexate use and lymphoproliferative disorder in patients with rheumatoid arthritis: results from a Japanese multi-institutional retrospective study. Mod Rheumatol 11 : 1-20, 2021.\n5. Kikuchi J , Kaneko Y , Kasahara H , et al . Methotrexate-associated intravascular large B-cell lymphoma in a patient with rheumatoid arthritis. Intern Med 55 : 1661-1665, 2016.27301524\n6. Iwami E , Ito F , Sasahara K , et al . Pulmonary intravascular large B-cell lymphoma in a patient administered methotrexate for rheumatoid arthritis. Intern Med 59 : 429-433, 2020.31619597\n7. Hagihara M , Mese T , Ohara S , Hua J , Ide S , Inoue M . Methotrexate-associated intravascular large B-cell lymphoma in a patient with rheumatoid arthritis: a very rare case. Intern Med 57 : 3001-3005, 2018.29780139\n8. Kida T , Kohno M , Chinen Y , et al . Intravascular lymphoma in a rheumatoid arthritis patient following short-term methotrexate treatment. Rheumatology (Oxford) 56 : 318-320, 2017.27818387\n9. Komeno Y , Akiyama M , Okochi Y , et al . Hemophagocytic syndrome-associated intravascular large B-cell lymphoma in a rheumatoid arthritis patient. Case Rep Hematol 2019 : 8947616, 2019.31612088\n10. Colavolpe C , Ebbo M , Trousse D , et al . FDG-PET/CT is a pivotal imaging modality to diagnose rare intravascular large B-cell lymphoma: case report and review of literature. Hematol Oncol 33 : 99-109, 2015.24850057\n11. Murase T , Yamaguchi M , Suzuki R , et al . Intravascular large B-cell lymphoma (IVLBCL): a clinicopathologic study of 96 cases with special reference to the immunophenotypic heterogeneity of CD5. Blood 109 : 478-485, 2007.16985183\n12. Murase T , Nakamura S , Kawauchi K , et al . An Asian variant of intravascular large B-cell lymphoma: clinical, pathological and cytogenetic approaches to diffuse large B-cell lymphoma associated with haemophagocytic syndrome. Br J Haematol 111 : 826-834, 2000.11122144\n13. Inui Y , Matsuoka H , Yakushijin K , et al . Methotrexate-associated lymphoproliferative disorders: management by watchful waiting and observation of early lymphocyte recovery after methotrexate withdrawal. Leuk Lymphoma 56 : 3045-3051, 2015.25721751\n14. Saito S , Kaneko Y , Yamaoka K , Tokuhira M , Takeuchi T . Distinct patterns of lymphocyte count transition in lymphoproliferative disorders in patients with rheumatoid arthritis treated with methotrexate. Rheumatology (Oxford) 56 : 940-946, 2017.28165538\n15. Bruce NC , Thomas MA . Methotrexate and its mechanisms of action in inflammatory arthritis. Nat Rev Rheumatol 16 : 145-154, 2020.32066940\n16. Bleyer WA . Methotrexate induced lymphoma? J Rheumatol 25 : 404-407, 1998.9517755\n17. Saito S , Suzuki K , Yoshimoto K , et al . Restoration of decreased T helper 1 and CD8+ T cell subsets is associated with regression of lymphoproliferative disorders developed during methotrexate treatment. Front Immunol 9 : 621, 2018.29670617\n\n",
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"title": "Development of Intravascular Large B-cell Lymphoma during Methotrexate Treatment for Rheumatoid Arthritis.",
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"abstract": "Noncirrhotic portal hypertension (NCPH) is a well-known clinical entity, but often underdiagnosed. One of the common causes of NCPH is nodular regenerative hyperplasia (NRH) that presents as nodularity with features of portal hypertension and thus often diagnosed as cirrhosis. Although NRH has no histologic fibrosis, the liver synthetic function remains intact; thus, clinical diagnosis is essential because management may differ from cirrhosis. We were asked to consult in this series of 4 patients who had new-onset ascites after kidney transplantation and were diagnosed with NCPH from NRH.",
"affiliations": "Department of Internal Medicine, Sacramento, CA.;Department of Internal Medicine, Sacramento, CA.;Department of Pathology, Sacramento, CA.;Transplant Nephrology, University of California Davis, Sacramento, CA.;Department of Internal Medicine, Sacramento, CA.",
"authors": "Piao|Cindy|C|;Koul|Abhinav|A|;Gui|Dorina|D|;Chen|Ling-Xin|LX|;Sarkar|Souvik|S|",
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"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\n32042840\nACGCR-19-0055\n10.14309/crj.0000000000000257\n00007\nCase Report\nLiver\nNoncirrhotic Portal Hypertension Secondary to Nodular Regenerative Hyperplasia Postrenal Transplant\nPiao Cindy MD1 Koul Abhinav MD12 Gui Dorina MD3 Chen Ling-xin MD4 Sarkar Souvik MD12 1 Department of Internal Medicine, Sacramento, CA\n2 Division of Gastroenterology and Hepatology, Sacramento, CA\n3 Department of Pathology, Sacramento, CA\n4 Transplant Nephrology, University of California Davis, Sacramento, CA\nCorrespondence: Souvik Sarkar, MD, Division of Gastroenterology and Hepatology, University of California, Davis, 4150 V St, PSSB 3500, Sacramento, CA 95817 (ssarkar@ucdavis.edu).\n12 2019 \n12 12 2019 \n6 12 e0025708 2 2019 20 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\nNoncirrhotic portal hypertension (NCPH) is a well-known clinical entity, but often underdiagnosed. One of the common causes of NCPH is nodular regenerative hyperplasia (NRH) that presents as nodularity with features of portal hypertension and thus often diagnosed as cirrhosis. Although NRH has no histologic fibrosis, the liver synthetic function remains intact; thus, clinical diagnosis is essential because management may differ from cirrhosis. We were asked to consult in this series of 4 patients who had new-onset ascites after kidney transplantation and were diagnosed with NCPH from NRH.\n\nOPEN-ACCESSTRUE\n==== Body\nINTRODUCTION\nNodular regenerative hyperplasia (NRH) is one of the causes of noncirrhotic portal hypertension (NCPH) characterized by hepatic regenerative nodules with the absence of fibrotic tissue.1,2 In previous autopsy studies, the incidence of NRH ranged between 0.72% and 2.6%.3,4 NRH appears to be adaptive hyperplasia of the hepatocytes in response to physiological or mechanical damage.5 Histologically, NRH is comprised of small nodules due to hepatocyte hypertrophy adjacent to atrophic, thin hepatocytes.5 Unlike cirrhosis, there are no areas of fibrosis seen between nodules. Patients with NRH are often asymptomatic, although they can present with clinical symptoms of portal hypertension such as hepatosplenomegaly, gastric variceal bleeding, and ascites.1 By contrast, liver nodules from focal nodular hyperplasia are benign hepatic tumors that often do not have any clinical significance.6 Histologically, focal nodular hyperplasia nodules are found to have malformed vessels and proliferation of small bile ducts.6 Immunosuppressive medications such as azathioprine have been associated with the development of NCPH in patients after kidney transplantation (KT) because of damage to the endothelial cells of hepatic veins.7 We present a series of 4 patients who developed NCPH due to NRH after KT, even without exposure to azathioprine.\n\nCASE REPORT\nFour male patients whose ages range from 34 to 69 years with stage V chronic kidney disease of varying etiologies developed new-onset ascites between 3 months and 4 years after undergoing KT. One patient received a kidney from an unrelated living donor. All 4 patients were initially started on tacrolimus and mycophenolate for immune suppression after KT, although one patient developed chronic diarrhea from mycophenolate and was switched to azathioprine. Peritoneal fluid analysis in all patients was notable for a serum-ascites albumin gradient >1.1 consistent with portal hypertensive ascites. Workup for intrinsic liver disease including autoimmune, infiltrative, and infectious causes was unremarkable. Patients did not have any cardiac dysfunction. Abdominal imaging showed evidence of splenomegaly in all patients, with perisplenic varices and a recanalized periumbilical vein seen in one patient. Before KT, the 4 patients did not have imaging that assessed previous liver morphology or vascular abnormalities. Three patients had an elevated hepatic venous pressure gradient ranging from 13 to 17 mm Hg, and one patient had an hepatic venous pressure gradient of 8 mm Hg. Liver biopsies were notable for areas of nodular regeneration bounded by narrowed hepatocellular plates associated with pericentral sinusoidal dilatation. Perisinusoidal and portal fibrosis were noted; however, there were no fibrous septa around the nodules (Figure 1).\n\nFigure 1. (A) Liver biopsy of patient B showing widened hepatocellular plates alternating with atrophic, narrowed hepatocellular plates associated with pericentral sinusoidal dilatation (hematoxylin & eosin stain) and (B) the condensed reticulin network in the internodular parenchyma (reticulin stain).\n\nAll 4 patients were diagnosed with NCPH secondary to NRH. Patient A was initially managed with diuretics; however, he developed refractory ascites requiring frequent therapeutic paracentesis. He ultimately underwent transjugular intrahepatic portosystemic shunt (TIPS) placement with near resolution of ascites without further need for paracentesis. However, his kidney transplant failed because of tubular necrosis in the setting of the recurrent ascites. Patient B also underwent intermittent therapeutic paracentesis for management of his ascites. He stabilized on a diuretic regimen and continues to be managed conservatively. Patient C discontinued his azathioprine; however, he continued to have multiple hospitalizations for volume overload. He underwent the TIPS procedure that controlled his ascites. However, he died because of unclear etiology at home. Patient D also has ascites refractory to diuretics and is currently undergoing evaluation for TIPS placement. Patients B and D have preserved kidney graft function 33 and 11 months after KT; their immunosuppressants have not been changed throughout the course of their liver disease.\n\nDISCUSSION\nNRH has been associated with exposure to immunosuppressants, chemotherapy, and antiviral drugs.7–9 There have been documented cases of NCPH developing after KT, almost exclusively in the setting of chronic azathioprine use. In some of those cases, cessation of azathioprine led to improvement and sometimes reversal of NCPH.10 Development of NRH has also been described after liver transplantation, often times without azathioprine exposure.11 Our case series describes the development of NCPH secondary to NRH in 4 patients who underwent KT, 3 of whom did not have exposure to azathioprine. This suggests an alternate pathophysiology responsible for the development of NRH in this patient population, which has been noted before, but the cause remains unclear.12 There have not been any reported cases of development of NRH in association with tacrolimus or mycophenolate, which were the immunosuppressants that were used in these 4 patients. Of note, all the patients described were male, liver synthetic function was preserved, and all patients had functioning allograft at first diagnosis of ascites. All the cases described were initially managed with diuretics and therapeutic paracentesis. However, 3 patients needed TIPS.\n\nTo summarize, NRH causing NCPH is an essential clinical entity that needs to be considered in post-KT patients presenting with portal hypertension regardless of choice of immunosuppressive therapy. Although NCPH may be successfully managed with diuretics or portal decompression, it carries significant patient morbidity. Diagnosis may be delayed and wrongly interpreted as cirrhosis, where management can differ. Our case demonstrates that clinicians must maintain a high level of suspicion for NCPH and NRH in noncirrhotic patients with new-onset ascites after renal transplantation.\n\nFurther work remains to elucidate the potential causes and risk factors for the occurrence of NCPH in patients after KT.\n\nDISCLOSURES\nAuthor contributions: C. Piao and A. Koul wrote the manuscript. D. Gui, L-x Chen, and S. Sarkar revised the manuscript. S. Sarkar is the article guarantor.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nREFERENCES\n1. Sarin SK Khanna R \nNon-cirrhotic portal hypertension\n. Clin Liver Dis . 2014 ;18 (2 ):451 –76\n24679506 \n2. Reshamwala PA Kleiner DE Heller T \nNodular regenerative hyperplasia: Not all nodules are created equal\n. Hepatology . 2006 ;44 (1 ):7 –14\n16799965 \n3. Wanless IR \nMicronodular transformation (nodular regenerative hyperplasia) of the liver: A report of 64 cases among 2,500 autopsies and a new classification of benign hepatocellular nodules\n. Hepatology . 1990 ;11 (5 ):787 –97\n.2189821 \n4. Nakanuma Y \nNodular regenerative hyperplasia of the liver: Retrospective survey in autopsy series\n. J Clin Gastroenterol . 1990 ;12 (4 ):460 –5\n.1975817 \n5. Hartleb M Gutkowski K Milkiewicz P \nNodular regenerative hyperplasia: Evolving concepts on underdiagnosed cause of portal hypertension\n. World J Gastroenterol . 2011 ;17 (11 ):1400 –9\n21472097 \n6. Maillette de Buy Wenniger L Terpstra V Beuers U \nFocal nodular hyperplasia and hepatic adenoma: Epidemiology and pathology\n. Dig Surg . 2010 ;27 (1 ):24 –31\n20357448 \n7. Ghabril M Vuppalanchi R \nDrug-induced nodular regenerative hyperplasia\n. Semin Liver Dis . 2014 ;34 (02 ):240 –5\n24879987 \n8. Vernier-Massouille G Cosnes J Lemann M \nNodular regenerative hyperplasia in patients with inflammatory bowel disease treated with azathioprine\n. Gut . 2007 ;56 (10 ):1404 –9\n17504943 \n9. Cotte L Bénet T Billioud C \nThe role of nucleoside and nucleotide analogues in nodular regenerative hyperplasia in HIV-infected patients: A case control study\n. J Hepatol . 2011 ;54 (3 ):489 –96\n21056493 \n10. Adler M Delhaye M Deprez C \nHepatic vascular disease after kidney transplantation: Report of two cases and review of the literature\n. Nephrol Dial Transpl . 1987 ;2 (3 ):183 –8\n.\n11. Devarbhavi H Abraham S Kamath PS \nSignificance of nodular regenerative hyperplasia occurring de novo following liver transplantation\n. Liver Transpl . 2007 ;13 (11 ):1552 –6\n17969192 \n12. Gerlag PG Lobatto S Driessen WM \nHepatic sinusoidal dilatation with portal hypertension during azathioprine treatment after kidney transplantation\n. J Hepatol . 1985 ;1 (4 ):339 –48\n.3902952\n\n",
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"title": "Noncirrhotic Portal Hypertension Secondary to Nodular Regenerative Hyperplasia Postrenal Transplant.",
"title_normalized": "noncirrhotic portal hypertension secondary to nodular regenerative hyperplasia postrenal transplant"
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"abstract": "Previous caesarean section is considered the main risk factor for uterine rupture. However, other surgical procedures performed on the uterus can also lead to rupture in future pregnancies.\n\n\n\nThe patient was a nulliparous woman, induced at gestational age of 41 + 6 with misoprostol. She developed severe persistent abdominal pain. Due to fetal bradycardia, an acute caesarean section was performed. Peroperatively a large rupture was identified in the uterine fundus and the placenta was detached into the abdomen. Medical history included a previous rightsided salpingectomy due to an extrauterine pregnancy located in the interstitial part of the right Fallopian tube.\n\n\n\nInterstitial extrauterine pregnancy is rare, and recommendations for mode of delivery for subsequent pregnancies remain unclear. The current case illustrates the importance of being aware of the risk of rupture when the patient has undergone previous gynaecological surgery other than caesarean section, and of ensuring awareness of the placenta's location.",
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"medline_ta": "Tidsskr Nor Laegeforen",
"mesh_terms": "D002585:Cesarean Section; D005260:Female; D006801:Humans; D016595:Misoprostol; D010298:Parity; D011247:Pregnancy; D011248:Pregnancy Complications; D014597:Uterine Rupture",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Uterine rupture in a nulliparous woman.",
"title_normalized": "uterine rupture in a nulliparous woman"
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"abstract": "Diabetic ketoacidosis (DKA) is a potentially fatal metabolic emergency of both type 1 and type 2 diabetes. Although there is a reduced risk of type 1 diabetes in schizophrenia, the incidence of DKA is tenfold higher than that of the general population. Thus, we aimed to investigate associations between exposure to antipsychotic medication (within 3 months prior to event) and DKA, type 1 diabetes and type 2 diabetes. We also reported related, clinically relevant outcomes.\n\n\n\nUsing a nested case-control study design, we identified cases of DKA, type 1 diabetes and type 2 diabetes in a previously diabetes-naive population with schizophrenia in Denmark from 1995 to 2014. Cases were matched (by age, sex and year of schizophrenia onset) 1:5 to schizophrenic control individuals who were alive and had not emigrated prior to event. Conditional logistic regression was used to compute ORs with 95% CIs. Other outcomes included diabetes aetiology of DKA, in-hospital mortality, DKA readmissions and temporal trends of use of insulin and oral glucose-lowering agents.\n\n\n\nOf 29,955 individuals with schizophrenia, we identified 28 individuals with DKA, 90 with type 1 diabetes and 2140 with type 2 diabetes. These were matched to 137, 410 and 9861 individuals in the control group, respectively. Antipsychotic exposure was associated with DKA (OR 2.60; 95% CI 1.06, 6.38) and type 2 diabetes (OR 1.64; 95% CI 1.48, 1.83). A trend towards increased risk of type 1 diabetes was found but remained insignificant (OR 1.38; 95% CI 0.84, 2.29). Diabetes aetiology of DKA was type 1 in eight cases and type 2 in 14 cases. Of the remaining six cases of DKA, aetiology could not be determined, as four were fatal within 8 days and for two, no prescriptions for insulin and oral glucose-lowering agents were redeemed. Of all DKA cases, six had more than one episode of DKA, and of all type 1 diabetes and type 2 diabetes cases, four and 11, respectively, had at least one episode. Use of insulin and oral glucose-lowering agents was higher among individuals with DKA relative to those with type 1 diabetes and type 2 diabetes.\n\n\n\nAntipsychotic exposure was associated with DKA and type 2 diabetes in a previously diabetes-naive schizophrenia population. Antipsychotic-associated DKA is relevant not only for psychiatrists but also for other physicians who may manage and admit such patients.",
"affiliations": "Department of Psychiatry, Aalborg University Hospital, Brandevej 5, 9220, Aalborg, Denmark. c.polcwiartek@gmail.com.;Department of Psychiatry, Aalborg University Hospital, Brandevej 5, 9220, Aalborg, Denmark.;Department of Psychiatry, Aalborg University Hospital, Brandevej 5, 9220, Aalborg, Denmark.;Department of Psychiatry, Aalborg University Hospital, Brandevej 5, 9220, Aalborg, Denmark.;Department of Psychiatry, Aalborg University Hospital, Brandevej 5, 9220, Aalborg, Denmark.;Department of Psychiatry, Aalborg University Hospital, Brandevej 5, 9220, Aalborg, Denmark.",
"authors": "Polcwiartek|Christoffer|C|0000-0001-9372-7484;Kragholm|Kristian|K|;Rohde|Christopher|C|;Hashemi|Nasseh|N|;Vang|Torkel|T|;Nielsen|Jimmi|J|",
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"issue": "60(9)",
"journal": "Diabetologia",
"keywords": "Antipsychotics; Diabetic ketoacidosis; Internal medicine; Mortality; Schizophrenia; Type 1 diabetes; Type 2 diabetes",
"medline_ta": "Diabetologia",
"mesh_terms": "D000328:Adult; D014150:Antipsychotic Agents; D016022:Case-Control Studies; D003922:Diabetes Mellitus, Type 1; D003924:Diabetes Mellitus, Type 2; D016883:Diabetic Ketoacidosis; D005260:Female; D006801:Humans; D007388:Internal Medicine; D008297:Male; D008875:Middle Aged; D012559:Schizophrenia",
"nlm_unique_id": "0006777",
"other_id": null,
"pages": "1678-1690",
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"pmid": "28593353",
"pubdate": "2017-09",
"publication_types": "D016428:Journal Article",
"references": "20520598;24313570;24065841;27474348;28379483;16052326;15337666;22835961;21775352;25784664;17604410;17474808;21775345;26231497;14750042;15285957;23461991;21954480;21737470;3558716;19164499;12716805;26934282;16513876;12046641;27397023;21775346;19552870;17679634;26360288;23344556;17062587;26975543;26032247;25582655;21775347;25601320;27592232;28097367;21775349;28103712",
"title": "Diabetic ketoacidosis and diabetes associated with antipsychotic exposure among a previously diabetes-naive population with schizophrenia: a nationwide nested case-control study.",
"title_normalized": "diabetic ketoacidosis and diabetes associated with antipsychotic exposure among a previously diabetes naive population with schizophrenia a nationwide nested case control study"
} | [
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"abstract": "BACKGROUND\nMultiple diverticulosis of the jejunum constitutes an uncommon pathology of the small bowel. The disease is often asymptomatic and must be taken into consideration in cases of unexplained malabsorption, anemia, chronic abdominal pain and discomfort.\nWe are thereby reporting a 50yr patient on chronic NSAID ingestion presenting to us with acute abdomen. On exploration, there were multiple (14) jejunal diverticuli on both mesenteric and antimesentric border from 10cm to 90cm distal to duedenojejunal junction with a perforation in one of the diverticulum, 80cm distal to the ligament of Treitz. We performed a resection of a 80-cm jejunal segment involving the multiple diverticula and an end to end jejunojejunostomy.\n\n\nCONCLUSIONS\nDrug-induced jejunal perforation is known, but jejunal diverticular perforation related to steroid/treatment has been reported only once previously. Long-term NSAID therapy usually induces clinically silent enteropathy characterized by increased intestinal permeability and inflammation. Jejunal diverticulosis is a challenging disorder from a diagnostic perspective, with no truly reliable diagnostic tests. The current treatment of choice for perforated jejunal diverticula causing generalized peritonitis is prompt laparotomy with segmental intestinal resection and primary anastomosis.\n\n\nCONCLUSIONS\nJejunal diverticula are rare lesions, and their perforation never features in the list of diagnoses for acute abdomen, especially in this part of the world. Further this unique case report opens the doors for further research to prove an assosiation between NSAID use and diverticular perforation which itself is a very rare entity.",
"affiliations": "R.G. Kar Medical College and Hospital, 1, Kshudiram Bose Sarani, Kolkata, West Bengal, 700004, India. Electronic address: pixelfinance2000@gmail.com.;PGIMER & DR. R.M.L. Hospital, New Delhi, 110001, India.",
"authors": "Gupta|Shobhit|S|;Kumar|Naveen|N|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.ijscr.2017.07.021",
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(17)30340-110.1016/j.ijscr.2017.07.021Case ReportJejunal diverticula with perforation in non steroidal anti inflammatory drug user: A case report Gupta Shobhit pixelfinance2000@gmail.comaKumar Naveen b⁎a R.G. Kar Medical College and Hospital, 1, Kshudiram Bose Sarani, Kolkata, West Bengal, 700004, Indiab PGIMER & DR. R.M.L. Hospital, New Delhi, 110001, India⁎ Corresponding author.22 7 2017 2017 22 7 2017 38 111 114 26 1 2017 10 7 2017 15 7 2017 © 2017 Published by Elsevier Ltd on behalf of IJS Publishing Group Ltd.2017This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).Highlights\n• Multiple diverticulosis of the jejunum constitutes an uncommon pathology of the small bowel.\n\n• Jejunal diverticular perforation related to steroid/treatment has been reported only once previously.\n\n• The current treatment of choice is prompt laparotomy with segmental intestinal resection and primary anastomosis.\n\n\n\nIntroduction\nMultiple diverticulosis of the jejunum constitutes an uncommon pathology of the small bowel. The disease is often asymptomatic and must be taken into consideration in cases of unexplained malabsorption, anemia, chronic abdominal pain and discomfort.\n\nCase presentaion\nWe are thereby reporting a 50 yr patient on chronic NSAID ingestion presenting to us with acute abdomen. On exploration, there were multiple (14) jejunal diverticuli on both mesenteric and antimesentric border from 10 cm to 90 cm distal to duedenojejunal junction with a perforation in one of the diverticulum, 80 cm distal to the ligament of Treitz. We performed a resection of a 80-cm jejunal segment involving the multiple diverticula and an end to end jejunojejunostomy.\n\nDiscussion\nDrug-induced jejunal perforation is known, but jejunal diverticular perforation related to steroid/treatment has been reported only once previously. Long-term NSAID therapy usually induces clinically silent enteropathy characterized by increased intestinal permeability and inflammation. Jejunal diverticulosis is a challenging disorder from a diagnostic perspective, with no truly reliable diagnostic tests. The current treatment of choice for perforated jejunal diverticula causing generalized peritonitis is prompt laparotomy with segmental intestinal resection and primary anastomosis.\n\nConclusion\nJejunal diverticula are rare lesions, and their perforation never features in the list of diagnoses for acute abdomen, especially in this part of the world. Further this unique case report opens the doors for further research to prove an assosiation between NSAID use and diverticular perforation which itself is a very rare entity.\n\nAbbreviation\nNSAID, non steroidal anti inflammatory drugsKeywords\nJejunumDiverticulaNSAIDPerforationLaparotomySegmental resectionAnastomosis\n==== Body\n1 Introduction\nMultiple diverticulosis of the jejunum constitutes an uncommon pathology of the small bowel [9]. The disease is often asymptomatic and must be taken into consideration in cases of unexplained malabsorption, anemia, chronic abdominal pain and discomfort [9]. Related complications such as diverticulitis, hemorrhage, obstruction and perforation present high mortality and morbidity rates. Drug-induced jejunal perforation is known, but jejunal diverticular perforation related to steroid/treatment has been reported only once previously [16]. Long-term NSAID therapy usually induces clinically silent enteropathy characterized by increased intestinal permeability and inflammation [17]. In patients with diverticular disease, NSAID use increases the risk of severe diverticular infection and perforation. Jejunal diverticulosis is a challenging disorder from a diagnostic perspective, with no truly reliable diagnostic tests. We are thereby reporting a 50 yr patient on chronic NSAID ingestion presenting to us with acute abdomen, on exploration of which there was jejunal diverticular perforation.\n\n2 Case report\nA 50-year old male patient was admitted to our emergency department with an acute onset of abdominal pain and nausea over 24 h. He had a history of intermittent abdominal pain mostly localized to epigastrium for 5 years. He was suffering from a chronic pain on back of his neck (? Cervical spondylosis) for which he was on chronic treatment with diclofenac plus paracetamol combination for 15 years prescribed by some local doctor. On physical examination he was having average built with temperature of 39.8 °C and pulse was 106, BP 110/72. Examination of the abdomen revealed muscular gaurding and rebound tenderness in all quadrants of the abdomen. There Bowel sounds were hypoactive. His white blood cell count was 16.500/mm3 and hemoglobin level was 13.2 gm/dL. Radiographic images showed no free gas under diaphragm and multiple air fluid levels suggestive of ileus were noted. The patient was initially resuscitated with intravenous fluids and intravenous third generation cephalosporins were administered. Patient kept nil per orally with nasogastric tube for aspiration. An emergent abdominal exploration was performed (Fig. 1).Fig. 1 Jejunal diverticula with perforation.\n\nFig. 1\n\nAt the time of surgery, there were flakes in the abdominal cavity, with multiple (14) jejunal diverticuli on both mesenteric and antimesentric border from 10 cm to 90 cm distal to duedenojejunal junction, there were charactestically multiple secondary divericular outpouchings in 10 diverticulas with unhealthy wall with a perforation in one of the diverticulum, 80 cm distal to the ligament of Treitz. The perforated diverticulum was wrapped by the Omentum and sealed with flakes. Although the perforated diverticulum was sealed off but as described earlier there were multiple secondary diverticulas with unhealthy walls with peritonitis, patient could not be managed with conservative treatment. Hence, we performed a resection of a 80-cm jejunal segment involving the multiple\n\ndiverticula and an end to end jejunojejunostomy. The patient’s postoperative period was uneventful. He began oral intake on postoperative day 3. The abdominal drains were removed on day 4. Patient developed wound infection at suture site which was managed with dressings and antibiotics. Patient was discharged on postoperative day 8. Histological examination of the perforated diverticulum revealed nonspecific inflammatory changes.\n\n3 Discussion\nJejunal diverticulosis was first described by Somerling in 1794 and by Sir Astley Cooper in 1807 [1]. Autopsy studies reveal an incidence between 1.3% and 4.6%, whereas radiologic studies show an incidence between 0.02% and 2.3% [1]. Over 80% of jejunal diverticula occur in patients 70 years and older [2]. But in our case patient age is 50 yrs. Jejunal diverticulosis may present acutely with complications in 10–30% of all patients [8].\n\nThe incidence has been found to be higher in men (58%) than women (42%) [3]. These false diverticula are acquired outpouchings of mucosa commonly found on the mesenteric border of the jejunum [1]. These pulsion-type false diverticula occur along the mesenteric border of the intestine, where blood vessels pierce the muscularis layer of the bowel wall, causing weak areas to develop. These weak areas lead to herniation of mucosa, submucosa, and serosa while excluding the muscularis layer. [2] The most common part of the small bowel to be affected by diverticula is the proximal jejunum (75%), followed by the distal (20%) and then the ileum (5%), in our case also it was present from 10 cm to 90 cm distal to DJ flexure (Fig. 2).Fig. 2 Ressected 80-cm Jejunal segment involving the multiple diverticula.\n\nFig. 2\n\nSeventy seven percent of cases demonstrated multiple as opposed to solitary diverticula [4]\n\nJejunal and jejuno-ileal localizations are less frequent involved than duodenal, but more prone to develop complications [5].\n\nOf these diverticula, 35% are associated with colonic diverticula, 26% with duodenal diverticula and 2% with oesophageal diverticula, respectively [6], [7].\n\nThe commonest GI diverticulum is sigmoid colon diverticulum. NSAIDs have been implicated as a risk factor for perforation in diverticulitis [19]. NSAIDs inhibit the cyclo-oxygenase enzyme and cause topical mucosal damage, increasing colonic permeability. Besides, they reduce prostaglandin synthesis, which is important in maintaining an effective mucosal barrier [19].\n\nThe disease is often asymptomatic and must be taken into consideration in cases of unexplained malabsorption, anemia, chronic abdominal pain and discomfort [9]. In our case also, patient was complaining of recurrent epigastric pain for last 5 yrs.\n\nTsiotos et al. analysed 112 cases of jejunoileal diverticulosis and of these, 42% of cases were asymptomatic. The remaining patients had symptoms of diarrhoea (58%), chronic abdominal pain (51%) or bloating (44%).Interestingly Tsiotos et al. also found an association with Raynaud’s phenomenon and systemic sclerosis [3].\n\nComplication rates as high as 46% for jejunal diverticulosis have been reported and are known to be fatal at times [10]. More acute complications are perforation, peritonitis, bleeding, and fistula formation [2].\n\nLargest study till date was review by Chendrasekhar et al[11] in 1995, they provided individual patient data for all case reports previously published, of 13 patients between 1971 and 1994 [11].\n\nThere seems to be a shift towards conservative treatment when properly diagnosed, a much higher percentage of accurate diagnosis, and small bowel resection is usually performed with lower mortality rates [12].\n\nPerforation mostly occurs into the mesenteric leaves of the jejunum, leading to a mesenteric abscess. Although the perforation may be contained within the mesentery, preventing leakage into the peritoneal cavity and resultant peritonitis, it also leads to a delay in diagnosis because the classical physical examination findings of an acute abdomen are absent, which may prove disastrous when frail or elderly patients are involved [15].\n\nInstigating factors for perforation were shown to be related to a necrotizing inflammatory reaction in 82% of cases, followed by blunt trauma (12%) and foreign body impaction (6%) [6]. Cocaine sniffing has also been noted as a risk factor [13]. Assosiation with amyloid disease or malignancy such as lympho sarcoma, MEN-I or fibrous histiocytoma has also been stated [14].\n\nIn our case no such association was found, no family history of such malignancy was found. Based upon the clinical findings along with radiological findings and history of long term use of NSAIDS, patient was suspected of enteric perforation with peritonitis,though the suspicion of jujenal diverticular perforation could not be made with the mentioned radiological findings beforehand. As the patient came to us at emergency and imaging modality other than the X −Ray and ultrasound facilities were not available in emergency setting in our hospital and moreover patient was from economically very backward society thus further expensive tests could not be conducted. Patient used to take some oral analgesics (NSAIDS) for last 15 years which could a contributing factor for the diverticular perforation, as it has been stated in previous study [16], but it was not proved histologically, as HPE report stated non specific inflammation, and no impacted tablets were found on HPE. As the patient came in emergency with features suggestive of perforation with peritonitis,we did not have much options such as of diagnostic laproscopy available in emergency at our centre,we had to do emergent laprotomy of the patient.\n\nDrug-induced jejunal perforation is known, but jejunal diverticular perforation related to steroid/NSAIDS treatment has been reported only once previously [16]. Long-term NSAID therapy usually induces clinically silent enteropathy characterized by increased intestinal permeability and inflammation [17]. In patients with diverticular disease, NSAID use increases the risk of severe diverticular infection and perforation [18].\n\nJejunal diverticulosis is a challenging disorder from a diagnostic perspective, with no truly reliable diagnostic tests.\n\nHowever, the current treatment of choice for perforated jejunal diverticula causing generalized peritonitis is prompt laparotomy with segmental intestinal resection and primary anastomosis. Exploratory laparotomy and resection of affected intestinal segment with primary anastomosis is mandatory in case of perforation, abscesses and obstruction [9]. If diverticula are extensive, resection may have to be limited to include only the segment containing the perforated diverticulum and to leave a segment of small bowel that still contains non-perforated diverticula in order to avoid short bowel syndrome. A total laparoscopic treatment of sizable jejunal diverticulum has been recently reported . Laparoscopy in the setting of diffusely dilated small bowel loops is difficult because the working space provided by the pneumoperitoneum is reduced. Further, small bowel manipulation and retraction in this setting carries a higher risk of serosal tears or enterotomy. Furthermore laproscopic facility is not available in emergency settings at many centres like in our case.\n\nThe complications related to the jejunal diverticula, when they arise, lead to a diagnostic dilemma since jejunal diverticula are not high on the list of differentials for acute abdomen, especially in India.\n\n4 Conclusion\nJejunal diverticula are rare lesions, and their perforation never features in the list of diagnoses for acute abdomen, especially in this part of the world. No strong association between diverticulosis and NSAID could be proved with confirmation, but no other comorbidity except this suggests an association with it. Further this unique case report opens the doors for further research to prove an assosiation between NSAID use and diverticular perforation which itself is a very rare entity. Moreover in our case the age was 50 yrs, thus we should have this differential diagnosis in mind in such age group also and not just elderly as stated in previous case reports.\n\nThe work has been reported in line with the scare criteria [20].\n\nConflicts of interest\nNone.\n\nFunding\nNone.\n\nEthical approval\nNone.\n\nConsent\nDuly informed written and signed consent was obtained from patient.\n\nAuthor contribution\nDr. Shobhit Gupta – Who performed the surgery.\n\nDr. Naveen Kumar – Who has written the paper and collected the data.\n\nGuarantor\nDr. Shobhit Gupta, Dr. Naveen Kumar.\n==== Refs\nReferences\n1 Williams R.A. Davidson D.D. Serota A.I. Wilson S.E. Surgical problems of diverticula of the small intestine Surg. Gynecol. Obstet. 152 1981 621 626 6784259 \n2 Ross C.B. Richards W.O. Sharp K.W. Diverticular disease of the jejunum and its complications Am. Surg. 56 5 1990 319 324 2110429 \n3 Tsiotos G.G. Farnell M.B. Ilstup D.M. Non-Meckelian jejunal or ileal diverticulosis: an analysis of 112 cases Surgery 116 1994 726 732 7940172 \n4 Lempinen M. Salmela K. Kemppainen E. Jejunal diverticulosis: a potentially dangerous entity Scand. J. Gastroenterol. 39 2004 905 909 15513392 \n5 Miller R.E. McCabe R.E. Salomon P.F. Knox W.G. Surgical complications of small bowel diverticula exclusive of Meckel's Ann. Surg. 171 1970 202 210 4983990 \n6 Baskin R.H. Jr. MAYO CW: Jejunal diverticulosis; a clinical study of 87 cases Surg. Clin. North Am. 152 1952 1185 1196 \n7 Benson R.E. Dixon C.F. Waugh J.M. Non-Meckelian diverticula of the jejunum and ileum Ann. Surg. 118 1943 377 393 17858273 \n8 Akhrass R. Yaffe M.B. Fischer C. Ponsky J. Shuck J.M. Small bowel diverticulosis: perceptions and reality J. Am. Coll. Surg. 184 1997 383 388 9100684 \n9 Falidas Evangelos Vlachos Konstantinos Mathioulakis Stavros Archontovasilis Fotis Villias Constantinos Multiple giant diverticula of the jejunum causingintestinal obstruction: report of a case and reviewof the literature World J. Emergency Surg. 6 2011 8 \n10 Davies N.M. Saleh J.Y. Skjodt N.M. Detection and prevention of NSAID-induced enteropathy J. Pharm. Pharmaceut. Sci. 3 2000 137 155 \n11 Chendrasekhar A. Timberlake G.A. Perforated jejunal diverticula:an analysis of reported cases Am. Surg. 61 1995 984 988 7486432 \n12 Spasojevic Milan Jens marius naesgaard, dejan ignjatovic. perforated midgut diverticulitis: revisited World J. Gastroenterol. 18 34 2012 4714 4720 23002340 \n13 Albu E. Parikh V. Alankar S. Perforated solitary jejunal diverticulum South. Med. J. 88 5 1995 575 576 7732450 \n14 Al-Samarrai A. Perforation of jejunal diverticulum Saudi J. Gastroenterol. 8 2002 62 63 19861793 \n15 Herrington J.L. Jr. Perforation of acquired diverticula of the jejunum. Analysis of reported cases Surgery 51 4 1962 426 433 13906829 \n16 Palanivelu C. Rangarajan M. Rajapandian S. Perforation of jejunal diverticula in steroids and nonsteroidal anti-Inflammatory drug abusers: a case series World J. Surg. 32 2008 1420 18330630 \n17 Goh H. Bourne R. Non-steroidal anti-inflammatory drugs and perforated diverticular disease: a case-control study Ann. R. Coll. Surg. Engl. 84 March(2) 2002 93 96 11995772 \n18 Piekarek K. Israelsson L.A. Perforated colonic diverticular disease: the importance of NSAIDs, opioids, corticosteroids, and calcium channel blockers Int. J. Colorectal Dis. 23 2008 1193 1197 18679693 \n19 Vermeulen J. Ven der Harst E. Lange J.F. Pathophysiology and prevention of diverticulitis and perforation Neth. J. Med. 68 October(10) 2010 303 21071775 \n20 Agha R.A. Fowler A.J. Saetta A. Barai I. Rajmohan S. Orgill DP and the SCARE group: the SCARE statement: consensus-based surgical case report guidelines Int. J. Surg. 34 2016 180 186 27613565\n\n",
"fulltext_license": "CC BY-NC-ND",
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"issue": "38()",
"journal": "International journal of surgery case reports",
"keywords": "Anastomosis; Diverticula; Jejunum; Laparotomy; NSAID; Perforation; Segmental resection",
"medline_ta": "Int J Surg Case Rep",
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"pages": "111-114",
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"title": "Jejunal diverticula with perforation in non steroidal anti inflammatory drug user: A case report.",
"title_normalized": "jejunal diverticula with perforation in non steroidal anti inflammatory drug user a case report"
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"abstract": "BACKGROUND\nBucolome is a non-steroidal anti-inflammatory drug and uricosuric agent, currently used only in Japan. It is known to induce drug interactions by inhibiting cytochrome P450 (CYP) 2C9. It is often used to enhance the anticoagulant effect of warfarin by utilizing its drug interactions. There are only a few reports on drug interactions of bucolome and the mechanism remain poorly understood.\n\n\nMETHODS\nAn 81-year-old woman with a history of type 2 diabetes mellitus was taking glimepiride 2 mg/day and voglibose 0.6 mg/day. After hospitalization, the patient underwent surgical aortic valve replacement surgery (day 0). Glimepiride and voglibose were resumed on the second postoperative day (day 2), and warfarin was started to prevent thromboembolism. Since the prothrombin time-international normalized ratio on day 9 was low at 1.24, 300 mg/day of bucolome was added to enhance the effect of warfarin. A gradual decrease in blood glucose levels was observed from the day after bucolome administration was initiated. Hypoglycemia in the 56-57 mg/dL range occurred before lunch and dinner on the 6th day (day 14) of bucolome administration, due to which voglibose was discontinued. Hypoglycemia below 70 mg/dL was not observed thereafter, and the general condition of the patient was stable.\n\n\nCONCLUSIONS\nBased on the clinical course and literature review, we believe that hypoglycemia in the present case was due to a drug interaction, caused by inhibition of CYP2C9 by bucolome and competitive inhibition of CYP2C9 by warfarin, which affected the pharmacokinetics of glimepiride. The possibility of hypoglycemia due to drug interactions should be considered by physicians, when bucolome is included to enhance the effect of warfarin, in patients taking glimepiride.",
"affiliations": "Department of Pharmacy, Fukuoka Tokushukai Hospital, 4-5 Sugukita, Kasuga-shi, Fukuoka, 816-0864, Japan. htateishi@csf.ne.jp.;Department of Pharmacy, Fukuoka Tokushukai Hospital, 4-5 Sugukita, Kasuga-shi, Fukuoka, 816-0864, Japan.;Department of Nutrition, Fukuoka Tokushukai Hospital, 4-5 Sugukita, Kasuga-shi, Fukuoka, 816-0864, Japan.;Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan.;Department of Pharmacy, Fukuoka Tokushukai Hospital, 4-5 Sugukita, Kasuga-shi, Fukuoka, 816-0864, Japan.;Department of Pharmacy, Fukuoka Tokushukai Hospital, 4-5 Sugukita, Kasuga-shi, Fukuoka, 816-0864, Japan.",
"authors": "Tateishi|Hiroki|H|http://orcid.org/0000-0003-4813-0392;Miyazu|Daisuke|D|;Kurinami|Miho|M|;Ieiri|Ichiro|I|;Hirakawa|Masaaki|M|;Watanabe|Hiroyuki|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.1186/s40780-021-00221-y",
"fulltext": "\n==== Front\nJ Pharm Health Care Sci\nJ Pharm Health Care Sci\nJournal of Pharmaceutical Health Care and Sciences\n2055-0294\nBioMed Central London\n\n221\n10.1186/s40780-021-00221-y\nCase Report\nHypoglycemia possibly caused by CYP2C9-mediated drug interaction in combination with bucolome: a case report\nhttp://orcid.org/0000-0003-4813-0392\nTateishi Hiroki htateishi@csf.ne.jp\n\n1\nMiyazu Daisuke 1\nKurinami Miho 2\nIeiri Ichiro 3\nHirakawa Masaaki 1\nWatanabe Hiroyuki 1\n1 grid.415151.5 0000 0004 0569 0055 Department of Pharmacy, Fukuoka Tokushukai Hospital, 4-5 Sugukita, Kasuga-shi, Fukuoka, 816-0864 Japan\n2 grid.415151.5 0000 0004 0569 0055 Department of Nutrition, Fukuoka Tokushukai Hospital, 4-5 Sugukita, Kasuga-shi, Fukuoka, 816-0864 Japan\n3 grid.411248.a 0000 0004 0404 8415 Department of Pharmacy, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan\n3 11 2021\n3 11 2021\n2021\n7 3910 7 2021\n23 8 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\nBucolome is a non-steroidal anti-inflammatory drug and uricosuric agent, currently used only in Japan. It is known to induce drug interactions by inhibiting cytochrome P450 (CYP) 2C9. It is often used to enhance the anticoagulant effect of warfarin by utilizing its drug interactions. There are only a few reports on drug interactions of bucolome and the mechanism remain poorly understood.\n\nCase presentation\n\nAn 81-year-old woman with a history of type 2 diabetes mellitus was taking glimepiride 2 mg/day and voglibose 0.6 mg/day. After hospitalization, the patient underwent surgical aortic valve replacement surgery (day 0). Glimepiride and voglibose were resumed on the second postoperative day (day 2), and warfarin was started to prevent thromboembolism. Since the prothrombin time-international normalized ratio on day 9 was low at 1.24, 300 mg/day of bucolome was added to enhance the effect of warfarin. A gradual decrease in blood glucose levels was observed from the day after bucolome administration was initiated. Hypoglycemia in the 56–57 mg/dL range occurred before lunch and dinner on the 6th day (day 14) of bucolome administration, due to which voglibose was discontinued. Hypoglycemia below 70 mg/dL was not observed thereafter, and the general condition of the patient was stable.\n\nConclusions\n\nBased on the clinical course and literature review, we believe that hypoglycemia in the present case was due to a drug interaction, caused by inhibition of CYP2C9 by bucolome and competitive inhibition of CYP2C9 by warfarin, which affected the pharmacokinetics of glimepiride. The possibility of hypoglycemia due to drug interactions should be considered by physicians, when bucolome is included to enhance the effect of warfarin, in patients taking glimepiride.\n\nKeywords\n\nBucolome\nGlimepiride\nHypoglycemia\nDrug–drug interaction\nCYP2C9\nissue-copyright-statement© The Author(s) 2021\n==== Body\npmcBackground\n\nBucolome is a non-steroidal anti-inflammatory drug and uricosuric agent, used in Japan since 1967. It is known to induce drug interactions by inhibiting cytochrome P450 (CYP) 2C9, and is often used to enhance the anticoagulant effect of warfarin by utilizing such drug interactions [1, 2]. There have been a few clinical reports on bucolome other than in combination with warfarin and on drug interactions due to bucolome. However, the underlying molecular mechanism of its drug interactions remains elusive. Glimepiride is a sulfonylurea antidiabetic drug, and drug interactions via CYP2C9 [3, 4]. Here, we report a case of hypoglycemia after the administration of bucolome to a patient taking glimepiride, a drug for diabetes mellitus, wherein hypoglycemia was speculated to be caused by an interaction between the two drugs. Due consideration was given to the privacy of the patient. This being a case report, the Ethical Review Committee of Fukuoka Tokushukai Hospital waived the requirement of approval by an institutional review board.\n\nCase presentation\n\nAn 81-year-old woman with type 2 diabetes and hypertension was on glimepiride 2 mg/day (twice a day, after breakfast and dinner), voglibose 0.6 mg/day (three times a day just before meals), telmisartan 40 mg/day (once a day after breakfast), and amlodipine 5 mg/day (once a day after breakfast). The four drugs were taken with good compliance for more than 6 months. Due to exertional dyspnea, she was admitted to our hospital emergency room. Her HbA1c level at admission was well-controlled at 6.1%. Her condition was diagnosed with aortic stenosis, and an aortic valve replacement was performed on an elective basis (day 0). Postoperatively, her respiratory status was good, and her circulatory dynamics were stable without the use of catecholamines. Meals were started on the evening of the first postoperative day. On the same day, ultra-rapid-acting insulin therapy was started using the sliding scale method, based on the pre-prandial blood glucose level. Glimepiride and voglibose were resumed on the second postoperative day, and warfarin was included to prevent thromboembolism. Warfarin was dose-adjusted using the prothrombin time-international normalized ratio (PT-INR). Since the PT-INR was low (1.24) on postoperative day 9, 300 mg/day of bucolome was started to enhance the effect of warfarin. The medications used post-surgery are shown in Fig. 1, and the changes in laboratory values are shown in Table 1. Fig. 1 Medications administered postoperatively until discharge. Injectable drugs that whose administration was completed by day 1 are omitted\n\nTable 1 Laboratory values of the patient\n\n\t\tPostoperative day\t\n\t\t1\t3\t5\t7\t10\t13\t15\t18\t\nAST\tU/L\t32\t20\t21\t23\t17\t14\t20\t18\t\nALT\tU/L\t8\t7\t10\t13\t12\t10\t13\t13\t\nLDH\tU/L\t358\t277\t248\t285\t271\t223\t241\t203\t\nAlb\tg/dL\t3.8\t3.1\t2.9\t3.0\t3.3\t3.2\t3.4\t3.6\t\nBUN\tmg/dL\t13.1\t19.2\t12.5\t7.9\t8.0\t6.1\t5.7\t10.5\t\nCre\tmg/dL\t0.78\t0.86\t0.58\t0.62\t0.72\t0.68\t0.66\t0.77\t\nAST aspartate transaminase, ALT alanine transaminase, LDH lactate dehydrogenase, Alb albumin, BUN blood urea nitrogen, Cre creatinine\n\nThe PT-INR began to increase after bucolome administration was initiated, and a decrease in blood glucose level was observed from day 2 of bucolome administration. On day 6 of bucolome administration, the patient experienced hypoglycemia in the range of 56–57 mg/dL before lunch and dinner. We suggested the possibility of drug-induced hypoglycemia associated with the administration of bucolome, and asked the physician to reduce the dose of antidiabetic drugs. Voglibose was discontinued the next day and increased blood glucose levels were observed before lunch, dinner, and bedtime. Contrastingly, the blood glucose levels before breakfast remained unchanged at 70–90 mg/dL. The trends in blood glucose levels are shown in Fig. 2. Thereafter, the patient was transferred to another hospital because hypoglycemia below 70 mg/dL was not observed and her general condition was stable (day 19). Information regarding hypoglycemia and PT-INR fluctuation during the initial hospitalization was provided to the transfer hospital by documenting it in a medication notebook. A special diet for patients with diabetes (1600 kcal/day) was provided during hospitalization and the food intake was consistent throughout. Apart from meals, maintenance fluid (20 mL/h, 3.4 kcal/h) was administered through peripheral vessels from postoperative day 1 to postoperative day 15. No significant changes in liver and kidney function or albumin levels were observed. Furthermore, the pharmacist confirmed that there was no drug overdose or intake of supplements. Fig. 2 Clinical course of the patient. Doses of warfarin, glimepiride, voglibose, and bucolome. PT-INR and blood glucose level trends from the postoperative period to the day of discharge.PT-INR: prothrombin time-international normalized ratio\n\nDiscussion\n\nA gradual decrease in blood glucose level of the patient was observed with the administration of bucolome; hypoglycemia occurred on the 6th day of bucolome administration. There are no reports on hypoglycemia as a side effect of Bucolome [5]. We suspected drug-induced hypoglycemia indirectly related to bucolome, because the patient’s food intake was consistent during hospitalization and her general condition remained stable without any postoperative complication such as infections.\n\nGlimepiride acts on pancreatic β-cells to promote insulin secretion, irrespective of the blood sugar levels. The half-life of glimepiride is 3–4 h, but the effect lasts for more than 24 h [6]. The unchanged form of glimepiride is the main pharmacologically active form. It is metabolized by CYP2C9, and the main metabolite has approximately one-third of the pharmacological activity of the unchanged form [6]. It has been reported that in patients taking glimepiride, the dose of glimepiride was significantly lower in the concomitant use group of typical CYP2C9 inhibitors such as metronidazole and fluconazole [3]. In addition, it has been reported that the area under curve of glimepiride was significantly decreased in the concomitant use group of rifampicin, which induces CYP2C9 [4]. From these reports it can be inferred that the concomitant use of drugs which are either CYP2C9 inducers or inhibitors, may cause changes in the blood concentration of glimepiride. Bucolome inhibits the metabolic activity of CYP2C9 and its concomitant use can increase the blood concentration of losartan, a typical substrate of CYP2C9 [1, 7]. These reports suggest that bucolome, a CYP2C9 inhibitor, may increase the blood concentration of glimepiride by inhibiting the metabolism of glimepiride, a substrate of CYP2C9. In the present case, hypoglycemia was observed on the next day after bucolome administration was initiated, and hypoglycemia in the range of 50 mg/dL occurred on the 6th day of bucolome administration. Since the biological half-life of bucolome is approximately 29 h [5], it takes time to reach a steady state. We believe that the inhibitory effect of bucolome on CYP2C9 increases gradually, while the hypoglycemic effect of glimepiride also simultaneously increases. Furthermore, the changes in blood glucose levels after bucolome administration suggest that bucolome can inhibit the metabolism of glimepiride.\n\nHerein, we must also consider the effects of warfarin. Warfarin is a drug that exhibits anticoagulant activity by acting on vitamin K epoxide reductase and inhibiting the production of coagulation factors. Warfarin is a racemic drug, and its S-form is three to five times more pharmacologically active than its R-form [8]. S-warfarin is mainly metabolized by CYP2C9, whereas the R-form is mainly metabolized by CYP3A4 and CYP1A2 [9]. Inhibition of CYP2C9, a metabolic enzyme that greatly influences the effect of warfarin, by bucolome causes an increase in the blood concentration of warfarin [10]. In this case, the PT-INR was high after the administration of bucolome, whereas it was not high when warfarin was administered alone. Interestingly, the blood glucose levels also decreased. It has been reported that the rate of hospitalization or frequency of emergency room visits due to hypoglycemia, was higher in the sulfonylurea and warfarin combination group than in the noncombination group [11]. The mechanism of hypoglycemia here, may be the competition for metabolism by CYP2C9; since sulfonylurea and warfarin are both primarily metabolized by CYP2C9, higher doses of warfarin may limit the rate at which sulfonylurea can be metabolized. This suggests that warfarin may enhance the hypoglycemic effect of glimepiride by inhibiting its metabolism via CYP2C9. It has also been reported that warfarin itself may have a hypoglycemic effect [12]. Since bucolome increases the blood concentration of warfarin [10], warfarin can possibly increase the risk of developing hypoglycemia. Furthermore, it has been reported that glimepiride competitively inhibits warfarin metabolism via CYP2C9 in an in vitro system [13]. Although there is a lack of knowledge on this subject, it is possible that both, glimepiride, a common substrate of CYP2C9, as well as bucolome, may have influenced the PT-INR changes in this case. When multiple CYP2C9 substrates are included in the treatment regimen, such as warfarin and glimepiride, it is necessary to consider the possibility that they may interact with each other.\n\nIn addition to the mechanism of inhibition of CYP2C9, interaction with serum protein via binding and/or substitution should also be considered. Warfarin, bucolome, and glimepiride have a high serum protein-binding capacity and can bind to albumin [8, 14, 15]. Warfarin and bucolome bind to binding site I, and glimepiride to binding sites I and II of albumin [16–18]. Therefore, it is possible that the binding displacement at binding site I may influence the effect of glimepiride. However, because many of the drug interactions due to serum protein-binding displacement are thought to have little effect on the concentration of the free drug in the blood for orally administered drugs [19–21], the drug interactions are unlikely to be the cause of hypoglycemia in this case.\n\nVoglibose and glimepiride have been reported to cause hypoglycemia, among the medications that the patient was taking. Voglibose is an α-glucosidase inhibitor that improves postprandial hyperglycemia. Voglibose hardly migrates into the blood, shows a direct medicinal effect in the intestinal tract, and is excreted in the feces [22]. Based on the pharmacological mechanism, it is unlikely that an α-glucosidase inhibitor alone can induce hypoglycemia. The incidence of hypoglycemia with voglibose alone is lower than that with other antidiabetic drugs [23, 24]. In this case, there were no complications, such as other diseases and infections, and the patient was consuming food without any problems. Although the hypoglycemia improved with the discontinuation of voglibose, it was not considered to be the direct cause of hypoglycemia. On the contrary, discontinuation of voglibose on the day after the onset of hypoglycemia caused an increase in blood glucose levels before lunch, dinner, and bedtime. This may be because voglibose suppressed the absorption of some dietary sugars in the small intestine, but when voglibose administration was discontinued, dietary sugars were absorbed in the small intestine and remained unmetabolized until the time of the next meal. In contrast, the early morning blood glucose level continued to decrease, regardless of voglibose discontinuation. This may be because voglibose has little effect on the early morning blood glucose level, while the effect of glimepiride continues.\n\nBased on the clinical course and literature review, we believe that the hypoglycemia in this case was due to a drug interaction, caused by inhibition of CYP2C9 by bucolome and competitive inhibition of CYP2C9 by warfarin, which affected the pharmacokinetics of glimepiride. Since, the duration from the occurrence of hypoglycemia to discharge was short, there was insufficient time to adjust the dosage of the antidiabetic drug. Although the discontinuation of voglibose prevented the patient from developing hypoglycemia (blood glucose levels below 70 mg/dL), glimepiride dosage should have been reduced or discontinued in consideration of the risk of hypoglycemia in the future. Pharmacists are required to foresee the occurrence of rare drug interactions from a pharmaceutical point of view, as in this case. In other words, it is important to provide information to physicians and nurses on the risk of hypoglycemia caused by the combination of bucolome and glimepiride and instruct patients on how to cope with the occurrence of hypoglycemia, for the safe management of drug therapy.\n\nIn clinical practice in Japan, bucolome is mostly used to enhance the effect of warfarin; therefore, we could not investigate the effect of bucolome alone on glimepiride. In addition, we suspected a drug interaction based only on blood glucose level trends; however, it is necessary to measure the blood concentration of glimepiride for a more accurate investigation. Additionally, genetic polymorphisms of CYP2C9 in the Japanese population, has been reported [25]; however, we were unable to determine the genotype of the patient. Therefore, it is necessary to accumulate similar cases, stratify them according to pharmacokinetics and pharmacodynamics, and analyze each process based on genomic pharmacology, to generate an appropriate design/strategy for drug use and safety information.\n\nIn conclusion, we have reported a case of drug-induced hypoglycemia due to glimepiride, which may have been caused by the concomitant use of bucolome. The possibility of hypoglycemia due to drug interactions should be considered when bucolome is used to enhance the effect of warfarin, in patients taking glimepiride.\n\nAbbreviations\n\nCYP Cytochrome P450\n\nPT-INR Prothrombin time-international normalized ratio\n\nThe authors thank the pharmacists at Fukuoka Tokushukai Hospital, who contributed to this study.\n\nAuthors’ contributions\n\nHT and DM monitored the patient’s blood glucose levels and intervened to change the course of her medication. HT was a major contributor in writing the manuscript. MK calculated the amount of sugar in the patient’s diet. MH, HW, and II revised the manuscript. All authors read and approved the final manuscript.\n\nFunding\n\nNo funding was received.\n\nAvailability of data and materials\n\nThe dataset generated and analyzed in this case report will not be shared due to the risk of identifying the patient.\n\nDeclarations\n\nEthics approval and consent to participate\n\nNot applicable.\n\nConsent for publication\n\nThe patient gave her consent for publication of this report.\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. Takahashi H Kashima T Kimura S Murata N Takaba T Iwade K Abe T Tainaka H Yasumori T Echizen aH Pharmacokinetic interaction between warfarin and a uricosuric agent, Bucolome: application of in vitro approaches to predicting in vivo reduction of (S)-warfarin clearance Drug Metab Dispos 1999 27 10 1179 1186 10497145\n2. Kodani E Atarashi H Inoue H Okumura K Yamashita T Status of Bucolome use and warfarin dose in anticoagulation therapy in patients with atrial fibrillation—a report from the J-RHYTHM registry Jpn J Electrocardiol 2013 33 3 195 208 10.5105/jse.33.195\n3. Tirkkonen T Heikkilä P Huupponen R Laine K Potential CYP2C9-mediated drug–drug interactions in hospitalized type 2 diabetes mellitus patients treated with the sulphonylureas glibenclamide, glimepiride or glipizide J Intern Med 2010 268 4 359 366 10.1111/j.1365-2796.2010.02257.x 20698928\n4. Niemi M Kivistö KT Backman JT Neuvonen PJ Effect of rifampicin on the pharmacokinetics and pharmacodynamics of glimepiride Br J Clin Pharmacol 2000 50 6 591 595 10.1046/j.1365-2125.2000.00295.x 11136298\n5. ASKA Pharmaceutical Co, Ltd., PARAMIDIN. (Bucolome) Pharmaceutical Interview Forms. 2021. https://www.aska-pharma.co.jp/iryouiyaku/news/filedownload.php?name=e9572696fcc133d2733a8ea3381db602.pdf. Accessed 5 Jun 2021.\n6. Sanofi-Aventis. US LLC. Amaryl (glimepiride) Product Monograph. USA. 2009. https://www.accessdata.fda.gov/drugsatfda_docs/label/2009/020496s021lbl.pdf. Accessed 5 Jun 2021.\n7. Kobayashi M Takagi M Fukumoto K Kato R Tanaka K Ueno K The effect of Bucolome, a CYP2C9 inhibitor, on the pharmacokinetics of losartan Drug Metab Pharmacokinet 2008 23 2 115 119 10.2133/dmpk.23.115 18445991\n8. O’Reilly RA Studies on the optical enantiomorphs of warfarin in man Clin Pharmacol Ther 1974 16 2 348 354 10.1002/cpt1974162348 4605176\n9. Kaminsky LS Zhang ZY Human P450 metabolism of warfarin Pharmacol Ther 1997 73 1 67 74 10.1016/S0163-7258(96)00140-4 9014207\n10. Matsumoto K Ishida S Ueno K Hashimoto H Takada M Tanaka K Kamakura S Miyatake K Shibakawa M The stereoselective effects of Bucolome on the pharmacokinetics and pharmacodynamics of racemic warfarin J Clin Pharmacol 2001 41 4 459 464 10.1177/00912700122010186 11304904\n11. Romley JA Gong C Jena AB Goldman DP Williams B Peters A Association between use of warfarin with common sulfonylureas and serious hypoglycemic events: retrospective cohort analysis BMJ. 2015 351 h6223 10.1136/bmj.h6223 26643108\n12. Nam YH Brensinger CM Bilker WB Leonard CE Han X Hennessy S Serious hypoglycemia and use of warfarin in combination with sulfonylureas or metformin Clin Pharmacol Ther 2019 105 1 210 218 10.1002/cpt.1146 29885251\n13. Iwakawa S Miyashita K Hashimoto Y Kuroda T Effect of glimepiride and glibenclamide on S-warfarin 7-hydroxylation by human liver Microsomes. Recombinant human CYP2C9.1 and CYP2C9.3 Biol Pharm Bull 2006 29 9 1983 1985 10.1248/bpb.29.1983 16946524\n14. Chan E McLachlan AJ Pegg M MacKay AD Cole RB Rowland M Disposition of warfarin enantiomers and metabolites in patients during multiple dosing with rac-warfarin Br J Clin Pharmacol 1994 37 6 563 569 10.1111/j.1365-2125.1994.tb04305.x 7917775\n15. Kakemi K Arita T Hashi M Sumii K The binding of 1-cyclohexyl-5-n-butyl-2,4,6-trioxoperhydropyrimidine with serum albumin Yakugaku Zasshi 1966 86 9 739 744 10.1248/yakushi1947.86.9_739 6010912\n16. Kragh-Hansen U Chuang VT Otagiri M Practical aspects of the ligand-binding and enzymatic properties of human serum albumin Biol Pharm Bull 2002 25 6 695 704 10.1248/bpb.25.695 12081132\n17. Takamura N Maruyama T Chosa E Kawai K Tsutsumi Y Uryu Y Yamasaki K Deguchi T Otagiri M Bucolome, a potent binding inhibitor for furosemide, alters the pharmacokinetics and diuretic effect of furosemide: potential for use of Bucolome to restore diuretic response in nephrotic syndrome Drug Metab Dispos 2005 33 4 596 602 10.1124/dmd.104.002782 15640375\n18. Matsuda R Li Z Zheng X Hage DS Analysis of multi-site drug-protein interactions by high-performance affinity chromatography: binding by glimepiride to normal or glycated human serum albumin J Chromatogr A 2015 1408 133 144 10.1016/j.chroma.2015.07.012 26189669\n19. Rolan PE Plasma protein binding displacement interactions--why are they still regarded as clinically important? Br J Clin Pharmacol 1994 37 2 125 128 10.1111/j.1365-2125.1994.tb04251.x 8186058\n20. Smith DA Di L Kerns EH The effect of plasma protein binding on in vivo efficacy: misconceptions in drug discovery Nat Rev Drug Discov 2010 9 12 929 939 10.1038/nrd3287 21119731\n21. Benet LZ Hoener BA Changes in plasma protein binding have little clinical relevance Clin Pharmacol Ther 2002 71 3 115 121 10.1067/mcp.2002.121829 11907485\n22. Hiraga K Pharmacokinetics of AO-128 and its influences on carbohydrate metabolism –a study in healthy volunteers Kiso rinsho 1992 26 283 294\n23. Fujimoto K Shibayama Y Yamaguchi E Honjo S Hamasaki A Hamamoto Y Glucose excursions and hypoglycemia in patients with type 2 diabetes treated with mitiglinide/voglibose versus glimepiride: a randomized cross-over trial J Diabetes 2018 10 8 675 682 10.1111/1753-0407.12658 29493100\n24. Iwamoto Y Kashiwagi A Yamada N Terao S Mimori N Suzuki M Tachibana H Efficacy and safety of vildagliptin and voglibose in Japanese patients with type 2 diabetes: a 12-week, randomized, double-blind, active-controlled study Diabetes Obes Metab 2010 12 8 700 708 10.1111/j.1463-1326.2010.01222.x 20590747\n25. Kirchheiner J Brockmöller J Clinical consequences of cytochrome P450 2C9 polymorphisms Clin Pharmacol Ther 2005 77 1 1 16 10.1016/j.clpt.2004.08.009 15637526\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2055-0294",
"issue": "7(1)",
"journal": "Journal of pharmaceutical health care and sciences",
"keywords": "Bucolome; CYP2C9; Drug–drug interaction; Glimepiride; Hypoglycemia",
"medline_ta": "J Pharm Health Care Sci",
"mesh_terms": null,
"nlm_unique_id": "101672177",
"other_id": null,
"pages": "39",
"pmc": null,
"pmid": "34727989",
"pubdate": "2021-11-03",
"publication_types": "D016428:Journal Article",
"references": "11136298;15640375;26189669;20698928;29885251;29493100;11907485;12081132;15637526;6010912;11304904;9014207;18445991;16946524;26643108;7917775;8186058;20590747;21119731;10497145;4605176",
"title": "Hypoglycemia possibly caused by CYP2C9-mediated drug interaction in combination with bucolome: a case report.",
"title_normalized": "hypoglycemia possibly caused by cyp2c9 mediated drug interaction in combination with bucolome a case report"
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"companynumb": "JP-Accord-245226",
"fulfillexpeditecriteria": "1",
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{
"abstract": "With the increasing use of various medications and supplements nowadays, the incidence of abnormal liver function tests and frank hepatic injury is has been increasing. Medications are now considered one of the most common causes of acute hepatic failure in the United States. Losartan was the first angiotensin 1 (AT1) receptor blocker approved by FDA for the treatment of arterial hypertension. It is a well-tolerated medication with few significant adverse effects. However, losartan-related hepatotoxicity has been reported rarely. We report a case of acute hepatic injury in an adult patient treated with losartan as a monotherapy for arterial hypertension.",
"affiliations": "Department of Internal Medicine, St. Michael's Medical Center, Seton Hall University School of Health and Medical Sciences, South Orange, NJ, USA.;Department of Internal Medicine, St. Michael's Medical Center, Seton Hall University School of Health and Medical Sciences, South Orange, NJ, USA.;Department of Internal Medicine, St. Michael's Medical Center, Seton Hall University School of Health and Medical Sciences, South Orange, NJ, USA.;Department of Internal Medicine, St. Michael's Medical Center, Seton Hall University School of Health and Medical Sciences, South Orange, NJ, USA.;Department of Internal Medicine, St. Michael's Medical Center, Seton Hall University School of Health and Medical Sciences, South Orange, NJ, USA.;Department of Internal Medicine, St. Michael's Medical Center, Seton Hall University School of Health and Medical Sciences, South Orange, NJ, USA.",
"authors": "Al-Halawani|Moh'd Z|MZ|;Thawabi|Mohammad|M|;Asslo|Fady|F|;Shaaban|Hamid|H|;Shamoon|Fayez|F|;Baddoura|Walid J|WJ|",
"chemical_list": null,
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"fulltext": "\n==== Front\nJ Family Med Prim CareJ Family Med Prim CareJFMPCJournal of Family Medicine and Primary Care2249-48632278-7135Medknow Publications & Media Pvt Ltd India JFMPC-3-27210.4103/2249-4863.141635Case ReportLosartan-induced Ischemic Hepatocellular Hepatotoxicity: A Case Report and Literature Review Al-Halawani Moh’d Z. Thawabi Mohammad Asslo Fady Shaaban Hamid Shamoon Fayez Baddoura Walid J. Department of Internal Medicine, St. Michael's Medical Center, Seton Hall University School of Health and Medical Sciences, South Orange, NJ, USAAddress for correspondence: Dr. Hamid Shaaban, Department of Internal Medicine, Saint Michael's Medical Center, 111 Central Avenue, Newark, NJ 07102, USA. E-mail: hamidshaaban@gmail.comJul-Sep 2014 3 3 272 274 Copyright: © Journal of Family Medicine and Primary Care2014This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.With the increasing use of various medications and supplements nowadays, the incidence of abnormal liver function tests and frank hepatic injury is has been increasing. Medications are now considered one of the most common causes of acute hepatic failure in the United States. Losartan was the first angiotensin 1 (AT1) receptor blocker approved by FDA for the treatment of arterial hypertension. It is a well-tolerated medication with few significant adverse effects. However, losartan-related hepatotoxicity has been reported rarely. We report a case of acute hepatic injury in an adult patient treated with losartan as a monotherapy for arterial hypertension.\n\nDrug-induced liver injuryhepatitislosartan\n==== Body\nIntroduction\nLosartan was the first angiotensin 1 (AT1) receptor blocker approved by Food and Drug Administration (FDA) for the treatment of arterial hypertension. It is a well-tolerated medication with few significant adverse effects. However, losartan-related hepatotoxicity has been reported rarely. We report a case of acute hepatic injury in an adult patient treated with losartan as a monotherapy for arterial hypertension.\n\nCase Report\nA 65-year-old Hispanic female with a medical history of hypertension presented with acute abdominal pain associated with nausea and nonbilious emesis of 2 days duration. The pain was not associated with fever, chills, or jaundice. Four months prior to her presentation, she was started on losartan 50 mg monotherapy for her hypertension. She denied taking any other medications or supplements. The patient had no history of tobacco smoking or alcohol intake. On review of systems, the patient denied any episodes of palpitation or light-headedness in the past. Physical examination was remarkable for epigastric and right upper quadrant tenderness. Initial laboratory results revealed elevated liver enzymes, with aspartate aminotransferase 1018 IU/L (Normal 15-41 IU/L), alanine transaminase 1184 IU/L (normal 14-54 IU/L), alkaline phosphatase (ALP) 142 IU/L (Normal 38-126 IU/L), bilirubin total 2.7 mg/dL (normal 0.4-2.0 mg/dL), bilirubin direct 1.3 mg/dL (normal 0.1–0.5 mg/dL), with normal levels of total protein, albumin, and prothrombin time. On further laboratory work-up, the patient had normal serum levels of amylase and lipase, negative viral hepatitis (A, B and C) panel, nondetectable acetaminophen serum level, undetectable antinuclear antibody and anti-smooth muscle antibody titers, and normal white cell and eosinophilic counts.\n\nHepatobiliary iminodiacetic acid/hepatobiliary scan was done and revealed a patent cystic duct; and a magnetic resonance cholangiopancreatography showed normal common bile duct diameter without any filling defects.\n\nThe decision was made to hold losartan on admission as it was the only medication she was exposed to. During her hospital stay, the clinical symptoms and laboratory findings improved rapidly within the first 4 days of hospitalization [Table 1]. The patient underwent liver biopsy on day 8. Of note, liver biopsy revealed normal hepatic tissue without abnormal findings. The patient was discharged home on the 9th day without re-challenge with losartan.\n\nTable 1 Pattern of liver enzymes during the hospital stay\n\nDiscussion\nLosartan was the first AT1 receptor blocker to be approved by FDA in 1995 for the treatment of arterial hypertension, reduction of the stroke risks in patients with hypertension or left ventricular hypertrophy, and treatment of diabetic nephropathy. In addition, losartan has other beneficial effects not seen in other medications of the same class such as uricosurea and attenuation of platelet aggregation.[1] Losartan was initially evaluated for its safety in 4058 patients with no recorded hepatotoxicity. However, postmarketing data reveals that losartan has been associated with occasional elevation of liver enzymes.[2]\n\nDrug related hepatotoxicity is a fairly uncommon problem, as it occurs in one in 10,000-100,000 patients using prescribed medications.[3] However, it is now considered as one of the most common causes of acute liver failure in the United States.[4] The clinical course of drug related hepatic injury can be described as hepatocellular, cholestatic, or mixed depending on the clinical symptoms, laboratory profiles and/or histological findings. A hepatocellular injury is characterized by a disproportionate elevation of aminotransferases when compared to ALP, while in cholestatic injury there is a disproportionate elevation of ALP when compared to aminotransferases. Mixed injury is a combination of both. Liver biopsy has been considered as an important assist in the diagnosis of drug related hepatic injury, however, its role in the diagnosis and causality assessment is unclear.[4]\n\nDifferent host-related, genetic and environmental risk factors play a role in drug related hepatotoxicity. Other risk factors include age, gender, race, tobacco smoke, alcohol intake and co-administration of other medications. However, the effects of these factors vary between different medications, and are not helpful in assessing the likelihood of drug related hepatotoxicity in individual cases.[5]\n\nDiscontinuation of the offending agent, dechallenge, is the first step once the diagnosis of drug related hepatotoxicity is suspected. Improvement can be seen within hours or days after stopping the medication. In minority of patients, acute liver failure may occur, which require emergent liver transplant. Re-challenge with the same medication is discouraged since it may lead to recurrent hepatic injury and possible hepatic failure.\n\nTo the present date, drug-induced hepatic injury in association with angiotensin receptor blockers (ARBs) use was reported in 17 cases; 5 cases with losartan use, 5 cases with irbesartan use, 4 cases with candesartan use and 3 cases with valsartan use. The most common pattern of the liver injury was hepatocellular; however, cholestatic and mixed patterns were also observed. The mechanism of liver injury was not well defined, but mostly resembled an idiosyncratic reaction. Onset of hepatotoxicity was variable, consisting with idiosyncratic reactions and arising as early as 8 days and up to 6 months after therapy initiation with an ARB. Normalization of liver enzymes was seen on average between 2 and 4 months after stopping the medication[67891011] [Table 2].\n\nTable 2 Case reports of angiotensin receptor blockers related hepatotoxicity\n\nIn our case, the patient had a hepatocellular pattern of injury as evident by the marked elevation of aminotransferases, reaching around 50 times the upper normal limit, with disproportionate elevation in bilirubin and ALP, which were minimally elevated making any extra hepatic obstruction unlikely. Hepatocellular injury with this high magnitude of aminotransferases elevation reaching >50 times the upper normal limit is usually seen with ischemic hepatopathy. Other causes of hepatocellular injury with marked aminotransferases elevation such as acute viral hepatitis, acetaminophen toxicity, autoimmune hepatitis, alcoholic hepatitis, Wilson disease, malignant infiltration, biliary obstruction, and sepsis were excluded by patient's presentation and diagnostic investigations. The temporal relationship between the onset of drug intake, the clinical presentation, the rapid clinical recovery and laboratory normalization after losartan discontinuation, with ruling out other causes of acute hepatitis are highly suggestive of a losartan-related liver injury. Applying the Council of International Organizations of Medical Science/Roussel Uclaf Causality Assessment Method scale for causality assessment of drug-induced hepatotoxicity yields >8 points for this reaction falling in the “highly probable” category.[12]\n\nIn summary, losartan and other ARBs are well-tolerated commonly used medications. However, in the presence of an unexplained liver injury, the possibility of drug related hepatotoxicity should be always ruled out in patients treated with losartan or other ARBs despite its rarity. To the best of our knowledge, we are reporting the 6th case of losartan-induced hepatitis and possibly the first report of a losartan-induced ischemic liver injury in the adult population.\n\nSource of Support: Nil.\n\nConflict of Interest: None declared.\n==== Refs\n1 Ripley E Hirsch A Fifteen years of losartan: What have we learned about losartan that can benefit chronic kidney disease patients? Int J Nephrol Renovasc Dis 2010 3 93 8 21694934 \n2 Cozaar prescribing information by Merck and Co., Inc Last revised on October 2013; last accessed on May 2014 Available from:\nhttp://www.merck.com/product/usa/pi_circulars/c/cozaar/cozaar_pi.pdf \n3 Larrey D Epidemiology and individual susceptibility to adverse drug reactions affecting the liver Semin Liver Dis 2002 22 145 55 12016546 \n4 Lee WM Drug-induced hepatotoxicity N Engl J Med 2003 349 474 85 12890847 \n5 Fontana RJ Seeff LB Andrade RJ Björnsson E Day CP Serrano J Standardization of nomenclature and causality assessment in drug-induced liver injury: Summary of a clinical research workshop Hepatology 2010 52 730 42 20564754 \n6 Nygaard B Strandgaard S Marked hepatotoxicity associated with losartan treatment Blood Press 1996 5 190 1 8790930 \n7 Bosch X Losartan-induced hepatotoxicity JAMA 1997 278 1572 9370501 \n8 Tabak F Mert A Ozaras R Biyikli M Ozturk R Ozbay G Losartan-induced hepatic injury J Clin Gastroenterol 2002 34 585 6 11960076 \n9 Andrade RJ Lucena MI Santalla F Hepatic injury associated with losartan Ann Pharmacother 1998 32 1371 9876824 \n10 Hariraj R Stoner E Jader S Preston DM Drug points: Prolonged cholestasis associated with irbesartan BMJ 2000 321 547 10968816 \n11 Andrade RJ Lucena MI Fernández MC Vega JL García-Cortés M Casado M Cholestatic hepatitis related to use of irbesartan: A case report and a literature review of angiotensin II antagonist-associated hepatotoxicity Eur J Gastroenterol Hepatol 2002 14 887 90 12172412 \n12 Danan G Benichou C Causality assessment of adverse reactions to drugs – I.A novel method based on the conclusions of international consensus meetings: Application to drug-induced liver injuries J Clin Epidemiol 1993 46 1323 30 8229110\n\n",
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"keywords": "Drug-induced liver injury; hepatitis; losartan",
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"title": "Losartan-induced Ischemic Hepatocellular Hepatotoxicity: A Case Report and Literature Review.",
"title_normalized": "losartan induced ischemic hepatocellular hepatotoxicity a case report and literature review"
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"abstract": "Two hundred seventy-nine consecutive patients with Stage II osteogenic sarcoma of the appendicular skeleton treated between 1976 and 1986 were studied to identify predictors of long-term survival. Survival was 77% and 73% at 5 and 10 years, respectively, with continuously disease-free survival being 70% and 69%. On univariate analysis, the most significant predictors of survival were the location of the primary lesion, local control of the tumor, and the degree of necrosis in the primary tumor after intravenous neoadjuvant chemotherapy (histologic response). On initial multivariate analysis, similarly, only location and histologic response to chemotherapy predicted disease-free outcome. After statistical control for local recurrence, only histologic response to chemotherapy was retained as an independent predictor, suggesting that in this data set, the location of primary lesion exerted its effect only secondarily through its association with the ability to provide local control. The risk of local recurrence was almost fivefold higher in tumors of the femur than in tumors of other locations (relative risk, 4.6) and, within the femur, was more than threefold higher in the proximal femur than in the distal femur (relative risk, 3.4). None of the other primary tumor or patient characteristics studied yielded independent predictive significance for survival. The rate of failure was almost fivefold as high in those with an incomplete response to chemotherapy compared with those with a complete response to chemotherapy (relative risk, 4.9; 95% confidence interval, 2.2 to 11). Even in those patients with minimal or no necrosis in the primary tumor, ultimately 62% and 54% were disease-free at 5 and 10 years, respectively.",
"affiliations": "Memorial Sloan-Kettering Cancer Center, New York, New York.",
"authors": "Glasser|D B|DB|;Lane|J M|JM|;Huvos|A G|AG|;Marcove|R C|RC|;Rosen|G|G|",
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"title": "Survival, prognosis, and therapeutic response in osteogenic sarcoma. The Memorial Hospital experience.",
"title_normalized": "survival prognosis and therapeutic response in osteogenic sarcoma the memorial hospital experience"
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"abstract": "Radiation thyroiditis resulting from radioactive iodine-131 treatment for Graves’ disease is an uncommon complication. Although a majority of patients are asymptomatic or manifest mild symptoms that can be managed conservatively, published literature describing severe radiation thyroiditis resulting in significant morbidity is lacking. We herein report six patients with severe radiation thyroiditis that resulted in hospitalisation, including an unusual complication of myopericarditis.",
"affiliations": "Department of Endocrinology, Singapore General Hospital, Singapore;Department of Endocrinology, Singapore General Hospital, Singapore;Department of Nuclear Medicine and Molecular Imaging, Singapore General Hospital, Singapore;Department of Endocrinology, Singapore General Hospital, Singapore",
"authors": "Tay|Wei Lin|WL|;Lee|Lynette Mei Yee|LMY|;Tong|Aaron Kian Ti|AKT|;Chng|Chiaw Ling|CL|",
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"title": "Severe radiation thyroiditis after radioactive iodine for treatment of Graves’ disease.",
"title_normalized": "severe radiation thyroiditis after radioactive iodine for treatment of graves disease"
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"abstract": "BACKGROUND\nActivated anaplastic lymphoma kinase (ALK) gene fusions are recurrent events in a small fraction of colorectal cancers (CRCs), although these events have not yet been exploited as in other malignancies.\n\n\nMETHODS\nWe detected ALK protein expression by immunohistochemistry and gene rearrangements by fluorescence in situ hybridisation in the ALKA-372-001 phase I study of the pan-Trk, ROS1, and ALK inhibitor entrectinib. One out of 487 CRCs showed ALK positivity with a peculiar pattern that prompted further characterisation by targeted sequencing using anchored multiplex PCR.\n\n\nRESULTS\nA novel ALK fusion with the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene (CAD-ALK fusion gene) was identified. It resulted from inversion within chromosome 2 and the fusion of exons 1-35 of CAD with exons 20-29 of ALK. After failure of previous standard therapies, treatment of this patient with the ALK inhibitor entrectinib resulted in a durable objective tumour response.\n\n\nCONCLUSIONS\nWe describe the novel CAD-ALK rearrangement as an oncogene and provide the first evidence of its drugability as a new molecular target in CRC.",
"affiliations": "Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.;Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, MI, Italy.;Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.;Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, MI, Italy.;Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.;Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.;Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.;Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.;Ignyta, Inc., 11111 Flintkote Avenue, San Diego, CA 92121, USA.;Ignyta, Inc., 11111 Flintkote Avenue, San Diego, CA 92121, USA.;Ignyta, Inc., 11111 Flintkote Avenue, San Diego, CA 92121, USA.;Ignyta, Inc., 11111 Flintkote Avenue, San Diego, CA 92121, USA.;Ignyta, Inc., 11111 Flintkote Avenue, San Diego, CA 92121, USA.;Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.;Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.;Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.;Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.;Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, MI, Italy.;Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, MI, Italy.;Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, MI, Italy.;Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.;Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy.",
"authors": "Amatu|Alessio|A|;Somaschini|Alessio|A|;Cerea|Giulio|G|;Bosotti|Roberta|R|;Valtorta|Emanuele|E|;Buonandi|Pasquale|P|;Marrapese|Giovanna|G|;Veronese|Silvio|S|;Luo|David|D|;Hornby|Zachary|Z|;Multani|Pratik|P|;Murphy|Danielle|D|;Shoemaker|Robert|R|;Lauricella|Calogero|C|;Giannetta|Laura|L|;Maiolani|Martina|M|;Vanzulli|Angelo|A|;Ardini|Elena|E|;Galvani|Arturo|A|;Isacchi|Antonella|A|;Sartore-Bianchi|Andrea|A|;Siena|Salvatore|S|",
"chemical_list": "D000970:Antineoplastic Agents; D001549:Benzamides; C033626:CAD trifunctional enzyme; D007191:Indazoles; D001221:Aspartate Carbamoyltransferase; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases; D004080:Dihydroorotase; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); C000607349:entrectinib",
"country": "England",
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"fulltext": "\n==== Front\nBr J CancerBr. J. CancerBritish Journal of Cancer0007-09201532-1827Nature Publishing Group bjc201540110.1038/bjc.2015.40126633560Short CommunicationNovel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer Entrectinib in colorectal cancerAmatu Alessio 1Somaschini Alessio 2Cerea Giulio 1Bosotti Roberta 2Valtorta Emanuele 1Buonandi Pasquale 1Marrapese Giovanna 1Veronese Silvio 1Luo David 3Hornby Zachary 3Multani Pratik 3Murphy Danielle 3Shoemaker Robert 3Lauricella Calogero 1Giannetta Laura 1Maiolani Martina 1Vanzulli Angelo 1Ardini Elena 2Galvani Arturo 2Isacchi Antonella 2Sartore-Bianchi Andrea 15Siena Salvatore 145*1 Niguarda Cancer Center, Ospedale Niguarda Ca' Granda, 20162 Milan, Italy2 Business Unit Oncology, Nerviano Medical Sciences Srl, Viale Pasteur 10, 20014 Nerviano, MI, Italy3 Ignyta, Inc., 11111 Flintkote Avenue, San Diego, CA 92121, USA4 Università degli Studi di Milano, 20122 Milan, Italy* E-mail: salvatore.siena@ospedaleniguarda.it5 These authors contributed equally as senior authors.\n\n22 12 2015 03 12 2015 22 12 2015 113 12 1730 1734 17 07 2015 12 10 2015 15 10 2015 Copyright © 2015 Cancer Research UK2015Cancer Research UKThis work is licensed under the Creative Commons Attribution-Non-Commercial-Share Alike 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-sa/4.0/Background:\nActivated anaplastic lymphoma kinase (ALK) gene fusions are recurrent events in a small fraction of colorectal cancers (CRCs), although these events have not yet been exploited as in other malignancies.\n\nMethods:\nWe detected ALK protein expression by immunohistochemistry and gene rearrangements by fluorescence in situ hybridisation in the ALKA-372-001 phase I study of the pan-Trk, ROS1, and ALK inhibitor entrectinib. One out of 487 CRCs showed ALK positivity with a peculiar pattern that prompted further characterisation by targeted sequencing using anchored multiplex PCR.\n\nResults:\nA novel ALK fusion with the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene (CAD-ALK fusion gene) was identified. It resulted from inversion within chromosome 2 and the fusion of exons 1–35 of CAD with exons 20–29 of ALK. After failure of previous standard therapies, treatment of this patient with the ALK inhibitor entrectinib resulted in a durable objective tumour response.\n\nConclusions:\nWe describe the novel CAD-ALK rearrangement as an oncogene and provide the first evidence of its drugability as a new molecular target in CRC.\n\nentrectinibgene fusionscolorectal cancerCAD-ALKALK\n==== Body\nActivated anaplastic lymphoma kinase (ALK) gene fusions, found in haematological and solid malignancies, have been successfully exploited as therapeutic targets in lung and inflammatory myofibroblastic tumours using the ALK kinase inhibitors crizotinib and ceritinib (Grande et al, 2011; Awad and Shaw, 2014). In colorectal cancer (CRC), ALK rearrangements are recurrent events found in 0.4–3% of samples analysed and involve as partner genes EML4, C2orf44, or PRKAR1A (reviewed by Aisner et al (2014)). Although expression of the resulting chimaeric transcripts was shown in some patients by PCR with reverse transcription (RT–PCR) analysis, the final evidence of ALK fusion protein expression in these tumours has been lacking, hampering the exploitation of these observations in the therapeutic setting of CRC.\n\nEntrectinib is a selective pan-TRK, ROS1, and ALK kinase inhibitor with strong preclinical activity in multiple cancer models where these targets are constitutively activated (Ardini et al, 2013; De Braud et al, 2014; Sartore-Bianchi et al, 2015). Entrectinib is currently being developed in phases I–II clinical studies in patients with tumours harbouring NTRK, ROS1, or ALK gene aberrations (De Braud et al, 2014).\n\nScreening of 487 CRC formalin-fixed, paraffin-embedded (FFPE) samples for ALK expression by immunohistochemistry (IHC) within the ALKA-372-001 phase I, first-in-human study of entrectinib identified a sample with high levels of ALK protein expression. This finding was extremely atypical and highly suggestive of a rearrangement event placing the ALK gene, not normally expressed in the colon, under ectopic control of a fusion partner promoter. We then confirmed by fluorescence in situ hybridisation (FISH) that an ALK gene rearrangement was in fact present (Medico et al, 2015). Here we report the molecular and clinical study of this CRC patient, which led to the discovery of a novel ALK rearrangement that was present in the primary tumour, in a thoracic lymph node, and in liver metastases. We also describe the objective response of this patient to entrectinib treatment, providing the first evidence of an ALK gene rearrangement as a clinically relevant therapeutic target in CRC.\n\nMaterials and methods\nWe detected ALK protein expression by IHC using the ALK mouse monoclonal antibody 5A4 (N-Histofine ALK Detection Kit; Nichirei Biosciences Inc., Histo-Line Laboratories s.r.l, Milan, Italy) and gene rearrangements by FISH using the LSI ALK Break Apart FISH Probe Kit (Vysis, Abbott Molecular, Abbott Park, IL, USA) as previously described (Medico et al, 2015).\n\nTo identify the ALK rearrangement partner, we subjected RNA from the primary tumour FFPE clinical samples to next-generation sequencing (NGS) analysis using targeted sequencing technology based on anchored multiplex PCR (Archer AMP; ARCHERDX, Boulder, CO, USA), customised for the detection of rearrangements of selected tyrosine kinases, including ALK, and allowing simultaneous identification of the fusion partner through an unbiased approach that did not require a priori knowledge of the gene fusion event. PCR/Sanger sequencing of the chimaeric transcript using primers spanning the fusion junction region confirmed the rearrangement. Mutations in KRAS and NRAS exons 2, 3, and 4 and BRAF exon 15; HER2 amplification; and ROS1 and NTRK rearrangements were assessed as previously described (Sartore-Bianchi et al, 2015; Siravegna et al, 2015; Valtorta et al, 2015).\n\nThe patient was enrolled in the ALKA-372-001 phase I study (EudraCT Number: 2012-000148-88) and received treatment with entrectinib 400 mg m−2 po qd, which was recently determined to be the recommended phase II dose (RP2D). Objective tumour response was measured by computed tomography (CT) using the Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) (Eisenhauer et al, 2009).\n\nResults\nThe patient was a 53-year-old woman with metastatic CRC (brain, thoracic lymph nodes and liver) who was in disease progression after standard therapies, including surgery (right hemicolectomy), external beam radiation therapy to the CNS and thoracic lymph nodes, and two lines of chemotherapy, both based on oxaliplatin, 5-fluorouracil/leucovorin, and bevacizumab, administered before and after the radiation therapy. The primary tumour resected in March 2012 was a grade 3 adenocarcinoma of the right colon metastatic to the supraclavicular lymph node biopsied in April 2012. At progression in March 2015, the patient gave written informed consent to a biopsy of liver metastases. All samples showed histology of primary CRC and CRC metastases (Figure 1A–C1). High levels of ALK protein were observed by IHC in the primary tumour, thoracic lymph node and liver metastasis (Figure 1A–C2), and the underlying ALK abnormality consisted of an ALK rearrangement as demonstrated by FISH (Figure 1A–C3). Further molecular characterisation showed wild-type KRAS and NRAS exons 2, 3, and 4 and BRAF exon 15, no amplification of HER2, and no ROS1 or NTRK rearrangements. Moreover, we found no amplification of the ALK gene. Further investigation by NGS identified an ALK rearrangement resulting from an inversion within chromosome 2, fusing exons 1–35 of the carbamoyl-phosphate synthetase 2, aspartate transcarbamylase, and dihydroorotase (CAD) gene with exons 20–29 of ALK (C35-A20), and confirmed by PCR/Sanger sequencing (Figure 2A and B).\n\nThese findings prompted us to enrol the patient in the ALKA-372-001 phase I study at the RP2D of 400 mg m−2 po qd of entrectinib, starting in March 2015. The patient presented at baseline with ECOG performance status 0, stable and asymptomatic CNS disease, and progressive liver metastases. The first-response assessment via CT, which was performed in April 2015, 4 weeks after the beginning of treatment, showed a partial response per RECIST v1.1 with a decrease in the sum of the target lesions by 38% (Figure 3). Computed tomography performed 4 weeks later in May 2015 confirmed this response. CNS metastases (brain and cerebellum) were stable. No drug-related adverse events were recorded, and the patient was responding and still under treatment with entrectinib as of July 2015.\n\nDiscussion\nIn CRC, recurrent genetic lesions conferring oncogene addiction are only recently emerging as experimental therapeutic targets. These lesions are presently confined to gene amplifications and mutations, such as HER2 (Siena et al, 2015b), MET (Bardelli et al, 2013), and BRAF (Yaeger et al, 2015). Activating gene rearrangements representing new potential therapeutic opportunities have only recently started to be exploited in the clinic (Ardini et al, 2014). We recently reported the existence of NTRK1 rearrangements as recurrent events in CRC, and we discovered TRKA as a target in CRC by identifying an LMNA-NTRK1 rearrangement, leading to sensitivity to treatment with entrectinib in a patient with CRC refractory to standard therapies (Ardini et al, 2014; Sartore-Bianchi et al, 2015). ALK rearrangements have also been reported in CRC (Aisner et al, 2014), but no data are available regarding the effectiveness of specific ALK therapeutic inhibition in this clinical setting.\n\nWe recently applied IHC as a screening strategy to detect ALK rearrangements in CRC, leading to the identification of a positive sample harbouring an ALK rearrangement, as confirmed by FISH (Medico et al, 2015). Here we report the molecular characterisation of this metastatic CRC, revealing a novel CAD-ALK gene rearrangement, and the successful treatment of this patient with entrectinib.\n\nThe CAD gene encodes a trifunctional protein that is associated with the enzymatic activities of the first three enzymes in the six-step pathway of pyrimidine biosynthesis: carbamoylphosphate synthetase (CPS II), aspartate transcarbamoylase, and dihydroorotase (Grande-García et al, 2013). CAD is expressed in normal colonic tissue, and its expression is increased in inflammatory bowel disease (Richmond et al, 2012). CAD is also detected at medium–high levels in CRC by IHC (Uhlén et al, 2015). The CAD-ALK chimaeric gene encompassed CAD exons 1–35 fused to the canonical exon 20 recombination site that was previously reported for ALK gene fusions (Grande et al, 2011; Awad and Shaw, 2014). The chimaeric protein comprises the carbamoyl phosphate synthetase large-chain oligomerisation domain fused to the entire ALK kinase domain, potentially resulting in constitutive dimerisation causing ALK kinase activation. The chimaeric protein is expected to be sensitive to ATP competitive inhibitors such as entrectinib because it encompasses a drug-binding region identical to the corresponding wild-type ALK kinase. A recent IHC screening effort to detect ALK expression in 172 Korean CRC cases resulted in the identification of a strongly positive rectal adenocarcinoma sample, which was found to harbour a CAD-ALK (C35-A20) rearrangement (Lee et al, 2015). In addition, one of the 50 CRC patients enrolled in a pathway-directed therapeutic trial (NEXT-1) was also found to harbour an EML4-ALK (E21, A20) rearrangement (Lee et al, 2015). These data confirm the existence of ALK rearrangements as rare recurrent events in CRC.\n\nTherapeutic inhibition of EML4-ALK with entrectinib in patients with non-small cell lung cancer has resulted in remarkable objective responses and clinical benefit (Siena et al, 2015a). We provide the first evidence that treatment with an ALK inhibitor is effective in metastatic CRC involving an ALK gene rearrangement. Entrectinib at RP2D rapidly induced tumour shrinkage, achieving an objective response within 4 weeks of commencing treatment, which lasted >4 months and was maintained at the time of the present report (July 2015). Although activated ALK rearrangements are rare events in CRC (Aisner et al, 2014; Medico et al, 2015), a screening strategy based on simple ALK assessment by IHC followed by targeted NGS based on anchored multiplex PCR (Zheng et al, 2014) represents a feasible strategy, which will enhance the identification of patients who can benefit from entrectinib treatment in CRC and other histologies (Siena et al, 2015b). The reason for reporting on a single case is the rarity of gene fusions in CRC; a large series for clinical studies would be possible only if pharmaceutical interest and rationale are triggered by the knowledge of successful uncommon cases such as this and other recently reported translocations (Sartore-Bianchi et al, 2015).\n\nThe innovation of the present report resides in the discovery of the novel CAD-ALK rearranged gene in CRC, whose pharmaceutical blockade with a single agent, entrectinib, led to a clinically meaningful anti-tumour effect. Thus for the first time, we provide the proof of concept that ALK alterations can act as drivers in CRC, building a new step towards personalised therapy in this clinical setting.\n\nWe thank Dr Antonio Maestri for patient referral, Dr Mauro Truini for supervising histology diagnosis and Dr Laura Raddrizzani for molecular analyses. This work was supported by grants from Fondazione Oncologia Niguarda Onlus, grant Terapia Molecolare dei Tumori (AS-B, SS); Associazione Italiana Ricerca Cancro (AIRC), grant 2010–2015 Special Program Molecular Clinical Oncology 5 × 1000 project 9970 (SS); European Union 7th Framework Programme, grant 259015 COLTHERES (SS); and Community Research and Development Information Service (CORDIS), grant 635342 MoTriColor (Molecularly guided trials with specific treatment strategies in patients with advanced newly molecular defined subtypes of colorectal cancer) (SS).\n\nASB is a consultant/advisory member for Amgen, Bayer, and Merck-Serono. SS is a consultant/advisory member for Amgen, Bayer, Eli-Lilly, Merck-Serono, Merus, Novartis, Roche, Sanofi, and Ignyta. DL, ZH, PM, DM, and RS are employees of Ignyta. AS, RB, EA, AG and AI are employees of Nerviano Medical Sciences. The remaining authors declare no conflict of interest.\n\nFigure 1 Histological, immunohistochemical, and fluorescence in situ hybridisation analyses of the primary right colonic tumour, lymph node, and liver metastasis of the case presented. Haematoxylin & eosin, immunohistochemical and FISH images of the primary colon tumour (A 1–3; N.M: normal mucosa, T: tumour), lymph node (B 1–3), and liver metastasis (C 1–3) of the patient presented in this report, showing malignant tumour (A1, B1, C1), ALK protein overexpression (A2, B2, C2) and ALK gene rearrangements (A3, B3, C3, white arrows). Original magnification of images: × 100 for haematoxylin & eosin and immunohistochemical staining, Insert × 400; × 630 for FISH analysis.\n\nFigure 2 Identification of the CAD-ALK gene rearrangement. (A) The upper section shows a schematic representation of the CAD-ALK genomic DNA rearrangement and the resulting transcript. The sequence spanning the rearrangement junction is also shown. Exons are represented by coloured boxes, and introns are represented by lines: CAD in red and ALK in light blue. The lower section shows the functional domains conserved in the chimaeric CAD-ALK protein. (B) Characterisation of the CAD-ALK transcript by PCR. Agarose gel showing amplification with primers for the rearranged CAD-ALK chimaeric transcript, spanning CAD exon 35 to ALK exon 20. The tumour sample was compared with a negative control sample (U138-MG cell line, expressing ALK full length).\n\nFigure 3 Computed tomography (CT) scans showing the objective tumour response to entrectinib. The baseline abdominal CT scan of March 2015 demonstrated liver involvement with the two largest lesions both in hepatic segment VII, measuring 27 and 33 mm in longest diameter, respectively (A, C arrows). At the first-response assessment, in April 2015, 4 weeks after the initiation of treatment, CT showed a RECIST partial response with an overall decrease in the sum of the target lesions of 38%, and lesions in segment VII displaying longest diameters of 15 and 22 mm (B, D arrows).\n==== Refs\nAisner DL, Nguyen TT, Paskulin DD, Le AT, Haney J, Schulte N, Chionh F, Hardingham J, Mariadason J, Tebbutt N, Doebele RC, Weickhardt AJ, Varella-Garcia M (2014 ) ROS1 and ALK fusions in colorectal cancer, with evidence of intratumoral heterogeneity for molecular drivers . Mol Cancer Res \n12 : 111 –118.24296758 \nArdini E, Bosotti R, Borgia AL, De Ponti C, Somaschini A, Cammarota R, Amboldi N, Raddrizzani L, Milani A, Magnaghi P, Ballinari D, Casero D, Gasparri F, Banfi P, Avanzi N, Saccardo MB, Alzani R, Bandiera T, Felder E, Donati D, Pesenti E, Sartore-Bianchi A, Gambacorta M, Pierotti MA, Siena S, Veronese S, Galvani A, Isacchi A (2014 ) The TPM3-NTRK1 rearrangement is a recurring event in colorectal carcinoma and is associated with tumor sensitivity to TRKA kinase inhibition . Mol Oncol \n8 : 1495 –1507.24962792 \nArdini E, Meninchicheri M, Banfi P, Casero D, Giorgini ML, Saccardo MB, Amboldi N, Avanzi N, Orsini P, Isacchi A, Presenti E, Galvani A (2013 ) The ALK inhibitor NMS-E628 also potently inhibits ROS1 and induces tumor regression in ROS-driven models . Proceedings of the 104th Annual Meeting of the American Association for Cancer Research 6–10 April 2013 Washington, DC, Cancer Res \n73 (8 Suppl): Abstract no. 2092 .\nAwad MM, Shaw AT (2014 ) ALK inhibitors in non-small cell lung cancer: crizotinib and beyond . Clin Adv Hematol Oncol \n12 : 429 –439.25322323 \nBardelli A, Corso S, Bertotti A, Hobor S, Valtorta E, Siravegna G, Sartore-Bianchi A, Scala E, Cassingena A, Zecchin D, Apicella M, Migliardi G, Galimi F, Lauricella C, Zanon C, Perera T, Veronese S, Corti G, Amatu A, Gambacorta M, Diaz LA, Sausen M, Velculescu VE, Comoglio P, Trusolino L, Di Nicolantonio F, Giordano S, Siena S (2013 ) Amplification of the MET receptor drives resistance to anti-EGFR therapies in colorectal cancer . 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Mol Cancer Ther \n10 : 569 –579.21474455 \nGrande-García A, Lallous N, Díaz-Tejada C, Ramón-Maiques S (2013 ) Structure, functional characterization, and evolution of the dihydroorotase domain of human CAD . Structure \n22 : 185 –198.24332717 \nLee J, Kim H, Hong J, Wang K, Kim S, Jang J, Kim S, Park J, Lim H, Kang W, Park Y, Lee J, Lee W, Park Y, Huh J, Yun S, Do I-G, Kim S, Balasubramanian S, Stephens P, Ross J, Li G, Hornby Z, Ali S, Miller V, Kim K-M, Ou S-H (2015 ) Detection of novel and potentially actionable anaplastic lymphoma kinase (ALK) rearrangement in colorectal adenocarcinoma by immunohistochemistry screening . 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"medline_ta": "Br J Cancer",
"mesh_terms": "D000077548:Anaplastic Lymphoma Kinase; D000970:Antineoplastic Agents; D001221:Aspartate Carbamoyltransferase; D001549:Benzamides; D002223:Carbamoyl-Phosphate Synthase (Glutamine-Hydrolyzing); D015179:Colorectal Neoplasms; D004080:Dihydroorotase; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007191:Indazoles; D008875:Middle Aged; D020794:Receptor Protein-Tyrosine Kinases",
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"title": "Novel CAD-ALK gene rearrangement is drugable by entrectinib in colorectal cancer.",
"title_normalized": "novel cad alk gene rearrangement is drugable by entrectinib in colorectal cancer"
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"abstract": "Invasive fungal infections (IFIs) are a significant cause of morbidity in solid organ transplant (SOT) recipients. Common causes among them are Aspergillus, Candida, and Cryptococcus. Antifungal prophylaxis has led to decrease in overall incidence of IFI; however, there is very little decline in the incidence of Cryptococcal infections of SOT recipients because effective prophylaxis is not available against this infectious agent. Spectrum of manifestation of Cryptococcal infection varies in immunocompetent and immunocompromised host with subclinical and self-limiting with lungs being the primary site in immunocompetent and central nervous system as the most common site in an immunocompromised host. Other preferred sites are cutaneous, pulmonary, urinary tract (prostate) and the bone. Herein, we describe a young adult renal transplant recipient male diagnosed as a rare case of biopsy proven Cryptococcal infection in transplant kidney manifesting as chronic allograft dysfunction.",
"affiliations": "Department of Internal Medical, Armed Forces Medical College, Pune, Maharashtra, India.;Department of Internal Medical, Armed Forces Medical College, Pune, Maharashtra, India.;Department of Nephrology, Armed Forces Medical College, Pune, Maharashtra, India.;Department of Internal Medical, Armed Forces Medical College, Pune, Maharashtra, India.",
"authors": "Agrawal|C|C|;Sood|V|V|;Kumar|A|A|;Raghavan|V|V|",
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"doi": "10.4103/ijn.IJN_298_16",
"fulltext": "\n==== Front\nIndian J NephrolIndian J NephrolIJNIndian Journal of Nephrology0971-40651998-3662Medknow Publications & Media Pvt Ltd India IJN-27-39210.4103/ijn.IJN_298_16Case ReportCryptococcal Infection in Transplant Kidney Manifesting as Chronic Allograft Dysfunction Agrawal C. Sood V. Kumar A. 1Raghavan V. Department of Internal Medical, Armed Forces Medical College, Pune, Maharashtra, India1 Department of Nephrology, Armed Forces Medical College, Pune, Maharashtra, IndiaAddress for correspondence: Dr. C. Agrawal, Department of Internal Medical, Armed Forces Medical College, Wanowrie, Pune - 411 040, Maharashtra, India. E-mail: chaturbhujagrawal06@rediffmail.comSep-Oct 2017 27 5 392 394 Copyright: © 2017 Indian Journal of Nephrology2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Invasive fungal infections (IFIs) are a significant cause of morbidity in solid organ transplant (SOT) recipients. Common causes among them are Aspergillus, Candida, and Cryptococcus. Antifungal prophylaxis has led to decrease in overall incidence of IFI; however, there is very little decline in the incidence of Cryptococcal infections of SOT recipients because effective prophylaxis is not available against this infectious agent. Spectrum of manifestation of Cryptococcal infection varies in immunocompetent and immunocompromised host with subclinical and self-limiting with lungs being the primary site in immunocompetent and central nervous system as the most common site in an immunocompromised host. Other preferred sites are cutaneous, pulmonary, urinary tract (prostate) and the bone. Herein, we describe a young adult renal transplant recipient male diagnosed as a rare case of biopsy proven Cryptococcal infection in transplant kidney manifesting as chronic allograft dysfunction.\n\nKeywords\nChronic allograft dysfunctionCryptococcosisinvasive fungal infections\n==== Body\nIntroduction\nInvasive fungal infections (IFIs) are a significant complication in solid organ transplant (SOT) recipients.[1]Cryptococcus causes up to 8% of IFIs in SOT recipients and is third in the frequency after Aspergillus and Candida.[23] Improvements in transplantation practices with wider use of antifungal prophylaxis have led to a decrease in the overall incidence of IFI, particularly those due to Candida and Aspergillus species.[45] However, there is minimal trend toward decline in the incidence of Cryptococcosis in SOT recipients as fluconazole prophylaxis is generally not used in the late post transplant period (after 1 year of transplant) when Cryptococcal infections usually occur. The overall incidence of Cryptococcosis in SOT recipients is 2.8% (range, 0.3%–5%), with mortality rates ranging between 33% and 42%.[23456] In an immunocompetent host, Cryptococcal infection is subclinical and self-limiting with lungs being the primary site; however, in an immunocompromised host, central nervous system (CNS) is the most common site for Cryptococcal infections, with other preferred sites being cutaneous, pulmonary, urinary tract (prostate) and the bone. In this communication, we describe a rare case of biopsy proven Cryptococcal infection in transplant kidney manifesting as chronic allograft dysfunction.\n\nCase Report\nA 31-year-old male, a serving soldier of Indian army, a case of end-stage renal disease since January 2010, due to mesangioproliferative glomerulonephritis, underwent renal transplantation on June 9, 2011, with donor being mother, (human leukocyte antigen –3/6 mismatch, cross-match negative, and panel reactive antibody being <10%). Pretransplant course involved 103 sessions of hemodialysis for 14 months before transplant, blood pressure control requiring three antihypertensive drugs, and supportive therapy for mineral bone disease. Immunosuppression protocol involved induction with basiliximab, steroid pulse on day minus 1 and intraoperatively, with maintenance by triple-drug immunosuppression (tacrolimus, mycophenolate mofetil, and prednisolone). Patient had delayed graft function; graft biopsy revealing acute tubular necrosis with no features to suggest acute rejection, requiring antithymocyte globulin therapy and two sessions of hemodialysis with subsequent recovery of renal function with baseline creatinine of 1.4 mg%. He also had new onset diabetes after transplant requiring insulin therapy. He developed Cryptococcal meningitis on February 10, 2014, with cerebrospinal fluid [CSF] analysis showing India ink and Cryptococcal antigen [CRAG] and culture growing Cryptococcus requiring cumulative Amphotericin B dose of 4.75 g, followed by maintenance therapy of fluconazole which was continued till CRAG became negative and cultures became sterile. He was asymptomatic till July 2014 with a baseline creatinine of 1.5 mg/dl and was continued on tacrolimus, azathioprine, and prednisolone. However, month later, patient started to have global continuous headache, which was severe in intensity resulting in disturbed sleep, recurrent vomiting, and poor appetite with decreased urine output. Subsequent evaluation did not reveal any signs of meningeal irritation; however, there was mild graft tenderness. Investigations revealed abnormal hematological profile with deranged renal function, with creatinine ranging from 2.8 to 3.2 mg/dl. Urine analysis revealed numerous pus cells; however, cultures were sterile. Graft ultrasonography did not reveal any perigraft collection. Subsequently, graft biopsy was done to ascertain the cause of graft dysfunction, which showed 15 glomeruli with features suggestive of chronic allograft nephropathy. Also noted were numerous round refractile periodic acid–Schiff (PAS) stain positive bodies, suggestive of yeast form of cryptococci, which were confirmed by Grocott stain [Figure 1]. Patient was again initiated on amphotericin B from September 22, 2014. He received cumulative dose of 9.2 g of amphotericin B along with fluconazole. He was continued on immunosuppressants in the form of sirolimus (Tacrolimus was stopped in view of graft dysfunction), azathioprine and prednisolone, insulin, antihypertensives (metoprolol, amlodipine, and indapamide), and supportive therapy. He showed good response to therapy with improvement in symptoms and creatinine levels settling to 2.4 mg/dl. Patients' clinical condition became much better and he is kept on regular follow-up.\n\nFigure 1 Histopathological examination findings: (a) Photomicrograph (H and E, ×100) renal biopsy showing few sclerosed glomeruli and dense inflammation. (b) Photomicrograph (H and E, ×400) showing numerous, round, refractile fungal yeast form. (c) Photomicrograph (PAS and Grocott, ×400) showing periodic acid–Schiff stain positivity (arrow) and Grocott stain positivity (inset) in the fungal yeast form\n\nDiscussion\nCryptococcus neoformans is encapsulated, basidiomycetous yeast that is present in the environment worldwide and has been isolated from a large variety of natural substrates, especially soil contaminated with pigeon droppings.[7] Cryptococcal disease is the third most common IFI after Candida and Aspergillus, representing 8% of IFI in SOT recipients in transplant-associated infection surveillance network database.[3] Vast majority of cases of cryptococcal disease are considered to be due to reactivation of quiescent or latent infection in immunocompromised state.[8] Indeed, as incidence of C. neoformans infection in human immunodeficiency virus (HIV)- infected patients has declined, organ transplant recipients have become the group of immunocompromised patients at highest risk for cryptococcosis. The trends in the incidence of Cryptococcosis in transplant recipients are less well delineated. Fungemia results from lymphohematogenous dissemination from an overt or subclinical pulmonary focus. Since the organism has a preference to invade the CNS, meningitis or meningoencephalitis is often the first clinical evidence of infection. Cryptococcosis in SOT recipients is typically a late occurring infection; the median time to onset is 16–21 months after transplantation.[39] The time to onset is earlier in liver and lung transplant recipients than in kidney transplant recipients, possibly due to higher intensity immunosuppression in the former subgroup.[3] The most sensitive and specific approach for diagnosis of Cryptococcal infection is microscopic examination of the aspirate in potassium hydroxide or India ink, revealing encapsulated yeast cells.[10] Additional investigations for precise diagnosis and to rule out systemic dissemination require isolation and identification of organism by culture. Sabouraud glucose agar is optimal for isolation of Cryptococcus from sputum, bronchoalveolar lavage, CSF, and urine (preferably after prostatic massage). The latex agglutination and enzyme immunoassay tests for detection of Cryptococcal capsular polysaccharide antigen in serum or CSF are excellent rapid diagnostic tests. Culture for C. neoformans is usually positive in 3–7 days and colonies appear as white to cream- colored with a mucoid consistency. In our case, patient presented with gradually deteriorating renal function, which later was confirmed by biopsy due to chronic allograft nephropathy; however, there were numerous round refractile PAS-positive bodies suggestive of yeast form of cryptococci. This finding is later confirmed by Grocott stain [Figure 1c].\n\nCalcineurin inhibitors do not appear to influence the incidence but may affect the extent of cryptococcal disease,[2] while on the other hand; corticosteroids are associated with an increased risk of Cryptococcosis in all non-HIV infected hosts.[1112] Temperature-dependent inhibition of Cryptococcus by Tacrolimus may prevent CNS infection but allow the growth of the fungus at cooler body sites, such as skin, soft tissue, orosteoarticular involvement. Induction treatment in these patients should include a lipid formulation of Amphotericin B, preferably with flucytosine. Patients with severe pulmonary Cryptococcosis may be treated with fluconazole. Our patient was given amphotericin B for 3 weeks, followed by fluconazole. He responded to this therapy adequately, resulting in resolution and symptomatic improvement. Most cases of relapsed documented previously in literature occur in the 1st year of management, supporting the use of suppressive therapy with fluconazole for 6–12 months.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nReferences\n1 Singh N Paterson DL Aspergillus infections in transplant recipients ClinMicrobiol Rev 2005 18 44 69 \n2 Singh N Forrest G AST Infectious Diseases Community of Practice. Cryptococcosis in solid organ transplant recipients Am J Transplant 2009 9 Suppl 4 S192 8 20070681 \n3 Pappas PG Alexander BD Andes DR Hadley S Kauffman CA Freifeld A Invasive fungal infections among organ transplant recipients: Results of the Transplant-Associated Infection Surveillance Network (TRANSNET) Clin Infect Dis 2010 50 1101 11 20218876 \n4 Fortún J Martín-Davila P Moreno S Barcena R de Vicente E Honrubia A Prevention of invasive fungal infections in liver transplant recipients: The role of prophylaxis with lipid formulations of amphotericin B in high-risk patients J Antimicrob Chemother 2003 52 813 9 14563893 \n5 Singh N Paterson DL Gayowski T Wagener MM Marino IR Preemptive prophylaxis with a lipid preparation of amphotericin B for invasive fungal infections in liver transplant recipients requiring renal replacement therapy Transplantation 2001 71 910 3 11349726 \n6 Singh N Dromer F Perfect JR Lortholary O Cryptococcosis in solid organ transplant recipients: Current state of the science Clin Infect Dis 2008 47 1321 7 18840080 \n7 Soltani M Bayat M Hashemi SJ Zia M Pestechian N Isolation of Cryptococcus neoformans and other opportunistic fungi from pigeon droppings J Res Med Sci 2013 18 56 60 23901339 \n8 Garcia-Hermoso D Janbon G Dromer F Epidemiological evidence for dormant Cryptococcus neoformans infection J Clin Microbiol 1999 37 3204 9 10488178 \n9 Singh N Alexander BD Lortholary O Dromer F Gupta KL John GT Cryptococcus neoformans in organ transplant recipients: Impact of calcineurin-inhibitor agents on mortality J Infect Dis 2007 195 756 64 17262720 \n10 Gupta RK Khan ZU Nampoory MR Mikhail MM Johny KV Cutaneous cryptococcosis in a diabetic renal transplant recipient J Med Microbiol 2004 53 445 9 15096556 \n11 Dromer F Mathoulin-Pélissier S Fontanet A Ronin O Dupont B Lortholary O French Cryptococcosis Study Group. Epidemiology of HIV-associated cryptococcosis in France (1985-2001): Comparison of the pre-and post-HAART eras AIDS 2004 18 555 62 15090810 \n12 Baddley JW Perfect JR Oster RA Larsen RA Pankey GA Henderson H Pulmonary cryptococcosis in patients without HIV infection: Factors associated with disseminated disease Eur J Clin Microbiol Infect Dis 2008 27 937 43 18449582\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0971-4065",
"issue": "27(5)",
"journal": "Indian journal of nephrology",
"keywords": "Chronic allograft dysfunction; Cryptococcosis; invasive fungal infections",
"medline_ta": "Indian J Nephrol",
"mesh_terms": null,
"nlm_unique_id": "8914356",
"other_id": null,
"pages": "392-394",
"pmc": null,
"pmid": "28904437",
"pubdate": "2017",
"publication_types": "D002363:Case Reports",
"references": "23901339;18840080;11349726;15096556;18449582;17262720;14563893;20218876;15653818;20070681;10488178;15090810",
"title": "Cryptococcal Infection in Transplant Kidney Manifesting as Chronic Allograft Dysfunction.",
"title_normalized": "cryptococcal infection in transplant kidney manifesting as chronic allograft dysfunction"
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"abstract": "Individuals with intellectual disability (ID) commonly suffer from comorbid psychiatric and behavioral disorders that are frequently treated by antipsychotic medications. All individuals exposed to first- and second/third- generation antipsychotics are at risk for developing tardive dyskinesia (TD), characterized by abnormal, involuntary movements of the mouth/tongue/jaw, trunk, and extremities. TD can be highly disruptive for affected individuals and their caregivers, causing embarrassment, isolation, behavioral disturbances, and reduced functioning and quality of life. Information on TD incidence in individuals with ID is limited, but 2 small US studies reported TD prevalence rates of 42-45% in inpatients with ID. The safety and efficacy of vesicular monoamine transporter type 2 (VMAT2) inhibitors approved for treatment of TD in adults have been demonstrated in multiple clinical trials, but they excluded individuals with ID. Clinical characteristics and treatment outcomes of 5 adults (aged 28-63 years) with mild-to-severe ID and TD are presented, illustrating TD symptoms before/after treatment. All individuals had multiple comorbid psychiatric, behavioral, and other medical conditions, history of antipsychotic exposure, and abnormal movements affecting the tongue/mouth/jaw (n = 5), upper extremities (n = 5), lower extremities (n = 3), and trunk (n = 2), resulting in diminished ability to speak (n = 2), ambulate (n = 3), and perform activities of daily living (n = 3). Treatment with valbenazine resulted in meaningful improvements in TD symptoms and improved daily functioning, demeanor, and social/caregiver interactions. Given the high likelihood of antipsychotic exposure in the ID population, it is appropriate to screen for TD at every clinical visit through careful monitoring for abnormal movements and questioning the individual/caregiver regarding abnormal movements or TD-related functional impairments (i.e., speaking, swallowing, eating, ambulating, and social functioning). In this study, 5 individuals with ID and TD received once-daily valbenazine and experienced marked improvement in TD symptoms and daily functioning, resulting in increased quality of life for affected individuals and caregivers.",
"affiliations": "Rolling Hills Hospital, Ada, OK, USA.;Oklahoma State University College of Osteopathic Medicine, Tulsa, OK, USA.;University Hospital and Medical Center, Tamarac, FL, USA.",
"authors": "Morton|Robert O|RO|https://orcid.org/0000-0003-0530-927X;Morton|Lucas C|LC|;Fedora|Rissa|R|",
"chemical_list": null,
"country": "United States",
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"doi": "10.1155/2020/8886980",
"fulltext": "\n==== Front\nCase Rep Psychiatry\nCase Rep Psychiatry\nCRIPS\nCase Reports in Psychiatry\n2090-682X 2090-6838 Hindawi \n\n10.1155/2020/8886980\nCase Series\nRecognition and Treatment of Tardive Dyskinesia in Individuals with Intellectual Disability\nhttps://orcid.org/0000-0003-0530-927XMorton Robert O. robert.morton@acadiahealthcare.com\n1\n Morton Lucas C. \n2\n Fedora Rissa \n3\n \n1Rolling Hills Hospital, Ada, OK, USA\n\n2Oklahoma State University College of Osteopathic Medicine, Tulsa, OK, USA\n\n3University Hospital and Medical Center, Tamarac, FL, USA\nAcademic Editor: Toshiya Inada\n\n\n2020 \n11 12 2020 \n2020 88869805 8 2020 18 11 2020 2 12 2020 Copyright © 2020 Robert O. Morton et al.2020This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Individuals with intellectual disability (ID) commonly suffer from comorbid psychiatric and behavioral disorders that are frequently treated by antipsychotic medications. All individuals exposed to first- and second/third- generation antipsychotics are at risk for developing tardive dyskinesia (TD), characterized by abnormal, involuntary movements of the mouth/tongue/jaw, trunk, and extremities. TD can be highly disruptive for affected individuals and their caregivers, causing embarrassment, isolation, behavioral disturbances, and reduced functioning and quality of life. Information on TD incidence in individuals with ID is limited, but 2 small US studies reported TD prevalence rates of 42-45% in inpatients with ID. The safety and efficacy of vesicular monoamine transporter type 2 (VMAT2) inhibitors approved for treatment of TD in adults have been demonstrated in multiple clinical trials, but they excluded individuals with ID. Clinical characteristics and treatment outcomes of 5 adults (aged 28–63 years) with mild-to-severe ID and TD are presented, illustrating TD symptoms before/after treatment. All individuals had multiple comorbid psychiatric, behavioral, and other medical conditions, history of antipsychotic exposure, and abnormal movements affecting the tongue/mouth/jaw (n = 5), upper extremities (n = 5), lower extremities (n = 3), and trunk (n = 2), resulting in diminished ability to speak (n = 2), ambulate (n = 3), and perform activities of daily living (n = 3). Treatment with valbenazine resulted in meaningful improvements in TD symptoms and improved daily functioning, demeanor, and social/caregiver interactions. Given the high likelihood of antipsychotic exposure in the ID population, it is appropriate to screen for TD at every clinical visit through careful monitoring for abnormal movements and questioning the individual/caregiver regarding abnormal movements or TD-related functional impairments (i.e., speaking, swallowing, eating, ambulating, and social functioning). In this study, 5 individuals with ID and TD received once-daily valbenazine and experienced marked improvement in TD symptoms and daily functioning, resulting in increased quality of life for affected individuals and caregivers.\n\nNeurocrine Biosciences, Inc\n==== Body\n1. Introduction\nIntellectual disability (ID) is characterized by significant limitations in cognitive functioning (i.e., learning, reasoning, and problem solving) and adaptive behaviors (i.e., communication, practical skills, and independent living) that originate before the age of 18 years [1]. Depending on the population and level of severity of ID assessed, prevalence estimates have varied from 1-3% [2, 3]. Individuals with ID commonly suffer from comorbid psychiatric disorders such as depression, schizophrenia, and bipolar disorder and present with challenging behaviors such as aggression, self-injury, or inappropriate social conduct. Antipsychotic medications, both first- and second/third- generation, are frequently used in these individuals to manage these psychiatric and behavioral issues [4–8]. In a Canadian population-based study of approximately 51,000 adults with ID, 39% received antipsychotic treatment, which increased to 56% in individuals living in group homes [7]. In a UK cohort of approximately 33,000 adults with ID, 28% were treated with antipsychotics [8].\n\nAll individuals who are exposed to antipsychotics (both first- and second/third- generation) are at risk for developing tardive dyskinesia (TD), a movement disorder characterized by abnormal and involuntary choreoathetoid (irregular, dancelike, and/or slow writhing) movements of the mouth, tongue, jaw, trunk, and extremities [9, 10]. According to The Diagnostic and Statistical Manual of Mental Disorders, 5th Edition (DSM-5), TD typically appears after at least a few months of antipsychotic use and may develop even sooner in older individuals [11]. However, there is no “safe” minimum period, as TD can appear after weeks or even days of antipsychotic exposure [12]. The symptoms of TD are persistent and can range in severity from mild to disabling or even life-threatening [13, 14]. Without proper treatment, remission is unlikely, even when antipsychotic medications are reduced or withdrawn [15, 16].\n\nWhile second-generation antipsychotics were initially thought to be associated with reduced risk of TD, growing evidence indicates that TD risk is significant for both second- and first-generation antipsychotics [17–20]. In a recent meta-analysis, the prevalence of TD among the general population was 30% in those receiving first-generation antipsychotics, 21% in those receiving second-generation antipsychotics, and 7% in first-generation naïve individuals receiving second-generation antipsychotics [17]. There is limited information regarding the incidence or prevalence of TD in individuals with ID, but a recent UK population-based cohort study provided evidence supporting the long-held assumption that people with ID are more susceptible to antipsychotic-induced movement disorders [21], and 2 small US inpatient studies reported TD prevalence rates of 42-45% in individuals with ID [22, 23].\n\nUntil recently, TD treatment options were limited to antipsychotic tinkering, off-label uses of medications (e.g., anticholinergics, which can exacerbate TD), and herbal supplements, all of which have weak or limited evidence of efficacy [24, 25]. In April 2017, a novel vesicular monoamine transporter type 2 (VMAT2) inhibitor, valbenazine, was approved in the US for the treatment of adults with TD. Valbenazine, a valine ester of a highly selective isomer of tetrabenazine ([+]-α-dihydrotetrabenazine), has demonstrated safety and efficacy in double-blind, placebo-controlled clinical trials and is considered (along with deutetrabenazine, a deuterated molecular form of tetrabenazine) the first-line therapy for treatment of TD; however, individuals with ID were excluded from the trials [24, 26–29].\n\nAppropriate recognition and treatment of TD in individuals with ID are essential, as TD symptoms can be highly disruptive for the affected individuals as well as their caregivers, causing embarrassment, isolation, increased behavioral disturbances, and reduction in daily functioning and quality of life. To help improve awareness of the clinical presentation and management of TD in individuals with ID, the current case series describes the clinical characteristics, symptoms, and outcomes of 5 individuals with ID who were diagnosed with TD and treated with once-daily valbenazine.\n\n2. Case Presentations\n2.1. Case 1\nA 63-year-old nonverbal male with moderate ID who lives in a group home had a history of multiple significant comorbid diagnoses, including arthritis, anemia, gastroesophageal reflux disease (GERD), hyperlipidemia, and Parkinson's disease (Table 1). In addition, the patient was diagnosed with major depressive disorder and had been treated for several years with the atypical antipsychotic, quetiapine (300 mg once daily (QD)).\n\nTD symptoms included constant tongue protrusion and intermittent chewing movements of the jaw that led to severe drooling and difficulty swallowing. The patient also had excessive, pronounced eye blinking, bilateral shoulder/hand/finger movements (predominant on the left side at rest), and constant left foot tapping. His abnormal body movements affected his balance and stability such that he could not stand stably without support and required a wheelchair for mobility (Table 2). In addition, his abnormal movements caused difficulty performing activities of daily living (ADLs), such as feeding himself. The duration of these symptoms is unknown. The patient was initiated on valbenazine (40 mg every night at bedtime (QHS) for 1 week, discontinued for 1 week due to lack of insurance, then resumed at 80 mg QHS) in April 2018. No other changes were made to the medication regimen at the time of valbenazine initiation. After 2 months of valbenazine treatment, the patient had no tongue protrusion or chewing movements and was able to close his mouth, which led to decreased drooling and improved swallowing. His eye blinking was less frequent and less pronounced, and he had minimal shoulder/hand/finger movements and no foot tapping. The decrease in abnormal movements led to improved stability and posture such that he could stand and ambulate with a walker (Table 2). Additionally, he was able to feed himself independently and was more interactive with caregivers. The patient remains stable on valbenazine (80 mg QHS) with no changes to his medication regimen and no reported adverse events (Table 1).\n\n2.2. Case 2\nA 63-year-old female with mild ID who lives at home with caregivers had a history of multiple significant comorbid diagnoses, including type 2 diabetes, fibromyalgia, GERD, hyperlipidemia, hypertension, hyperthyroidism, overactive bladder, and neuropathy (Table 1). In addition, the patient was diagnosed with schizoaffective disorder, bipolar type, and had prior long-term exposure to the atypical antipsychotics, olanzapine (20 mg QD) and risperidone (3 mg QD).\n\nTD symptoms were repetitive tongue protrusion, lip smacking, and chewing movements of the mouth/jaw that led to unclear speech and difficulty communicating. The patient also had constant bilateral arm/hand/finger movements which caused instability during ambulation and led to the need for wheelchair assistance (Table 2). Her abnormal movements, especially the tongue protrusions, had caused her to become very self-conscious and isolated. The exact duration of the TD symptoms is unknown, but the patient reported having them for at least 4 years. She was initiated on valbenazine (40 mg QHS for 1 week, then escalated to 80 mg QHS) in June 2017. At the same time that valbenazine was initiated, olanzapine and risperidone were discontinued due to parkinsonism and switched to asenapine (titrated over 2 weeks from 5 mg QD to 10 mg twice-daily (BID)).\n\nWithin 1 week of initiating valbenazine treatment, caregivers noted an improvement in TD symptoms and no adverse events. After 2 months of valbenazine treatment, the patient had minimal tongue protrusion and lip/jaw movement, resulting in clearer speech, and her arm/hand/finger movements were decreased, leading to improved stability during ambulation (Table 2). She no longer needed a wheelchair and needed less assistance for ADLs such as personal hygiene. She was less isolated and able to go to a restaurant for the first time in months and had started participating in family and church activities. The patient remains stable on valbenazine (80 mg QHS) with no changes to her medication regimen and no reported adverse events (Table 1).\n\n2.3. Case 3\nA 28-year-old male with moderate ID who lives in a group home had a history of significant comorbid diagnoses, including autism spectrum disorder (ASD), hypertension, hypothyroidism, and GERD (Table 1). Psychiatric diagnoses included excoriation disorder and schizoaffective disorder, bipolar type. In addition, he was anxious, restless, irritable, easily provoked, and physically aggressive and had begun isolating himself from group activities. The patient's medication history included long-term exposure to quetiapine (200/400/200 mg once daily (QD)).\n\nTD symptoms were intermittent chewing movement of the jaw, constant bilateral hand/arm movements (e.g., opening and closing of hands/fingers; finger tapping), repetitive bilateral foot tapping, and truncal rocking (Table 2). The duration of these symptoms is unknown. He was initiated on valbenazine (40 mg QHS for 1 week, then escalated to 80 mg QHS) in February 2018. Due to persistent psychosis, the patient was also tapered off quetiapine and started on clozapine (titrated over 2 weeks to 300 mg daily).\n\nFour days after starting valbenazine treatment, improvement in abnormal movements was noted. After 2 months of valbenazine treatment, the patient had no abnormal jaw movements, minimal to no arm/hand/finger movements or foot tapping, and no truncal movements (Table 2). Caregivers reported that the improvements in movements seemed to result in less isolating, aggressive, and confrontative behavior. He was also more cooperative, was less resistant to caregiver assistance with ADLs, and had increased participation in group home activities. The patient remains stable on valbenazine (80 mg QHS) with no changes to his medication regimen and no reported adverse events.\n\n2.4. Case 4\nA 61-year-old male with moderate ID who lives in a large group home had a history of multiple significant comorbid diagnoses, including type 2 diabetes, enuresis, hyperlipidemia, hypertension, hypothyroidism, GERD, glaucoma, and tachycardia (Table 1). Psychiatric diagnoses included major depressive disorder, impulse control disorder, obsessive-compulsive disorder, and schizophrenia (paranoid type), for which he had received long-term treatment with multiple typical antipsychotics (chlorpromazine (dose, duration unknown), haloperidol (dose, duration unknown), and thioridazine (dose, duration unknown)) and atypical antipsychotics (clozapine (dose, duration unknown), quetiapine (600 mg QD, duration unknown), and risperidone (25 mg BID, duration unknown)) and was currently receiving treatment with clozapine (50 mg BID and 100 mg QHS).\n\nTD symptoms included intermittent tongue thrusting, chewing motion of the jaw, facial grimacing, and nodding/forward movement of head and neck. In addition, he had frequent eye blinking and constant bilateral hand movement (Table 2). Prior to the onset of his TD symptoms, the patient had been very social and active and was voted “citizen of the year” in his group home, but as his TD symptoms progressed, he had become very agitated, irritable, impatient, and isolated and had stopped participating in group activities. Valbenazine treatment (40 mg QHS for 1 week, then escalated to 80 mg QHS) was initiated in October 2017. No other changes were made to the medication regimen.\n\nTwo weeks after starting treatment with valbenazine, abnormal facial movements had improved, and 1 month after initiation, there was no tongue thrusting or chewing motion, minimal facial grimacing and head/neck movement, and normal eye blinking. By 2 months, there were no abnormal hand movements, and he began integrating back into group activities (Table 2). The patient remains stable on valbenazine (80 mg QHS) with no other medication changes and no reported adverse events.\n\n2.5. Case 5\nA 45-year-old male with mild ID who lives at home with caregivers had a history of significant comorbid diagnoses of hepatitis C, seizures, chronic obstructive pulmonary disease, and paranoid schizophrenia (Table 1). His medication history included prior exposure to the typical antipsychotic, haloperidol (dose, duration unknown), and multiple atypical antipsychotics (aripiprazole, brexpiprazole, olanzapine, quetiapine, risperidone, and ziprasidone (all doses, durations unknown)) and current treatment with clozapine (350 mg daily).\n\nTD symptoms were throughout all body areas, including intermittent lip puckering, jaw movements, facial grimacing, and truncal rocking, as well as constant bilateral shoulder, arm, and hand movement, including piano-playing movements of the fingers (Table 2). His abnormal movements had escalated over the past few months to the point that he had become unable to ambulate and needed wheelchair assistance as well as caregiver assistance with most of his ADLs. In addition, he had become increasingly anxious and hopeless, and had expressed suicidal thoughts. The patient was initiated on valbenazine (40 mg QD for 1 week, then escalated to 80 mg QD) in October 2018. No other changes were made to the medication regimen.\n\nFour days after starting valbenazine treatment, there was a noticeable decrease in abnormal movements, and he was able to ambulate independently with a walker. Two weeks after starting treatment, there were almost no abnormal movements. After 3 weeks of valbenazine, the patient was able to walk independently with a walker, was more independent with his ADLs, and appeared more organized in speech (Table 2). (80 mg QHS) with no changes to other medications and no reported adverse events.\n\n3. Discussion\nThe safety and efficacy of valbenazine, the first approved treatment for TD in adults, have been demonstrated in multiple clinical trials [26, 27, 30, 31]. However, individuals with ID were not included in these trials, as subjects were required to have the capacity to provide informed consent to participate.\n\nThis case series presents the clinical characteristics and treatment outcomes of 5 adults (aged 28–63 years) with mild-to-severe ID and TD. All 5 individuals had multiple comorbid psychiatric, behavioral, and other medical conditions; a history of antipsychotic exposure; and abnormal movements affecting the tongue or jaw (n = 5), face or eyes (n = 3), head (n = 1), upper extremities (n = 5), lower extremities (n = 3), and trunk (n = 2), which resulted in diminished ability to speak (n = 2), ambulate (n = 3), and perform ADLs (n = 3). Once-daily valbenazine resulted in marked improvements in TD symptoms within a few weeks of starting treatment, resulting in improvements in daily functioning, demeanor, and social and caregiver interactions. All 5 individuals remained stable after initiation of valbenazine treatment with no adverse events and no TD-related changes to concomitant medications (antipsychotic medications were changed concurrently with valbenazine initiation in 2 individuals due to Parkinsonism and persistent psychosis). The characteristics and outcomes seen in these cases are illustrative of 80-90 additional ID with TD cases seen in our facility.\n\nChallenges in recognizing TD in individuals with ID include a lack of continuity of care in this population, resulting in incomplete or unreliable medical histories, often with an uncertain history of antipsychotic exposure. Furthermore, a lack of known baseline “characteristic” movements for an individual may lead to the assumption that abnormal movements are part of the underlying ID, rather than recognized as possible TD. Individuals with ID and caregivers may be more accepting of adverse events than nondisabled individuals, while others may not be able to report their movement symptoms due to lack of or limited verbal abilities; caregiver input in these situations is crucial. Finally, routine assessments for abnormal movements may be cursory because of the mistaken belief that second-generation antipsychotics do not cause TD.\n\nGiven the relatively high likelihood of antipsychotic exposure in the ID population, it is appropriate to screen for TD at every clinical visit through careful monitoring for abnormal movements, particularly in the face, mouth, extremities, and trunk. In addition to careful observation, clinicians should ask questions of both the individual (if they are verbal) and caregiver regarding any abnormal movements or TD-related functional impairments, such as speaking, swallowing, eating, ambulating, social functioning, or other daily activities.\n\nThe recent availability of VMAT2 inhibitors has led to increased potential for improved care and quality of life for those affected by TD and a resurgence of interest in improving awareness of TD [32–34]. In this case series, 5 individuals with ID and TD received once-daily valbenazine and experienced marked improvement in their TD symptoms and daily functioning, resulting in increased quality of life for the affected individuals and their caregivers.\n\nAcknowledgments\nNeurocrine Biosciences, Inc, provided paid writing support in the preparation of this manuscript to Prescott Medical Communications Group (Chicago, IL). Writing and editorial support were provided by Jennifer Kaiser, PhD, at Prescott Medical Communications Group with support from Neurocrine. Some of the data within this manuscript have been previously virtually presented at the 18th annual meeting of the American Academy of Developmental Medicine and Dentistry, June 5-7, 2020.\n\nData Availability\nNot applicable. No datasets were generated or analyzed.\n\nConsent\nWritten informed consent was obtained from the patients for publication of this case report.\n\nConflicts of Interest\nDr. Morton has received consulting fees from Neurocrine Biosciences, Inc. Lucas Morton and Rissa Fedora report no competing interests.\n\nTable 1 Summary of ID individuals treated with valbenazine for TD.\n\nCase number (gender, age, and living situation)\tID severity\tSignificant comorbid diagnoses\tMedicationsa\t\nAntipsychotic\tOther\t\nCase 1\n(M, 63 yr, group home)\tModerate cognitive impairment; nonverbal, caregiver-dependent for most ADLs\tPsychiatric: major depressive disorder\nOther: arthritis, anemia, GERD, hyperlipidemia, and Parkinson's disease\tPrior: quetiapine\nCurrent: quetiapine\tPrior: atorvastatin, benztropine, carbidopa-levodopa-entacapone, donepezil, duloxetine, escitalopram, memantine, omeprazole, pregabalin, and tramadol\nCurrent: atorvastatin, benztropine, carbidopa-levodopa, donepezil, duloxetine, escitalopram, memantine, omeprazole, pregabalin, tramadol, and valbenazine\t\n\n\n\t\nCase 2\n(F, 63 yr, lives at home with caregiver)\tMild cognitive impairment; caregiver-dependent for some ADLs\tPsychiatric: schizoaffective disorder (bipolar type)\nOther: diabetes (type 2), fibromyalgia, GERD, hyperlipidemia, hypertension, hypothyroidism, overactive bladder, and neuropathy\tPrior: olanzapine, risperidone\nCurrent: asenapine\tPrior: benztropine, fluoxetine, gabapentin, levothyroxine, memantine, metformin, mirabegron, N-acetylcysteine, pantoprazole, simvastatin, and topiramate\nCurrent: fluoxetine, levothyroxine, memantine, metformin, N-acetylcysteine, oxybutynin, pantoprazole, simvastatin, and valbenazine\t\n\n\n\t\nCase 3\n(M, 28 yr, group home)\tModerate cognitive and physical impairment; caregiver-dependent for mobility and most ADLs\tPsychiatric: excoriation disorder, schizoaffective disorder (bipolar type)\nOther: ASD, hypertension, hypothyroidism, GERD, and seizures\tPrior: quetiapine\nCurrent: clozapine\tPrior: clonazepam, famotidine, lamotrigine, liothyronine, N-acetylcysteine, pindolol, and valproate\nCurrent: famotidine, lacosamide, lamotrigine, levothyroxine, lithium, N-acetylcysteine, pindolol, valbenazine, and valproate\t\n\n\n\t\nCase 4\n(M, 61 yr, group home)\tModerate cognitive impairment; caregiver-dependent for some ADLs\tPsychiatric: depressive disorder, impulse control disorder, OCD, and schizophrenia (paranoid type)\nOther: diabetes (type 2), enuresis, hyperlipidemia, hypertension, hypothyroidism, GERD, glaucoma, and tachycardia\tPrior: chlorpromazine, clozapine, haloperidol, quetiapine, risperidone, and thioridazine\nCurrent: clozapine\tPrior: atorvastatin, bethanechol, escitalopram, famotidine, lisinopril, memantine, N-acetylcysteine, and naltrexone\nCurrent: atorvastatin, doxazosin, escitalopram, famotidine, glycopyrrolate, latanoprost, levothyroxine, memantine, N-acetylcysteine, pindolol, and valbenazine\t\n\n\n\t\nCase 5\n(M, 45 yr, lives at home with caregiver)\tMild cognitive impairment\tPsychiatric: schizophrenia (paranoid type)\nOther: COPD, hepatitis C, and seizures\tPrior: aripiprazole, brexpiprazole, haloperidol, olanzapine, quetiapine, risperidone, and ziprasidone\nCurrent: clozapine\tPrior: benztropine, buspirone, carbamazepine, citalopram, and fluoxetine\nCurrent: duloxetine, gabapentin, and valbenazine\t\n\naRelated to significant comorbid diagnoses. Abbreviations: ADHD, attention-deficit/hyperactivity disorder; ADLs, activities of daily living; ASD, autism spectrum disorder; COPD, chronic obstructive pulmonary disease; F, female; GERD, gastroesophageal reflux disease; ID, intellectual disability; M, male; OCD, obsessive-compulsive disorder; TD, tardive dyskinesia; yr, years.\n\nTable 2 TD symptoms and daily functioning in ID individuals before and after treatment with valbenazine.\n\n\tTD symptoms/TD-related functional impairmenta\t\nBefore valbenazine\tAfter valbenazine (80 mg)\t\nCase 1\n(M, 63 yr)\t(i) Constant tongue protrusion and intermittent chewing movements of jaw; severe drooling and difficulty swallowing\n(ii) Excessive, pronounced eye blinking\n(iii) Bilateral shoulder/hand/finger movement\n(iv) Constant left foot tapping\n(v) Instability during standing and ambulating; wheelchair assistance required, and caregiver assistance needed with some ADLs\t(i) No tongue protrusion or chewing movements of jaw; able to close mouth; reduced drooling and improved swallowing\n(ii) Reduced frequency and less pronounced eye blinking\n(iii) Minimal shoulder/hand/finger movement\n(iv) No foot tapping\n(v) Improved stability during standing and ambulating; able to ambulate with walker, and less caregiver assistance needed with ADLs\t\n\n\n\t\nCase 2\n(F, 63 yr)\t(i) Repetitive tongue thrusting; lip smacking; chewing movements of mouth/jaw; and unclear speech\n(ii) Constant bilateral arm/hand/finger movements\n(iii) Instability during ambulation; some wheelchair assistance required\t(i) Minimal tongue thrusting and lip and mouth/jaw movements; clearer speech\n(ii) Minimal arm/hand/finger movements\n(iii) Improved stability during ambulation; less assistance required for some ADLs\t\n\n\n\t\nCase 3\n(M, 28 yr)\t(i) Intermittent chewing movement of jaw\n(ii) Constant bilateral arm/hand/finger movements\n(iii) Repetitive bilateral foot tapping\n(iv) Truncal rocking\t(i) No jaw movements\n(ii) Minimal to no arm/hand/finger movements\n(iii) Minimal to no foot tapping\n(iv) No truncal rocking\t\n\n\n\t\nCase 4\n(M, 61 yr)\t(i) Intermittent tongue thrusting, chewing motion of jaw, and facial grimacing\n(ii) Intermittent nodding/forward movement of head/neck\n(iii) Frequent eye blinking\n(iv) Constant bilateral hand movement\t(i) No tongue thrusting or chewing motion of jaw, and minimal facial grimacing\n(ii) Minimal head/neck movement\n(iii) Normal eye blinking\n(iv) No hand movement\t\n\n\n\t\nCase 5\n(M, 45 yr)\t(i) Intermittent lip puckering, jaw movements and facial grimacing; unclear speech\n(ii) Constant bilateral shoulder/hand/finger movement\n(iii) Repetitive bilateral foot tapping\n(iv) Truncal rocking\n(v) Instability during ambulation; wheelchair assistance required, and caregiver assistance required for some ADLs\t(i) Very minimal lip/jaw movements and no facial grimacing; clearer speech\n(ii) Minimal shoulder/hand/finger movement\n(iii) Minimal foot tapping\n(iv) Minimal truncal rocking\n(v) Improved stability during ambulation; able to ambulate independently with a cane, and less assistance required for ADLs\t\n\naIn nonverbal or minimally verbal patients, based on caregiver reports and clinician observation during patient visits. Abbreviations: ADLs, activities of daily living; F, female; ID, intellectual disability; M, male; TD, tardive dyskinesia; yr, years.\n==== Refs\n1 Schalock R. L. Borthwick-Duffy S. A. Bradley V. J. Intellectual Disability: Definition, Classification, and Systems of Supports 2010 11th edition Washington DC American Association on Intellectual and Developmental Disabilities \n2 Zablotsky B. Black L. I. Blumberg S. J. Estimated prevalence of children with diagnosed developmental disabilities in the United States 2014-2016 NCHS Data Brief 2017 291 1 8 \n3 Boat T. F. Wu J. T. National Academies of Sciences Engineering, and Medicine Boat T. F. Wu J. T. Prevalence of Intellectual Disabilities. In: Mental Disorders and Disabilities Among Low-Income Children 2015 Washington DC National Academies Press \n4 Cooper S. A. Smiley E. Jackson A. Adults with intellectual disabilities: prevalence, incidence and remission of aggressive behaviour and related factors Journal of Intellectual Disability Research 2009 53 3 217 232 10.1111/j.1365-2788.2008.01127.x 2-s2.0-60749092530 19178617 \n5 Cooper S. A. Smiley E. Morrison J. Williamson A. Allan L. Mental ill-health in adults with intellectual disabilities: prevalence and associated factors The British Journal of Psychiatry 2007 190 1 27 35 10.1192/bjp.bp.106.022483 2-s2.0-33846323584 17197653 \n6 Axmon A. Bjorne P. Nylander L. Ahlstrom G. Psychiatric diagnoses in older people with intellectual disability in comparison with the general population: a register study Epidemiology and Psychiatric Sciences 2018 27 5 479 491 10.1017/S2045796017000051 2-s2.0-85013380391 28228177 \n7 Lunsky Y. Khuu W. Tadrous M. Vigod S. Cobigo V. Gomes T. Antipsychotic use with and without comorbid psychiatric diagnosis among adults with intellectual and developmental disabilities Canadian Journal of Psychiatry 2018 63 6 361 369 10.1177/0706743717727240 2-s2.0-85043334160 28830241 \n8 Sheehan R. Hassiotis A. Walters K. Osborn D. Strydom A. Horsfall L. Mental illness, challenging behaviour, and psychotropic drug prescribing in people with intellectual disability: UK population based cohort study BMJ 2015 p. h4326 10.1136/bmj.h4326 2-s2.0-84947710694 26330451 \n9 Savitt D. Jankovic J. Tardive syndromes Journal of the Neurological Sciences 2018 389 35 42 10.1016/j.jns.2018.02.005 2-s2.0-85042592680 29506749 \n10 Caroff S. N. Ungvari G. S. Cunningham Owens D. G. Historical perspectives on tardive dyskinesia Journal of the Neurological Sciences 2018 389 4 9 10.1016/j.jns.2018.02.015 2-s2.0-85042046084 29454494 \n11 American Psychiatrie Association Diagnostic and Statistical Manual of Mental Disorders 2013 5th Washington, D.C American Psychiatric Association \n12 Frei K. Truong D. D. Fahn S. Jankovic J. Hauser R. A. The nosology of tardive syndromes Journal of the Neurological Sciences 2018 389 10 16 10.1016/j.jns.2018.02.008 2-s2.0-85041740652 29433810 \n13 Ascher-Svanum H. Zhu B. Faries D. Peng X. Kinon B. J. Tohen M. Tardive dyskinesia and the 3-year course of schizophrenia: results from a large, prospective, naturalistic study The Journal of Clinical Psychiatry 2008 69 10 1580 1588 10.4088/JCP.v69n1008 2-s2.0-54949153722 19192441 \n14 Chong S. A. Tay J. A. Subramaniam M. Pek E. Machin D. Mortality rates among patients with schizophrenia and tardive dyskinesia Journal of Clinical Psychopharmacology 2009 29 1 5 8 10.1097/JCP.0b013e3181929f94 2-s2.0-62649152952 19142099 \n15 Zutshi D. Cloud L. J. Factor S. A. Tardive syndromes are rarely reversible after discontinuing dopamine receptor blocking agents: experience from a university-based movement disorder clinic Tremor and Other Hyperkinetic Movements 2020 4 p. 266 10.5334/tohm.199 \n16 Vinuela A. Kang U. J. Reversibility of tardive dyskinesia syndrome Tremor and Other Hyperkinetic Movements 2020 4 p. 282 10.5334/tohm.217 \n17 Carbon M. Hsieh C. H. Kane J. M. Correll C. U. Tardive dyskinesia prevalence in the period of second-generation antipsychotic use: a meta-analysis The Journal of Clinical Psychiatry 2017 78 3 e264 e278 10.4088/JCP.16r10832 2-s2.0-85016946440 28146614 \n18 Caroff S. N. Hurford I. Lybrand J. Campbell E. C. Movement disorders induced by antipsychotic drugs: implications of the CATIE schizophrenia trial Neurologic Clinics 2011 29 1 127 148 10.1016/j.ncl.2010.10.002 2-s2.0-78650251837 21172575 \n19 Peluso M. J. Lewis S. W. Barnes T. R. Jones P. B. Extrapyramidal motor side-effects of first- and second-generation antipsychotic drugs The British Journal of Psychiatry 2012 200 5 387 392 10.1192/bjp.bp.111.101485 2-s2.0-84860584750 22442101 \n20 Woods S. W. Morgenstern H. Saksa J. R. Incidence of tardive dyskinesia with atypical versus conventional antipsychotic medications: a prospective cohort study The Journal of Clinical Psychiatry 2010 71 4 463 474 10.4088/JCP.07m03890yel 2-s2.0-77951072007 20156410 \n21 Sheehan R. Horsfall L. Strydom A. Osborn D. Walters K. Hassiotis A. Movement side effects of antipsychotic drugs in adults with and without intellectual disability: UK population-based cohort study BMJ Open 2017 7 8, article e017406 10.1136/bmjopen-2017-017406 2-s2.0-85027044637 28775195 \n22 Fodstad J. C. Bamburg J. W. Matson J. L. Tardive dyskinesia and intellectual disability: an examination of demographics and topography in adults with dual diagnosis and atypical antipsychotic use Research in Developmental Disabilities 2010 31 3 750 759 10.1016/j.ridd.2010.01.017 2-s2.0-77950691038 20207106 \n23 Matson J. L. Fodstad J. C. Neal D. Dempsey T. Rivet T. T. Risk factors for tardive dyskinesia in adults with intellectual disability, comorbid psychopathology, and long-term psychotropic use Research in Developmental Disabilities 2010 31 1 108 116 10.1016/j.ridd.2009.08.002 2-s2.0-70350707623 19720497 \n24 Bhidayasiri R. Jitkritsadakul O. Friedman J. H. Fahn S. Updating the recommendations for treatment of tardive syndromes: a systematic review of new evidence and practical treatment algorithm Journal of the Neurological Sciences 2018 389 67 75 10.1016/j.jns.2018.02.010 2-s2.0-85041909885 29454493 \n25 Bhidayasiri R. Fahn S. Weiner W. J. Evidence-based guideline: treatment of tardive syndromes: report of the Guideline Development Subcommittee of the American Academy of Neurology Neurology 2013 81 5 463 469 10.1212/WNL.0b013e31829d86b6 2-s2.0-84881305397 23897874 \n26 Hauser R. A. Factor S. A. Marder S. R. KINECT 3: a phase 3 randomized, double-blind, placebo-controlled trial of valbenazine for tardive dyskinesia The American Journal of Psychiatry 2017 174 5 476 484 10.1176/appi.ajp.2017.16091037 2-s2.0-85018390919 28320223 \n27 O'Brien C. F. Jimenez R. Hauser R. A. NBI-98854, a selective monoamine transport inhibitor for the treatment of tardive dyskinesia: a randomized, double-blind, placebo-controlled study Movement Disorders 2015 30 12 1681 1687 10.1002/mds.26330 2-s2.0-84944514959 26346941 \n28 Anderson K. E. Stamler D. Davis M. D. Deutetrabenazine for treatment of involuntary movements in patients with tardive dyskinesia (AIM-TD): a double-blind, randomised, placebo-controlled, phase 3 trial The Lancet Psychiatry 2017 4 8 595 604 10.1016/S2215-0366(17)30236-5 2-s2.0-85021358072 28668671 \n29 Fernandez H. H. Factor S. A. Hauser R. A. Randomized controlled trial of deutetrabenazine for tardive dyskinesia: the ARM-TD study Neurology 2017 88 21 2003 2010 10.1212/WNL.0000000000003960 2-s2.0-85019850856 28446646 \n30 Factor S. A. Remington G. Comella C. L. The effects of valbenazine in participants with tardive Dyskinesia The Journal of Clinical Psychiatry 2017 78 9 1344 1350 10.4088/JCP.17m11777 2-s2.0-85040044118 29141124 \n31 Marder S. R. Singer C. Lindenmayer J.-P. A phase 3, 1-year, open-label Trial of valbenazine in adults with tardive dyskinesia Journal of Clinical Psychopharmacology 2019 39 6 620 627 10.1097/JCP.0000000000001111 31688452 \n32 Hauser R. A. Truong D. Tardive dyskinesia: out of the shadows Journal of the Neurological Sciences 2018 389 1 3 10.1016/j.jns.2018.02.009 2-s2.0-85041950853 29449008 \n33 Meyer J. M. Future directions in tardive dyskinesia research Journal of the Neurological Sciences 2018 389 76 80 10.1016/j.jns.2018.02.004 2-s2.0-85041711038 29433809 \n34 Scorr L. M. Factor S. A. VMAT2 inhibitors for the treatment of tardive dyskinesia Journal of the Neurological Sciences 2018 389 43 47 10.1016/j.jns.2018.02.006 2-s2.0-85041731755 29433808\n\n",
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"journal": "Case reports in psychiatry",
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"references": "20156410;29433808;26330451;29433809;29449008;19720497;29454493;20207106;28668671;29141124;29506749;25374768;22442101;28830241;23897874;31688452;19192441;28320223;19142099;28446646;25493205;28146614;29454494;17197653;29433810;21172575;28228177;26346941;19178617;28775195;29235982",
"title": "Recognition and Treatment of Tardive Dyskinesia in Individuals with Intellectual Disability.",
"title_normalized": "recognition and treatment of tardive dyskinesia in individuals with intellectual disability"
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"abstract": "Acute myeloid leukemia (AML) is a heterogeneous disease often associated with poor prognosis. We previously showed that the localization of KIT-D816V at endolysosomes is critical to activate aberrant Akt signaling and Chlorpromazine (CPZ) perturbs the intracellular localization, leading to cell death in AML cells with KIT-D816V. We report that daily administration of CPZ, prescribed for controlling anxiety disorder in patient with AML harboring KIT-D816V, led to a dramatic reduction in AML cells. In vitro and in vivo experiments showed that CPZ inhibited the growth and survival of the patient-derived AML cells, implying potent efficacy of CPZ in AML with KIT-D816V.",
"affiliations": "Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka.;Department of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka.",
"authors": "Rai|Shinya|S|;Tanaka|Hirokazu|H|;Espinoza|J Luis|JL|;Kumode|Takahiro|T|;Matsumura|Itaru|I|",
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"doi": "10.1016/j.lrr.2021.100256",
"fulltext": "\n==== Front\nLeuk Res Rep\nLeuk Res Rep\nLeukemia Research Reports\n2213-0489\nElsevier\n\nS2213-0489(21)00023-6\n10.1016/j.lrr.2021.100256\n100256\nArticle\nPotent efficacy of chlorpromazine in acute myeloid leukemia harboring KIT-D816V mutation\nRai Shinya Conceptualization;Data curation;Writing – original draft\nTanaka Hirokazu Conceptualization;Data curation;Writing – review & editing htanaka@med.kindai.ac.jp\n⁎\nEspinoza J. Luis Conceptualization;Writing – original draft;Writing – review & editing\nKumode Takahiro\nMatsumura Itaru\nDepartment of Hematology and Rheumatology, Kindai University Faculty of Medicine, Osaka-sayama, Osaka\n⁎ Corresponding author. htanaka@med.kindai.ac.jp\n12 6 2021\n2021\n12 6 2021\n15 10025626 2 2021\n30 4 2021\n11 6 2021\n© 2021 The Authors. Published by Elsevier Ltd.\n2021\n\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/).\nAcute myeloid leukemia (AML) is a heterogeneous disease often associated with poor prognosis. We previously showed that the localization of KIT-D816V at endolysosomes is critical to activate aberrant Akt signaling and Chlorpromazine (CPZ) perturbs the intracellular localization, leading to cell death in AML cells with KIT-D816V. We report that daily administration of CPZ, prescribed for controlling anxiety disorder in patient with AML harboring KIT-D816V, led to a dramatic reduction in AML cells. In vitro and in vivo experiments showed that CPZ inhibited the growth and survival of the patient-derived AML cells, implying potent efficacy of CPZ in AML with KIT-D816V.\n\nKeywords\n\nAcute myeloid leukemia\nKit-d816v\nChlorpromazine\nIntracellular trafficking\nReceptor tyrosine kinase\n==== Body\n1 Introduction\n\nAcute myeloid leukemia (AML) is a heterogeneous disease, and several genes are recurrently mutated in AML, which constitute the base for the new genomic classifications, predictive biomarkers, and new therapeutic targets. Despite the enormous progress achieved in the understandings of the disease, the standard therapy of AML has remained virtually unchanged for the past several decades.\n\nKIT is a receptor tyrosine kinase (RTKs) which is expressed on the surface of hematopoietic stem/progenitor cells. A point mutation in the KIT gene at amino acid 816 (KIT-D816V) is an activating mutation that is found in about 30% of patients in core-binding factor (CBF)–AML [1]. In addition, the same mutation is typical of systemic mastocytosis, a rare disorder characterized by overproduction of mast cells that accumulate in the skin and organs. Although AML-M2 (according to the FAB classification) accompanied by the chromosomal translocation t(8;21)(q22;q22), in the following denoted as RUNX1-RUNX1T1, is classified into a good prognostic group, KIT exon 17 mutation is a poor prognostic factor in AML patients with RUNX1-RUNX1T12.\n\nWild-type (WT)-KIT plays an important role in the proliferation and maintenance of normal cells. Upon ligand binding, WT-KIT is internalized and transferred to early endosomes and after delivering proper signals to downstream molecules, a fraction of WT-KIT is transferred via late endosomes for its degradation in lysosomes. Notably, the intracellular trafficking of KIT-D816V is different and it may persist in intracellular compartments [3], leading to the sustained and aberrant oncogenic KIT signaling in endolysosomes and endoplasmic reticulum, which result in the uncontrolled proliferation of malignant cells [4].\n\nWe recently showed that Chlorpromazine (CPZ), which is a widely used as an antipsychotic drug, interferes with the intracellular localization of KIT-D816V, leading to cell death in AML cells with KIT-D816V in vitro and in vivo[5]. We herein report that daily administration of CPZ, prescribed for controlling anxiety disorder in an AML patient with RUNX1-RUNX1T1 harboring KIT-D816V, led to a dramatic reduction in AML cells.\n\n2 Materials & methods\n\nIn vitro and in vivo experiments were performed as described before [5]. The sample was obtained after written informed consent following institutional guidelines of Kindai University Faculty of Medicine (Authorization Number: 24–017, −018) per Declaration of Helsinki principles. The animal experiment was conducted after getting the approval from the committee of animal experiments in our university (Approval ID 06-13).\n\n3 Results\n\n3.1 Clinical course\n\nA 70-year female with end-stage thyroid cancer was referred to our hospital in 2016 because of the symptoms of weakness. Laboratory tests revealed a Hb level of 7.7 g/dL, a white blood cell count (WBC) of 4200/μl, and a platelet count of 102,000/μL. A bone marrow (BM) aspirate showed increased myeloblasts of 20.2%, which were positive for myeloperoxidase staining. She was eventually diagnosed as having AML with RUNX1-RUNX1T1 harboring the KIT-D816V [1] (Fig. 1a). She had been diagnosed as having follicular thyroid cancer in 2006 and had received total thyroidectomy followed by radioactive iodine remnant ablation therapy. In 2016, thyroid cancer recurred with multiple pulmonary metastases and massive right iliac bone metastases, which gradually progressed thereafter. She was judged as not eligible for any antileukemic therapy due to her poor performance status, and thus only palliative care was offered. Twenty-one days after the diagnosis of AML, she was admitted to our hospital due to a rapid increase of AML blasts (WBC 15,000/μl, AML blasts 83.6%). CPZ was given to her to relieve insomnia refractory to standard sleep drugs and to ameliorate the symptoms of anxiety disorders. The starting dose of CPZ was 50 mg, qd at night, which was further increased up to 75 mg qd, leading to the successful control of the symptoms (Fig. 1b). Although grade 1 somnolence was observed, it was manageable without dose reduction of CPZ. Finally, CPZ did not show any other sign of side effect during the administration period. Fourteen days after starting CPZ, the number of AML blasts decreased drastically in peripheral blood (PB), and the patient was discharged on day 50 after the diagnosis of AML. The patient continued CPZ at 75 mg qd, and AML blasts were kept at a very low level in PB. However, she discontinued CPZ on day 70 after AML diagnosis because her anxiety disorder was resolved at that time. On day 84, she was readmitted to our hospital due to the deterioration of the symptoms caused by thyroid cancer metastasis. Laboratory tests revealed a concomitant recovery of the neutrophil count, however, the number of AML blasts slightly increased, suggesting imminent AML progression. Because of her symptoms of anxiety disorders, we restarted CPZ at the same dose, which again resulted in a reduction of AML blasts. However, she finally died of respiratory failure due to multiple lung metastases of thyroid cancer (Fig. 1b).Fig. 1 The clinical course of an AML patient with KIT-D816V, who received CPZ. (a) Genomic DNA was extracted using a Wizard genomic DNA purification kit (Promega), and human KIT gene was analyzed by Sanger sequencing. The sequence in AML cells with KIT-D816V mutation is shown. (b) Changes in total number of white blood cells (WBC) and AML blasts, the percentage of neutrophils (upper panel), and the levels of hemoglobin (Hb) and platelet (Plt) (lower panel) in the peripheral blood are shown. Relevant time points such as diagnosis, hospitalization and discharge are indicated by arrows. CPZ was performed during the indicated periods. Transfusion of red cell concentrate (RCC) and platelet concentrate (PC) was performed as indicated in clinical practice.\n\nFig 1\n\n3.2 CPZ inhibits the growth/survival of AML cells with KIT-D816V in vitro and in vivo\n\nGiven the remarkable clinical improvement of the AML associated with CPZ administration, we assumed that the drug directly induced anti-leukemic effects in this patient. Therefore, in an attempt to obtain experimental evidence of the putative anti-leukemia effects of CPZ, we performed in vitro and in vivo experiments using AML cells isolated from the patient. At first, we performed annexin V staining using her AML cells after the culture with or without CPZ. As shown in Fig. 2a, CPZ treatment increased apoptotic cells detected as an Annexin V-positive fraction. Furthermore, we found that not only her AML cells but also the human (h)CD34+hCD38− fraction, which contains AML initiating cells, were highly sensitive to CPZ in vitro (Fig. 2b, c). Next, we tested anti-leukemic activities of CPZ in a xenograft mouse model using her AML cells at the same CPZ concentrations utilized in our previous study [5]. For the first few days after transplantation, the CPZ treated mice slept for half a day, and slight weight loss was observed compared to the control mice, however, the side effect of weight loss was transient. The body weight was comparable between the two groups at eight weeks after transplantation (Fig. 2d), and the mice on the CPZ group did not show any sign of sickness prior to being euthanized. In control mice, mean percentage of hCD45+ cells in the BM were 5.16% at eight weeks after transplantation, and these cells harbor KIT-D816V mutation, indicating engraftment of her AML cells. In contrast, CPZ drastically reduced AML cells in the CPZ treated mice (mean percentage of hCD45+ cells; 1.46%, p = 0.031) (Fig. 2e). These results are consistent with the assumption that AML remission observed in this patient was very likely induced by CPZ.Fig. 2 Experimental evidence of the anti-leukemia effects of CPZ in vitro and in vivo. (a) Bone marrow mononuclear cells (BMMNCs) were isolated from the patient. These cells were cultured in the presence of SCF, FL, and TPO with 7.0 μM CPZ (right panel) or without CPZ (left panel) for 72 h, and then apoptotic cells were detected as Annexin V-positive cells by flow cytometry. (b) BMMNCs were cultured in the presence of SCF, FL, and TPO with or without 7.0 μM CPZ for 72 h, and then cell growth was quantified. Relative viable cell numbers after CPZ treatment were calculated using untreated cells as a reference. (c) hCD34+hCD38−AML cells were isolated from BMMNCs of the patient and cultured in the presence of SCF, FL, and TPO with or without 7.0 μM CPZ for 72 h and then cell growth was quantified. The results indicate the standard error of the mean (SEM) from three independent experiments. *p<0.05, Student's t-test. (d) Eight weeks after transplantation, the body weight was compared between the two groups. The results indicate the mean ± SEM from three independent experiments. (e) After transplantation of primary AML cells from the patient, mice were treated with CPZ or normal saline (as a control). Eight weeks after transplantation, the proportion of hCD45+ cells in the BM was assessed by flow cytometry. Figures depict the mean ± SEM of the%hCD45+ cells in each group (n = 3). *p<0.05, Student's t-test.\n\nFig 2\n\n4 Discussion\n\nWe here report a case in which CPZ, given for treating refractory insomnia and anxiety disorder, was effective for her AML with KIT-D816V. Discontinuation of CPZ led to AML relapse. However, CPZ was again effective for relapsed AML, whereas this patient consequently died due to lung metastasis of thyroid cancer.\n\nAML with RUNX1-RUNX1T1 is considered a distinct AML entity that associates with a good prognosis [1]. As for the prognostic impact of KIT mutation, however, controversial results have been reported [2]. Whereas some reports showed that KIT mutation was a poor prognostic factor in CBF–AML, other studies reported that the KIT mutation has no prognostic impact on CBF–AML [1,2]. Recently, the adverse effects of KIT mutation were observed only in AML patients with RUNX1-RUNX1T1 in the large prospective study [2].\n\nThe development of tyrosine kinase inhibitors with clinical utility in AML is an area of active research. Since the imatinib is a KIT inhibitor, it has been tested in AML with or without KIT-D816V. Although it certainly induced partial clinical responses in subsets of AML patients treated within clinical trials, its effects were limited and thus currently, there is no promising KIT inhibitor that can be utilized for AML.\n\nCPZ is a phenothiazine drug that has been utilized for many years to treat several psychiatric disorders. Pharmacologically, CPZ acts as an antagonist on different postsynaptic and presynaptic receptors, including dopamine, serotonin, and histamine 1 receptor, which accounts for its versatility and clinical utility in various disorders [5,6]. In addition, preclinical studies have reported that CPZ has antitumor activities in several cellular systems [5,7,8]. Furthermore, it has been reported that CPZ inhibits clathrin-mediated endocytosis through disruption of clathrin-coated pit formation by a reversible translocation of clathrin and its adapter proteins from the plasma membrane to intracellular vesicles and subsequently induces anti-tumor effects against various cancer cell lines [5,9].\n\nOncogenic KIT-D816V can cause aberrant signals not just from the plasma membrane, but also from intracellular compartments. It accumulates on endolysosomes through clathrin-mediated endocytosis from the cell surface, where it activates aberrant Akt signaling [4]. We recently showed that the localization of KIT-D816V at endolysosomes is critical to activate aberrant Akt signaling, and CPZ perturbs the intracellular localization of KIT-D816V at endolysosomes, thereby exhibiting anti-leukemic activities against AML cells with KIT-D816V [5]. Importantly, in vitro and in vivo experiments showed that CPZ effectively inhibited the growth and survival of her AML cells. There are some reports in which spontaneous remission of AML has been observed, particularly during the course of severe infection or after blood transfusion have been reported [10], they are extremely rare cases and may be in association with the emergence of a powerful immune response in the host that eradicates AML cells.\n\nIn conclusion, we have presented a case where CPZ was effective for AML with KIT-D816V. In vitro and in vivo studies showed that CPZ effectively inhibited the growth and survival of her AML cells. These results support the potent efficacy of CPZ in AML with KIT-D816V. We believe that testing the efficacy of CPZ in clinical trials with a large number of patients is warranted.\n\nCRediT authorship contribution statement\n\nShinya Rai: . Hirokazu Tanaka: . J. Luis Espinoza: . Takahiro Kumode: Data curtion. Itaru Matsumura: Writing – review & editing.\n\nDeclaration of Competing Interest\n\nItaru Matsumura Honoraria: Astellas, Novartis, Shionogi Pharmaceuticals No other potential conflicts of interest were reported.\n==== Refs\nReferences\n\n1 Swerdlow S.H. Campo E. Pileri S.A. The 2016 revision of the World Health Organization classification of lymphoid neoplasms Blood 127 20 2016 2375 2390 26980727\n2 Ishikawa Y. Kawashima N. Atsuta Y. Prospective evaluation of prognostic impact of KIT mutations on acute myeloid leukemia with RUNX1-RUNX1T1 and CBFB-MYH11 Blood Adv. 4 1 2020 66 75 31899799\n3 Choudhary C. Olsen J.V. Brandts C. Mislocalized activation of oncogenic RTKs switches downstream signaling outcomes Mol. Cell. 36 2 2009 326 339 19854140\n4 Obata Y. Toyoshima S. Wakamatsu E. Oncogenic Kit signals on endolysosomes and endoplasmic reticulum are essential for neoplastic mast cell proliferation Nat. Commun. 5 2014 5715 25493654\n5 Rai S. Tanaka H. Suzuki M. Chlorpromazine eliminates acute myeloid leukemia cells by perturbing subcellular localization of FLT3-ITD and KIT-D816V Nat. Commun. 11 1 2020 4147 32811837\n6 Seeman P. An update of fast-off dopamine D2 atypical antipsychotics Am. J. Psychiatry 162 10 2005 1984 1985\n7 Shin S.Y. Lee K.S. Choi Y.K. The antipsychotic agent chlorpromazine induces autophagic cell death by inhibiting the Akt/mTOR pathway in human U-87MG glioma cells Carcinogenesis 34 9 2013 2080 2089 23689352\n8 Lee W.Y. Lee W.T. Cheng C.H. Repositioning antipsychotic chlorpromazine for treating colorectal cancer by inhibiting sirtuin 1 Oncotarget 6 29 2015 27580 27595 26363315\n9 Vercauteren D. Vandenbroucke R.E. Jones A.T. The use of inhibitors to study endocytic pathways of gene carriers: optimization and pitfalls Mol. Ther. 18 3 2010 561 569 20010917\n10 Hoshino T. Taki T. Takada S. Hatsumi N. Sakura T. Spontaneous remission of adult acute myeloid leukemia with t(8;16)(p11;p13)/MOZ-CBP fusion Leuk. Lymphoma 59 1 2018 253 255 28535725\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2213-0489",
"issue": "15()",
"journal": "Leukemia research reports",
"keywords": "Acute myeloid leukemia; Chlorpromazine; Intracellular trafficking; Kit-d816v; Receptor tyrosine kinase",
"medline_ta": "Leuk Res Rep",
"mesh_terms": null,
"nlm_unique_id": "101608906",
"other_id": null,
"pages": "100256",
"pmc": null,
"pmid": "34194969",
"pubdate": "2021",
"publication_types": "D002363:Case Reports",
"references": "26363315;23689352;20010917;16199855;28535725;25493654;26980727;19854140;32811837;31899799",
"title": "Potent efficacy of chlorpromazine in acute myeloid leukemia harboring KIT-D816V mutation.",
"title_normalized": "potent efficacy of chlorpromazine in acute myeloid leukemia harboring kit d816v mutation"
} | [
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"companynumb": "JP-SUN PHARMACEUTICAL INDUSTRIES LTD-2022R1-325808",
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"activesubstancename": "CHLORPROMAZINE"
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{
"abstract": "Oral bisphosphonates are widely used drugs for the treatment of various indications such as postmenopausal osteoporosis. Ulcerations of the upper gastrointestinal tract, predominantly reported for alendronate, are common side effects. The occurrence of ulcerations within the oral cavity is less well known and probably underreported. Especially in cases of incorrect mode of intake, oral bisphosphonates are prone to induce oral ulcerations by as yet incompletely delineated mechanisms. We herein report on 2 elderly female patients suffering from oral ulcerations, which could be attributed to inadequate ingestion of alendronate. Possible ways to cause damage to the oral mucosa include non-specific toxic and pro-apoptotic effects, partly via bisphosphonate-mediated interference with intracellular signalling such as the mevalonate downstream pathway. Adequate patient advice in terms of correct use of oral bisphosphonates is crucial in order to prevent mucosal damage. Otherwise, prompt treatment cessation or a switch to an intravenously administered bisphosphonate is likely to achieve complete healing.",
"affiliations": "Department of Dermatology, Venereology and Allergology, University Hospital Wx00FC;rzburg, Wx00FC;rzburg, Germany.",
"authors": "Lengfeld|Julia|J|;Buder-Bakhaya|Kristina|K|;Goebeler|Matthias|M|;Wobser|Marion|M|",
"chemical_list": "D050071:Bone Density Conservation Agents; D019386:Alendronate",
"country": "Switzerland",
"delete": false,
"doi": "10.1159/000439347",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1018-8665",
"issue": "232(1)",
"journal": "Dermatology (Basel, Switzerland)",
"keywords": null,
"medline_ta": "Dermatology",
"mesh_terms": "D000368:Aged; D019386:Alendronate; D050071:Bone Density Conservation Agents; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D019226:Oral Ulcer; D015663:Osteoporosis, Postmenopausal",
"nlm_unique_id": "9203244",
"other_id": null,
"pages": "117-21",
"pmc": null,
"pmid": "26458129",
"pubdate": "2016",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Bisphosphonate-Mediated Oral Ulcers: A Rare Differential Diagnosis of Erosive Oral Lesions.",
"title_normalized": "bisphosphonate mediated oral ulcers a rare differential diagnosis of erosive oral lesions"
} | [
{
"companynumb": "DE-ACTAVIS-2015-28248",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
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"actiondrug": "1",
"activesubstance": {
"activesubstancename": "ALENDRONIC ACID"
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... |
{
"abstract": "We discuss the clinical and imaging perspective in a case of a 78-year-old male who developed slurring of speech and ataxia acute in onset for the last 3 days. During his hospital stay, he developed multiple episodes of focal seizures without secondary generalization involving the angle of mouth on the right side. The patient had ataxia and positive cerebellar signs. In the past, the patient was treated for amoebic liver abscess and had undergone percutaneous aspiration of abscess. The patient was prescribed oral metronidazole and was discharged. This time, the patient underwent magnetic resonance imaging examination, which revealed lesion highly suggestive of metronidazole-induced encephalopathy. The offending drug was discontinued immediately after which the patient improved clinically. A follow-up scan was performed after 12 days and showed complete resolution of lesions.",
"affiliations": "Department of Medicine, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India.",
"authors": "Iqbal|Asif|A|;Tripathi|Kamlakar|K|;Rai|Madhukar|M|;Dwivedi|Amit Nandan Dhar|AN|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/0972-2327.120472",
"fulltext": "\n==== Front\nAnn Indian Acad NeurolAnn Indian Acad NeurolAIANAnnals of Indian Academy of Neurology0972-23271998-3549Medknow Publications & Media Pvt Ltd India AIAN-16-56910.4103/0972-2327.120472Case ReportClinical and imaging perspective and unanswered questions in a case of metronidazole induced encephalopathy Iqbal Asif Tripathi Kamlakar Rai Madhukar Dwivedi Amit Nandan Dhar 1Department of Medicine, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, India1 Department of Radiodiagnosis and Imaging, Institute of Medical Sciences, BHU, Varanasi, Uttar Pradesh, IndiaFor correspondence: Dr. Amit Nandan Dhar Dwivedi, Department of Radiodiagnosis and Imaging, Institute of Medical Sciences, BHU, Varanasi - 221 005, Uttar Pradesh, India. E-mail: amitnandan21@yahoo.comOct-Dec 2013 16 4 569 571 03 9 2012 04 11 2012 Copyright: © Annals of Indian Academy of Neurology2013This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.We discuss the clinical and imaging perspective in a case of a 78-year-old male who developed slurring of speech and ataxia acute in onset for the last 3 days. During his hospital stay, he developed multiple episodes of focal seizures without secondary generalization involving the angle of mouth on the right side. The patient had ataxia and positive cerebellar signs. In the past, the patient was treated for amoebic liver abscess and had undergone percutaneous aspiration of abscess. The patient was prescribed oral metronidazole and was discharged. This time, the patient underwent magnetic resonance imaging examination, which revealed lesion highly suggestive of metronidazole-induced encephalopathy. The offending drug was discontinued immediately after which the patient improved clinically. A follow-up scan was performed after 12 days and showed complete resolution of lesions.\n\nKey Words\nDiffusion-weighted imagingfluid-attenuated inversion-recoverymetronidazole-induced encephalopathymagnetic resonance imaging\n==== Body\nIntroduction\nMetronidazole is a common antimicrobial agent used in the treatment of anaerobic and protozoal infections. The common adverse drug reactions to metronidazole include nausea, vomiting, epigastric pain, metallic taste, diarrhea and rash. In very rare instances, the drug is implicated in serious neurologic side-effects, including peripheral neuropathy, ataxia, dysarthria, seizures and encephalopathy.[1] Brain lesions of patients clinically diagnosed to have metronidazole-induced encephalopathy (MIE) were typically located at the cerebellar dentate nucleus, midbrain, dorsal pons, medulla and splenium of the corpus callosum.[2] We present a case of a 78-year-old male who was prescribed metronidazole at a dose of 800 mg three times daily for 6 weeks. The patient eventually developed neurologic manifestations compatible with encephalopathy. The magnetic resonance imaging (MRI) findings were highly suggestive of MIE. Upon discontinuation of metronidazole, the patient showed clinical improvement. A follow-up MRI as early as 12 days showed resolution of the lesions.\n\nCase Report\nWe discuss the case of a 78-year-old male who developed slurring of speech and ataxia acute in onset for the last 3 days. During the hospital stay, he developed multiple episodes of focal seizures without secondary generalization involving the angle of mouth on the right side. The patient complained of headache not associated with vertigo, tinnitus or visual complaints. There was no recent history of toxin exposure or trauma. Five weeks prior to admission, the patient was admitted for amoebic liver abscess. He underwent percutaneous aspiration of abscess. The patient was prescribed oral metronidazole 800 mg thrice daily for 6 weeks and was discharged. At the time of admission, he had taken the drug for 5 weeks (35 days). On examination, the patient was well oriented. Sensory motor and cranial nerve examination were unremarkable. The patient had cerebellar signs in the form of ataxia dysdiadochokinesia and impaired co-ordination in both the upper and the lower limbs. Reflexes were within normal limits. The patient underwent MRI examination, which revealed symmetrical areas of altered signal intensity, appearing hyperintense on T2-weighted and fluid-attenuated inversion-recovery (FLAIR) images involving the dentate nuclei, dorsal pons and midbrain [Figures 1 and 2]. Diffusion-weighted/apparent diffusion coefficient (ADC) mapping was suggestive of T2 shine through due to cytotoxic edema rather than restricted diffusion [Figures 3 and 4]. Given the history of metronidazole and characteristic distribution of lesions on MRI, the patient was diagnosed as a case of MIE. The offending drug was discontinued immediately, after which the patient improved clinically. A follow-up scan was performed after 12 days, which showed complete resolution of the lesions [Figures 5 and 6].\n\nFigure 1 Axial fluid-attenuated inversion-recovery image shows hyperintense signal in characteristic bilateral dentate nuclei\n\nFigure 2 Axial fluid-attenuated inversion-recovery image shows hyperintense signal in bilateral vermis and tonsillar region\n\nFigure 3 Corresponding diffusion weighted imaging shows hyperintense signal in dentate nuclei\n\nFigure 4 Diffusion weighted imaging showing hyperintense signal in vemis and tonsillar region\n\nFigure 5 Follow-up scanning after 12 days at same level shows complete resolution of lesions\n\nFigure 6 Follow-up scanning after 12 days at level of tonsils shows complete resolution of lesions\n\nDiscussion\nThe mechanism of metronidazole toxicity has not been elucidated. The signal intensity changes observed on the diffusion-weighted images most likely represent interstitial edema. Ahmed et al.[3] speculated that, because of the reversibility of the MRI changes, the cause of the changes associated with acute toxic insult were most likely due to “axonal swelling with increased water content” And not demyelination. Proposed mechanisms include binding of metronidazole to RNA, DNA and inhibitory neurotransmitters, as well as inducing both vasogenic and cytotoxic edema.[4] The typical locations of lesions by MRI in patients with MIE are the cerebellar dentate nuclei, midbrain (tectum, red nucleus, tegmentum around periaqueductal gray matter), dorsal pons, dorsal medulla and corpus callosum (splenium). These were always bilateral and symmetric. FLAIR and diffusion weighted imaging (DWI) was performed in our patient, and demonstrated increased signal intensity on T2 and FLAIR sequences and isotropic DW images. ADC maps demonstrated an increase in the ADCs corresponding to the areas of abnormal DW image signal intensity, suggestive of T2 shine through. Follow-up MRI performed after 12 days showed absence of identifiable signal intensity abnormality on the DW images and normalization of the ADC values. The quantitative ADC maps confirm that the observed high DWI signal intensity is due to vasogenic edema with associated increased ADC values, not restricted diffusion, which would suggest an ischemic process.[5] Ahmed et al.[3] first described the imaging findings of metronidazole toxicity in a 45-year-old woman who developed nausea, vomiting, vertigo, dysarthria and confusion after consuming 35 g metronidazole over a 30-day course of therapy. Horlen et al.[6] reported imaging findings of presumed metronidazole toxicity in a 35-year-old male patient with liver cirrhosis who had consumed greater than 60 g metronidazole over a 55-day period and developed clinical symptoms consistent with metronidazole toxicity. Our patient consumed 84 g metronidazole over a period of 35 days. In each of the cases, including ours, the symptoms rapidly normalized following cessation of metronidazole therapy. The rapidity with which the signal intensity abnormality resolves remains to be elucidated. To the best of our knowledge, earliest follow-up MRI was obtained after 12 days in our case. The duration of treatment with metronidazole before cerebellar symptoms manifest is variable, ranging from 28 days to 3 months,[12] and cumulative doses range from 25 g to 90 g.[12] In our patient, the symptoms developed at a dose of 84 g. Patients usually experience complete resolution of the symptoms after discontinuation of metronidazole, sometimes within a few days. Our patient's symptoms and signs resolved within days of stopping metronidazole. The MRI changes also resolved, thereby implicating the drug as the causative agent. The differential diagnosis of T2 hyperintense, bilaterally symmetrical dentate nuclei includes methyl bromide intoxication, maple syrup urine disease and enteroviral encephalomyelitis.[789]\n\nConclusions\nMIE is a rare subacute cerebellar syndrome. Its diagnosis requires a high index of suspicion. Withdrawal of the offending metronidazole drug is the only definitive treatment for MIE as the condition is a form of drug intoxication. MRI is complementary in this entirely clinical diagnosis. How early the lesions resolve on follow-up imaging is uncertain. No definitive dosage of drug can be estimated as toxicity has been reported at low as well as at high doses.\n\nSource of Support: Nil\n\nConflict of Interest: Nil\n==== Refs\n1 Kim KH Choi JW Lee JY Kim TD Paek JH Lee EJ Two cases of metronidazole-induced encephalopathy Korean J Gastroenterol 2005 45 195 200 15778547 \n2 Kim E Na DG Kim EY Kim JH Son KR Chang KH MR imaging of metronidazole-induced encephalopathy: Lesion distribution and diffusion-weighted imaging findings AJNR Am J Neuroradiol 2007 28 1652 8 17885234 \n3 Ahmed A Loes DJ Bressler EL Reversible magnetic resonance imaging findings in metronidazole-induced encephalopathy Neurology 1995 45 588 9 7898724 \n4 Kusumi RK Plouffe JF Wyatt RH Fass RJ Central nervous system toxicity associated with metronidazole therapy Ann Intern Med 1980 93 59 60 7396319 \n5 Lee SS Cha SH Lee SY Song CJ Reversible inferior colliculus lesion in metronidazole-induced encephalopathy: Magnetic resonance findings on diffusion-weighted and fluid attenuated inversion recovery imaging J Comput Assist Tomogr 2009 33 305 8 19346865 \n6 Horlen CK Seifert CF Malouf CS Toxic metronidazole-induced MRI changes Ann Pharmacother 2000 34 1273 5 11098341 \n7 Geyer HL Schaumburg HH Herskovitz S Methyl bromide intoxication causes reversible symmetric brainstem and cerebellar MRI lesions Neurology 2005 64 1279 81 15824365 \n8 Jan W Zimmerman RA Wang ZJ Berry GT Kaplan PB Kaye EM MR diffusion imaging and MR spectroscopy of maple syrup urine disease during acute metabolic decompensation Neuroradiology 2003 45 393 9 12736767 \n9 Zimmerman RD MR imaging findings of enteroviral encephalomyelitis: An outbreak in Taiwan AJNR Am J Neuroradiol 1999 20 1775 6 10588095\n\n",
"fulltext_license": "CC BY-NC-SA",
"issn_linking": "0972-2327",
"issue": "16(4)",
"journal": "Annals of Indian Academy of Neurology",
"keywords": "Diffusion-weighted imaging; fluid-attenuated inversion-recovery; magnetic resonance imaging; metronidazole-induced encephalopathy",
"medline_ta": "Ann Indian Acad Neurol",
"mesh_terms": null,
"nlm_unique_id": "101273955",
"other_id": null,
"pages": "569-71",
"pmc": null,
"pmid": "24339581",
"pubdate": "2013-10",
"publication_types": "D002363:Case Reports",
"references": "10588095;7898724;7396319;19346865;15778547;12736767;17885234;15824365;11098341",
"title": "Clinical and imaging perspective and unanswered questions in a case of metronidazole induced encephalopathy.",
"title_normalized": "clinical and imaging perspective and unanswered questions in a case of metronidazole induced encephalopathy"
} | [
{
"companynumb": "IN-BAUSCH-SYM-2013-13519",
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"occurcountry": "IN",
"patient": {
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{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METRONIDAZOLE"
},
"drugadditional": null,
... |
{
"abstract": "Multi-organ failure syndrome (MOFS) is a rare life threatening complication of sickle cell disease. It is precipitated by severe vaso-occlusive episodes. We report a Saudi boy with sickle cell anemia, who developed acute MOFS following anaphylaxis to ceftriaxone administration. He had a dramatic recovery after red blood cell exchange transfusion and peritoneal dialysis.",
"affiliations": "Department of Pediatrics, Taiba University, Madina Maternity and Children's Hospital, PO Box 6205, Madina Al-Munawara, Kingdom of Saudi Arabia. zhawsawi@yahoo.com",
"authors": "Al-Hawsawi|Zakaria M|ZM|;Turkistani|Waheed A|WA|;Al-Aidaros|Mohamed A|MA|;Al-Harbi|Dalal L|DL|",
"chemical_list": "D000900:Anti-Bacterial Agents; D002443:Ceftriaxone",
"country": "Saudi Arabia",
"delete": false,
"doi": null,
"fulltext": null,
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"issn_linking": "0379-5284",
"issue": "31(7)",
"journal": "Saudi medical journal",
"keywords": null,
"medline_ta": "Saudi Med J",
"mesh_terms": "D000755:Anemia, Sickle Cell; D000900:Anti-Bacterial Agents; D002443:Ceftriaxone; D002675:Child, Preschool; D006801:Humans; D008297:Male; D009102:Multiple Organ Failure; D012529:Saudi Arabia",
"nlm_unique_id": "7909441",
"other_id": null,
"pages": "826-8",
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"pmid": "20635020",
"pubdate": "2010-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Ceftriaxone induced acute multi-organ failure syndrome in a Saudi boy with sickle cell disease.",
"title_normalized": "ceftriaxone induced acute multi organ failure syndrome in a saudi boy with sickle cell disease"
} | [
{
"companynumb": "SA-LUPIN PHARMACEUTICALS INC.-2015-03244",
"fulfillexpeditecriteria": "1",
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"abstract": "Immune checkpoint blockade therapy is gaining popularity among oncologists for treatment of solid and hematologic malignancies. The widespread use of these agents resulted in increasing incidence of renal immune-related adverse events. Reported renal toxicity described so far includes acute interstitial nephritis, minimal change disease, and immune complex glomerulonephritis. We report the case of a 79-year-old female with metastatic non-small cell lung cancer on anti-PD-1 therapy nivolumab. After the 4th administration of nivolumab, the treatment course was complicated with normal anion gap metabolic acidosis. Urine and blood studies were in favor of distal renal tubular acidosis (RTA). Following a negative workup for an underlying etiology, immunotherapy-induced RTA was suspected. Withholding of the offending agent and initiation of steroid therapy resulted in adequate response. The present report provides the first presentation of RTA as a renal immune-related adverse event secondary to nivolumab. Nephrologists and oncologists should be familiar with potentially life-threatening renal side effects induced by immune checkpoint inhibitors.",
"affiliations": "Department of Internal Medicine, Northwell Health Staten Island University Hospital, Staten Island, NY, USA.;Department of Hematology and Oncology, Northwell Health Staten Island University Hospital, Staten Island, NY, USA.;Department of Nephrology, Northwell Health Staten Island University Hospital, Staten Island, NY, USA.;Department of Hematology and Oncology, Northwell Health Staten Island University Hospital, Staten Island, NY, USA.",
"authors": "El Bitar|Sandy|S|0000-0002-2625-9171;Weerasinghe|Chanudi|C|;El-Charabaty|Elie|E|;Odaimi|Marcel|M|0000-0002-3244-1957",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.1155/2018/8408015",
"fulltext": "\n==== Front\nCase Rep Oncol MedCase Rep Oncol MedCRIONMCase Reports in Oncological Medicine2090-67062090-6714Hindawi 10.1155/2018/8408015Case ReportRenal Tubular Acidosis an Adverse Effect of PD-1 Inhibitor Immunotherapy http://orcid.org/0000-0002-2625-9171El Bitar Sandy sandybitar87@gmail.com\n1\nWeerasinghe Chanudi \n2\nEl-Charabaty Elie \n3\nhttp://orcid.org/0000-0002-3244-1957Odaimi Marcel \n2\n\n1Department of Internal Medicine, Northwell Health Staten Island University Hospital, Staten Island, NY, USA\n2Department of Hematology and Oncology, Northwell Health Staten Island University Hospital, Staten Island, NY, USA\n3Department of Nephrology, Northwell Health Staten Island University Hospital, Staten Island, NY, USAAcademic Editor: Raffaele Palmirotta\n\n2018 31 1 2018 2018 840801526 10 2017 18 1 2018 Copyright © 2018 Sandy El Bitar et al.2018This 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.Immune checkpoint blockade therapy is gaining popularity among oncologists for treatment of solid and hematologic malignancies. The widespread use of these agents resulted in increasing incidence of renal immune-related adverse events. Reported renal toxicity described so far includes acute interstitial nephritis, minimal change disease, and immune complex glomerulonephritis. We report the case of a 79-year-old female with metastatic non-small cell lung cancer on anti-PD-1 therapy nivolumab. After the 4th administration of nivolumab, the treatment course was complicated with normal anion gap metabolic acidosis. Urine and blood studies were in favor of distal renal tubular acidosis (RTA). Following a negative workup for an underlying etiology, immunotherapy-induced RTA was suspected. Withholding of the offending agent and initiation of steroid therapy resulted in adequate response. The present report provides the first presentation of RTA as a renal immune-related adverse event secondary to nivolumab. Nephrologists and oncologists should be familiar with potentially life-threatening renal side effects induced by immune checkpoint inhibitors.\n==== Body\n1. Introduction\nNovel therapeutic agents targeting PD-1 signaling are increasing in popularity among oncologists. Pembrolizumab and nivolumab have been approved by the US Food and Drug Administration for treatment of several malignancies and are showing high rates of durable clinical responses [1]. However, due to their immunologic effects, there have been a number of reported toxicities termed as immune-related adverse events (irAEs), classified and graded by the National Cancer Institute clinical terminology criteria of adverse events (CTCAE).\n\nRenal adverse events are uncommon, with the highest rate reported in a phase II lung cancer trial at 4% [2, 3]. Three different forms of renal irAE have been described so far: acute interstitial nephritis, minimal change disease, and immune complex glomerulonephritis [4–7]. All three forms manifest as acute kidney injury (AKI) and rise in serum creatinine.\n\nIn this report, we present a case of nivolumab-induced renal tubular acidosis successfully treated with steroids and sodium bicarbonate.\n\n2. Case Presentation\nA 79-year-old woman with past medical history of stage IV non-small cell lung cancer (NSCLC), heart failure with preserved ejection fraction, and dyslipidemia presented to the emergency department with generalized weakness and fatigue. Patient was initiated on nivolumab 3 months prior to presentation as a second line treatment following failure of chemotherapy with carboplatin and pemetrexed, confirmed by progressive disease on PET/CT scan. Home medications included rosuvastatin, docusate sodium, and low-dose furosemide. Patient received nivolumab 240 mg every 2 weeks. Following her fourth dose, she started complaining of worsening generalized fatigue and progressive weakness. Upon outpatient evaluation, her creatinine was found to be elevated at 2.9 mg/dl from a normal baseline. Nivolumab and furosemide were held, and patient received intravenous fluid hydration in the clinic. A renal sonogram was unremarkable. Repeat blood work few days later showed improved renal function. However, the patient's functional status declined over the next few days limiting her out of bed activity. She was sent to the emergency department for further workup.\n\nOn admission, vital signs were within normal limits. Physical exam was unremarkable except for trace lower extremity edema bilaterally.\n\nInitial blood work showed a sodium level of 137 meq/L, potassium of 2.4 meq/L, chloride of 116 meq/L, bicarbonate of 11 meq/L, BUN of 23 mg/dL, and creatinine of 1.67 mg/dL. Arterial PH was acidotic at 7.21 with a CO2 of 27 suggestive of nonanion gap metabolic acidosis with adequate respiratory compensation.\n\nUrine analysis revealed few white blood cells and red blood cells but no casts. Urine studies demonstrated a urine PH of 6.5 and a urine anion gap of 22. The fractional excretion of sodium (FeNa) was calculated at 0.5%.\n\nThe clinical picture was suggestive of prerenal AKI (FeNa < 1%) and renal tubular acidosis (RTA). Gentle hydration with sodium bicarbonate drip was started, and the patient was given potassium supplementation.\n\nOn further investigation, the patient had a negative autoimmune workup except for an ANA of 1 : 320. SPEP, UPEP, free light chains, and hepatitis serology were negative. Thyroid function tests were within normal range.\n\nThe alkaline urine PH in the setting of a significantly low serum bicarbonate level suggested a distal-type RTA. After ruling out common etiologies of RTA, nivolumab was considered as the likely culprit for a drug-induced RTA.\n\nOn day 2 of hospitalization, repeat blood work revealed mild increase in serum bicarbonate to 13 meq/L and improved serum creatinine to 1.39 mg/dl. In the context of a suspected drug-induced RTA secondary to nivolumab irAE, the patient was started on dexamethasone 4 mg every 8 hrs and her fluid rate was increased to target administration of 3 mmol/kg/day of bicarbonate.\n\nOn day 4 of hospitalization, the serum bicarbonate increased to 19 meq/L and serum creatinine was back to baseline. Patient was transitioned to oral sodium bicarbonate and prednisone. Her functional status improved significantly, and she was discharged on day 6 of hospitalization. Her discharge labs revealed a sodium of 142 meq/L, potassium of 3.3 meq/L, chloride of 112 meq/L, bicarbonate of 21 meq/L, and creatinine at 0.95 mg/dL.\n\nThe patient was discharged home on oral bicarbonate and a prednisone taper.\n\nRepeat labs 1 week after discharge were stable. Follow-up with nephrology and hematology was set up. However, the patient returned to the hospital with acute hypoxic respiratory failure due to massive pulmonary embolism secondary to heparin-induced thrombocytopenia and expired.\n\n3. Discussion\nThe incidence and nature of renal irAEs in oncology are increasing with the introduction of immunotherapy. Cytotoxic T-lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1) are two important immune checkpoint receptors expressed by T lymphocytes and targeted by the new therapies. CTLA-4 plays a critical role in the early immune response occurring in lymphoid tissues. As T-cell receptors (TCR) bind antigen/MHC on antigen-presenting cells (APC), the coinhibitory receptor CTLA-4 overexpressed in many cancers is activated, leading to the inhibition of memory T-cell function. Following the priming and activation of T-cell lymphocytes, the coinhibitory PD-1 receptor expressed by T-cells of peripheral tissue binds to their ligands on cancerous cells (PDL-1 and PDL-2). This association results in T-cell anergy and decrease in cytokine release, hence suppressing the antitumor response [8, 9]. Nivolumab is a new PD-1 antibody with antitumor activity. It binds to PD-1 receptor and blocks its inhibitory pathway, hence stimulating lymphocyte cells to target tumor cells. It is now being used for treatment of non-small lung cancer, metastatic melanoma, renal cell carcinoma, squamous cell carcinoma of the head and neck, and classical Hodgkin lymphoma, as first or second line treatment [1, 2]. Studies have shown response rates as high as 40% in patients with solid tumors [2, 3]. In advanced NSCLC, response rate can reach up to 20% [2]. Nevertheless, these high numbers happen at the expense of several adverse effects. On a physiological level, immune checkpoint inhibitory pathways suppress immune response against self-antigens. Targeting these regulators may enhance an inflammatory response of normal tissue, resulting in immune invasion and damage [9]. The most common toxicities included cutaneous, gastrointestinal, hepatic, endocrine, and renal side effects. Hofmann et al. conducted a retrospective chart review study for reported adverse events of pembrolizumab and nivolumab noting renal involvement in only 1-2% of reported irAEs [10].\n\nThree different forms of renal AEs have been reported so far: acute tubulointerstitial nephritis (ATIN), immune complex GN, and minimal change disease [4–7]. Irrespective of the underlying mechanism of irAEs, most respond well to steroid therapy. Based on the data derived from case series and case reports, treatment with glucocorticoids resulted in an excellent overall prognosis [10].\n\nIn our patient, the AKI was believed to be prerenal, considering the calculated FeNa was below 1% and the adequate response to intravenous fluids. However, the worsening acidosis despite improved renal function was suggestive of RTA. Extensive workup for an underlying etiology was negative, suggesting a drug-induced RTA secondary to nivolumab. Despite the elevated titer of ANA, it remains nonspecific as the rest of the autoimmune panel was negative. The alkaline urine PH despite significantly low serum bicarbonate and the adequate response to relatively low alkali supplementation was more in favor of a distal RTA. The underlying mechanism for autoimmune distal RTA is secondary to distal tubule proton pump defect from immunologic injury or autoantibodies [11]. Bearing in mind the importance of PD-1 signaling in minimizing the T-cell-mediated renal inflammation [10], anti-PD-1 agents are likely to induce immunologic injuries similar to that seen in autoimmune diseases resulting in RTA.\n\nEstablishing a relation between a certain drug and a side effect can be challenging, especially when a patient is exposed to multiple nephrotoxic drugs. In our case, the patient received maintenance pemetrexed, an antifolate drug, for 8 cycles. During the treatment period and 3 months after discontinuation of pemetrexed, her kidney function remained intact. Moreover, the association in time between administering nivolumab and the development of RTA, followed by normalization after administration of corticosteroids, is in favor of nivolumab-induced RTA.\n\nIncrease in use of immune checkpoint inhibitors should warrant attention to adverse side effects, mainly renal complications. To our knowledge, our case is the first to describe nivolumab-induced renal AEs manifesting as RTA. Early detection and initiation of steroid therapy/bicarbonate replacement can result in favorable outcomes. Renal monitoring for patients on anti-PD-1 agents is vital for early management of irAEs and prevention of severe renal damage.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n==== Refs\n1 Topalian S. L. Hodi F. S. Brahmer J. R. Safety, activity, and immune correlates of anti-PD-1 antibody in cancer New England Journal of Medicine 2012 366 26 2443 2454 10.1056/NEJMoa1200690 2-s2.0-84862859820 22658127 \n2 Borghaei H. Paz-Ares L. Horn L. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer New England Journal of Medicine 2015 373 17 1627 1639 10.1056/NEJMoa1507643 2-s2.0-84944937210 26412456 \n3 Rizvi N. A. Mazieres J. Planchard D. Activity and safety of nivolumab, an anti-PD-1 immune checkpoint inhibitor, for patients with advanced, refractory squamous non-small-cell lung cancer (CheckMate 063): a phase 2, single-arm trial Lancet Oncology 2015 16 3 257 265 10.1016/s1470-2045(15)70054-9 2-s2.0-84924901863 25704439 \n4 Jung K. Zeng X. Bilusic M. Nivolumab-associated acute glomerulonephritis: a case report and literature review BMC Nephrology 2016 17 1 p. 188 10.1186/s12882-016-0408-2 2-s2.0-84997418192 \n5 Murakami N. Borges T. J. Yamashita M. Riella L. V. Severe acute interstitial nephritis after combination immune-checkpoint inhibitor therapy for metastatic melanoma Clinical Kidney Journal 2016 9 3 411 417 10.1093/ckj/sfw024 2-s2.0-84978986900 27274826 \n6 Vandiver J. W. Singer Z. Harshberger C. Severe hyponatremia and immune nephritis following an initial infusion of nivolumab Targeted Oncology 2016 11 4 553 556 10.1007/s11523-016-0426-9 2-s2.0-84960076189 26940583 \n7 Bickel A. Koneth I. Enzler-Tschudy A. Neuweiler J. Flatz L. Fruh M. Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma BMC Cancer 2016 16 1 p. 656 10.1186/s12885-016-2718-y 2-s2.0-84982245105 \n8 Ribas A. Tumor immunotherapy directed at PD-1 New England Journal of Medicine 2012 366 26 2517 2519 10.1056/NEJMe1205943 2-s2.0-84862882003 22658126 \n9 La-Beck N. M. Jean G. W. Huynh C. Alzghari S. K. Lowe D. B. Immune checkpoint inhibitors: new insights and current place in cancer therapy Pharmacotherapy 2015 35 10 963 976 10.1002/phar.1643 2-s2.0-84945122687 26497482 \n10 Hofmann L. Forschner A. Loquai C. Cutaneous, gastrointestinal, hepatic, endocrine, and renal side-effects of anti-PD-1 therapy European Journal of Cancer 2016 60 190 209 10.1016/j.ejca.2016.02.025 2-s2.0-84964345287 27085692 \n11 Cohen E. P. Bastani B. Cohen M. R. Kolner S. Hemken P. Gluck S. L. Absence of H(+)-ATPase in cortical collecting tubules of a patient with Sjogren’s syndrome and distal renal tubular acidosis Journal of American Society of Nephrology 1992 3 2 264 271\n\n",
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"title": "Renal Tubular Acidosis an Adverse Effect of PD-1 Inhibitor Immunotherapy.",
"title_normalized": "renal tubular acidosis an adverse effect of pd 1 inhibitor immunotherapy"
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"abstract": "OBJECTIVE\nRivaroxaban is an anticoagulant prescribed for the management of atrial fibrillation. We describe a correlation between rivaroxaban and spontaneous vitreous hemorrhage.\n\n\nMETHODS\nThree patients developed spontaneous vitreous hemorrhage after initiating rivaroxaban anticoagulation. All 3 patients were taking an additional anticoagulant at the time of hemorrhage.\n\n\nCONCLUSIONS\nRivaroxaban is increasingly prescribed as a replacement for warfarin sodium in the management of atrial fibrillation. Rivaroxaban anticoagulation may be associated with spontaneous vitreous hemorrhage. The risk of hemorrhage may be particularly elevated during the transition period when patients are switched from baseline anticoagulant to rivaroxaban therapy and are taking both anticoagulants simultaneously.",
"affiliations": "Retina Associates of Orange County, Laguna Hills, California.;Retina Associates of Orange County, Laguna Hills, California2University of Southern California, Eye Institute, Keck School of Medicine, Los Angeles.",
"authors": "Jun|Judy H|JH|;Hwang|John C|JC|",
"chemical_list": "D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D010975:Platelet Aggregation Inhibitors; D014859:Warfarin; D000069552:Rivaroxaban; D000077144:Clopidogrel; D013988:Ticlopidine",
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"title": "Association of rivaroxaban anticoagulation and spontaneous vitreous hemorrhage.",
"title_normalized": "association of rivaroxaban anticoagulation and spontaneous vitreous hemorrhage"
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"abstract": "A 26-year-old male presented with symptoms of acute esophageal obstruction immediately after swallowing an 800-mg ibuprofen tablet. Multiple attempts to extract the pill with a variety of traditional endoscopic retrieval devices were unsuccessful. We successfully destroyed the pill using a threaded-tip biliary stent retrieval device to drill a hole in the center of the pill, which allowed us to use a rat-tooth forceps to crush the pill. This case report demonstrates a novel use of this device in a challenging esophageal pill extraction.",
"affiliations": "Naval Medical Center San Diego, San Diego, CA.;Naval Medical Center San Diego, San Diego, CA.;Naval Medical Center San Diego, San Diego, CA.;Naval Medical Center San Diego, San Diego, CA.",
"authors": "Lacey|Brent W|BW|;Caufield|Sean|S|;Lavery|Eric|E|;Partridge|Brett|B|",
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"fulltext": "\n==== Front\nACG Case Rep JACG Case Rep JcrjACG Case Reports Journal2326-3253American College of Gastroenterology crj.2014.2510.14309/crj.2014.25Case ReportEndoscopyA Novel Approach to Management of Esophageal Pill Impaction Lacey Brent W. MDCaufield Sean MDLavery Eric MDPartridge Brett MDNaval Medical Center San Diego, San Diego, CACorrespondence: Brent W. Lacey, Naval Medical Center San Diego, 34800 Bob Wilson Dr., San Diego, CA, 92108 (brent.lacey@med.navy.mil).4 2014 04 4 2014 1 3 126 127 10 2 2014 16 3 2014 Copyright © Lacey et al.2014This is an open-access article. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/A 26-year-old male presented with symptoms of acute esophageal obstruction immediately after swallowing an 800-mg ibuprofen tablet. Multiple attempts to extract the pill with a variety of traditional endoscopic retrieval devices were unsuccessful. We successfully destroyed the pill using a threaded-tip biliary stent retrieval device to drill a hole in the center of the pill, which allowed us to use a rat-tooth forceps to crush the pill. This case report demonstrates a novel use of this device in a challenging esophageal pill extraction.\n==== Body\nIntroduction\nEsophageal foreign body impaction can be managed with a variety of standard endoscopic retrieval devices, but anatomic features and the nature of the foreign body can make successful extraction difficult or impossible with standard techniques. We present this case to demonstrate a novel approach to the management of a challenging esophageal pill impaction.\n\nCase Report\nA 26-year-old male presented with symptoms of acute esophageal obstruction immediately after swallowing an 800-mg ibuprofen tablet. He could not swallow oral secretions and complained of focal anterior neck pain. During an urgent upper endoscopy, we encountered a circular, hard pill tightly impacted at a mid-esophageal stricture. The esophagus had a narrow caliber and the diagnostic endoscope could only be advanced to a point just proximal to the pill (Figure 1A). Multiple attempts to extract the pill with a variety of traditional endoscopic retrieval devices, including rat-tooth forceps, polypectomy snare, retrieval net, biopsy forceps, and three-pronged grasper, were unsuccessful.\n\nFigure 1 (A) Impacted pill encountered at 25 cm from the incisors. (B) A Soehendra threaded-tip biliary stent retrieval device was used to drill through the pill, (C) yielding a central defect. (D) A rat-tooth forceps was subsequently able to gain sufficient leverage to destroy the pill.\n\nAfter consideration of management options for refractory esophageal impaction (including surgical referral), we chose to attempt to disrupt the pill with a 7 French threaded-tip Soehendra biliary stent retriever (Cook Medical, Winston-Salem, NC). The stent retriever was centered in the lumen and placed gently against the center of the pill (Figure 1B). Clockwise rotation of the threaded tip created a central defect within the pill matrix (Figure 1C), then we used the rat-tooth forceps to rapidly crush the remaining pill, working off the central defect (Figure 1D). After pulverizing the impacted pill, we observed an esophageal stricture 8 mm in diameter (Figure 2), which we traversed with a narrow caliber (5.5 mm) upper endoscope and completed the examination. The patient recovered uneventfully. The endoscopic appearance and biopsies of the esophagus were consistent with eosinophilic esophagitis, which subsequently required esophageal dilation for treatment.\n\nFigure 2 Endoscopic view of the esophageal stricture after destruction of the pill.\n\nDiscussion\nThe biliary stent retrieval device (Figure 3) has a threaded tip designed to be advanced over a guidewire into a metal biliary stent to facilitate extraction.1 Since its introduction, the device has been used for other purposes, such as expanding a hole in a metallic mesh stent for multiple stenting of a hilar biliary obstruction,2 EUS-guided drainage of a pancreatic pseudocyst,3 dilating refractory pancreatic duct strictures,4 and dilating pancreaticojejunostomy strictures.5 This is the first published case using the device for management of an esophageal pill impaction. The threaded tip may cut rapidly, so it is important to drill through the pill carefully, checking progress frequently lest the device damage the esophageal wall. This device does not use electrocautery. Once a hole is created in the center of the pill, standard devices such as the rat-tooth forceps used in this case have the necessary leverage to crush the pill easily.\n\nFigure 3 Soehendra threaded-tip biliary stent retrieval device. Image courtesy of Cook Medical.\n\nWhen encountering an esophageal pill impaction refractory to extraction with standard endoscopic retrieval devices, endoscopists may consider utilizing a threaded-tip biliary stent retriever. Further studies would be required to determine the efficacy and safety of the stent retriever in the removal of a variety of impacted foreign bodies within the gastrointestinal tract.\n\nDisclosures\nAuthor contributions: BW Lacey was the primary author of the final manuscript and the article guarantor. S. Caufield, E. Lavery, and B. Partridge contributed to and edited the final manuscript.\n\nFinancial disclosure: None to report.\n\nInformed consent was obtained for this case report.\n==== Refs\nReferences\n1 Diehl DL , Adler DG , Conway JD , et al ; ASGE Technology Committee . Endoscopic retrieval devices . Gastrointest Endosc . 2009 ;69 (6 ):997 –1003 .19410038 \n2 Hara T , Yamaguchi T , Sudo K , et al. Expansion of a metallic mesh stent hole using a Soehendra stent retriever in multiple stenting of biliary hilar obstruction . Endoscopy . 2008 ;(suppl 40 ):E147 –8 .18633875 \n3 Yamaguchi T , Ishihara T , Tadenuma H , et al. Use of a Soehendra stent retriever to treat a pancreatic pseudocyst with EUS-guided cystogastrostomy . Endoscopy . 2004 ;36 (8 ):755 .15280996 \n4 Ziebert JJ , DiSario JA \nDilation of refractory pancreatic duct strictures: The turn of the screw . Gastrointest Endosc . 1999 ;49 (5 ):632 –5 .10228264 \n5 Partridge BJ , Tokar JL , Kennish J , et al. The endoscopic management of pancreaticojejunostomy strictures . [ASGE Video Forum 2010] \nGastrointest Endosc . 2010 ;71 (5 ):AB100 –101 .\n\n",
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"title": "A Novel Approach to Management of Esophageal Pill Impaction.",
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"abstract": "Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, a Notch pathway ligand highly expressed on SCLC cells. Rova-T was evaluated alone or in combination with platinum-based chemotherapy (cisplatin or carboplatin combined with etoposide [CE]) in frontline treatment of extensive-stage SCLC.\n\n\n\nOne cycle of CE pre-enrollment was permitted (later mandated). The following four cohorts were enrolled: Rova-T monotherapy (0.3 mg/kg, every 6 [q6] wk × 2; cohort 1; n = 4); Rova-T induction (0.3 mg/kg, q6 wk × 2) followed by CE every 21 days (q21) × 4 (cohort 2; n = 5); Rova-T (0.1 or 0.2 mg/kg, q6 wk × 2) overlapping with CE q21 × 4 (cohort 3; n = 14); and Rova-T maintenance (0.3 mg/kg, q6 wk × 2) after CE q21 × 4 (cohort 4; n = 3).\n\n\n\nA total of 26 patients were dosed (cohort 3: 14; cohorts 1, 2, and 4 combined: 12). Median age was 66 years, and 73% had Eastern Cooperative Oncology Group performance status of 1. In cohort 3, seven patients (50%) had confirmed objective responses, with a median progression-free survival of 5.2 months and median overall survival of 10.3 months. Compared with cohorts 1, 2, and 4 combined, cohort 3 had lower frequency of some Rova-T-related adverse events of special interest, such as pleural effusion (0 versus 33%), pericardial effusion (0 versus 17%), ascites (0 versus 8%), peripheral edema (36% versus 42%), generalized edema (0 versus 8%), pneumonia (7% versus 25%), and hypoalbuminemia (0 versus 17%).\n\n\n\nLower Rova-T doses may be associated with lower incidence of some Rova-T-related adverse events of special interest. Rova-T 0.2 mg/kg plus CE (cohort 3) was tolerable; however, there was no clear efficacy benefit of adding Rova-T to CE.",
"affiliations": "Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland. Electronic address: chann1@jhmi.edu.;UPMC Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania.;University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, Ohio.;Division of Medical Oncology, Washington University School of Medicine, St. Louis, Missouri.;Oncology Hematology Care, Inc., Cincinnati, Ohio.;AbbVie Inc., North Chicago, Illinois.;AbbVie Inc., North Chicago, Illinois.;AbbVie Inc., North Chicago, Illinois.;AbbVie Inc., Redwood City, California.;AbbVie Inc., North Chicago, Illinois.;AbbVie Inc., North Chicago, Illinois.;Division of Medical Oncology, Department of Medicine, University of Colorado Denver, Aurora, Colorado.",
"authors": "Hann|Christine L|CL|;Burns|Timothy F|TF|;Dowlati|Afshin|A|;Morgensztern|Daniel|D|;Ward|Patrick J|PJ|;Koch|Martina M|MM|;Chen|Chris|C|;Ludwig|Carrianne|C|;Patel|Maulik|M|;Nimeiri|Halla|H|;Komarnitsky|Philip|P|;Camidge|D Ross|DR|",
"chemical_list": "D061067:Antibodies, Monoclonal, Humanized; D001570:Benzodiazepinones; D018796:Immunoconjugates; C000620223:rovalpituzumab tesirine; D005047:Etoposide; D016190:Carboplatin",
"country": "United States",
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"issue": "16(9)",
"journal": "Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer",
"keywords": "DLL3; Frontline; Platinum-based chemotherapy; Rovalpituzumab tesirine; Small cell lung cancer",
"medline_ta": "J Thorac Oncol",
"mesh_terms": "D000368:Aged; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D001570:Benzodiazepinones; D016190:Carboplatin; D005047:Etoposide; D006801:Humans; D018796:Immunoconjugates; D008175:Lung Neoplasms; D055752:Small Cell Lung Carcinoma",
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"references": null,
"title": "A Phase 1 Study Evaluating Rovalpituzumab Tesirine in Frontline Treatment of Patients With Extensive-Stage SCLC.",
"title_normalized": "a phase 1 study evaluating rovalpituzumab tesirine in frontline treatment of patients with extensive stage sclc"
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... |
{
"abstract": "BACKGROUND\nKaposi's sarcoma (KS) is a rare angioproliferative disorder of the vascular endothelium. The development of KS requires Human Herpes Virus 8 (HHV-8) infection. An associated HIV infection is usually seen. Isolated scrotal KS has rarely been reported. In this article, we present a case of KS that primarily involved the scrotum in a HIV negative patient.\n\n\nMETHODS\nA 71-year old male patient admitted to the outpatient department due to nodular lesions on the scrotum. The patient declared that these lesions were present for nearly 5 years. Past medical history revealed that he underwent left thoracotomy and upper lobectomy in 2006 for adenosquamous lung carcinoma. Then, he received a single cycle of adjuvant chemotherapy consisted of docetaxel and cisplatin. Physical examination revealed 3 black small nodules on the scrotum. The anti-HIV test was negative. All scrotal lesions were surgically excised. The pathological investigation revealed KS of the lymphangioma-like type.\n\n\nCONCLUSIONS\nThe pathogenesis of KS has still not been clearly elucidated. However, it is known that all forms of KS are associated with HHV-8 infections. A defect in immune system was almost always necessary. Therefore, KS is usually associated with HIV infection. KS of the penis has been reported in HIV negative patients. Very few cases of scrotal KS have been presented. In a recent review, only 1 patient had scrotal KS out of 32 cases with HIV negative KS. In our case, the patient received a cycle of chemotherapy that might affect his immune system. The lymphangioma-like type is a common morphological sub-type. While lymph edemas are commonly observed in this sub-type, no edema in the lymphs was present in our case.\n\n\nCONCLUSIONS\nClassical KS is generally observed in the lower extremities, it can rarely affect scrotal skin as isolated lesions. Therefore, a careful physical examination should also include scrotum for these patients.",
"affiliations": "Department of Urology, Duzce University School of Medicine, Duzce, Turkey. Electronic address: hamidozmen@hotmail.com.;Department of Urology, Duzce University School of Medicine, Duzce, Turkey.;Department of Urology, Duzce University School of Medicine, Duzce, Turkey.;Department of Urology, Duzce University School of Medicine, Duzce, Turkey.;Department of Urology, Duzce University School of Medicine, Duzce, Turkey.",
"authors": "Ozmen|Hamid|H|;Baba|Dursun|D|;Kacagan|Coskun|C|;Kayikci|Ali|A|;Cam|Kamil|K|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": null,
"fulltext": "\n==== Front\nInt J Surg Case RepInt J Surg Case RepInternational Journal of Surgery Case Reports2210-2612Elsevier S2210-2612(14)00369-110.1016/j.ijscr.2014.11.019ArticleCase report: HIV negative isolated scrotal Kaposi's sarcoma Ozmen Hamid hamidozmen@hotmail.com⁎Baba Dursun Kacagan Coskun Kayikci Ali Cam Kamil Department of Urology, Duzce University School of Medicine, Duzce, Turkey⁎ Corresponding author at: Department of Urology, Duzce University School of Medicine, Konuralp 81620, Duzce, Turkey. Tel.: +90 380 542 13 90; fax: +90 380 542 13 87. hamidozmen@hotmail.com13 11 2014 13 11 2014 2014 5 12 1086 1087 5 7 2014 11 10 2014 6 11 2014 © 2014 The Authors2014This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/3.0/).Highlights\n• We present a case of Kaposi's sarcoma that primarily involved the scrotal region.\n\n• We present a case of Kaposi's sarcoma that involved in HIV negative patient.\n\n• Classical KS is generally observed in the lower extremities, it can rarely affect scrotal skin as isolated lesions. Therefore, a careful physical examination should also include scrotum for these patients.\n\n\n\nINTRODUCTION\nKaposi's sarcoma (KS) is a rare angioproliferative disorder of the vascular endothelium. The development of KS requires Human Herpes Virus 8 (HHV-8) infection. An associated HIV infection is usually seen. Isolated scrotal KS has rarely been reported. In this article, we present a case of KS that primarily involved the scrotum in a HIV negative patient.\n\nPRESENTATION OF CASE\nA 71-year old male patient admitted to the outpatient department due to nodular lesions on the scrotum. The patient declared that these lesions were present for nearly 5 years. Past medical history revealed that he underwent left thoracotomy and upper lobectomy in 2006 for adenosquamous lung carcinoma. Then, he received a single cycle of adjuvant chemotherapy consisted of docetaxel and cisplatin. Physical examination revealed 3 black small nodules on the scrotum. The anti-HIV test was negative. All scrotal lesions were surgically excised. The pathological investigation revealed KS of the lymphangioma-like type.\n\nDISCUSSION\nThe pathogenesis of KS has still not been clearly elucidated. However, it is known that all forms of KS are associated with HHV-8 infections. A defect in immune system was almost always necessary. Therefore, KS is usually associated with HIV infection. KS of the penis has been reported in HIV negative patients. Very few cases of scrotal KS have been presented. In a recent review, only 1 patient had scrotal KS out of 32 cases with HIV negative KS. In our case, the patient received a cycle of chemotherapy that might affect his immune system. The lymphangioma-like type is a common morphological sub-type. While lymph edemas are commonly observed in this sub-type, no edema in the lymphs was present in our case.\n\nCONCLUSION\nClassical KS is generally observed in the lower extremities, it can rarely affect scrotal skin as isolated lesions. Therefore, a careful physical examination should also include scrotum for these patients.\n\nKeywords\nCase reportKaposi's sarcomaScrotum\n==== Body\n1 Introduction\nKaposi's sarcoma (KS) is a rare angioproliferative disorder of the vascular endothelium. The development of KS requires the presence of a Human Herpes Virus 8 (HHV-8) infection. A strong association with HIV infection is well known. The classical form was first defined as “idiopathic multiple pigmented sarcoma” by Moritz Kaposi in 1872.1 The skin lesions are classically characterized by macules, plaques and nodules that are of a purple, red, blue, dark brown or black appearance. While KS primarily affects mucocutaneous tissues, it can also affect internal organs. Classical KS mostly affects the lower extremities. Penile KS is relatively common, while isolated scrotal KS has rarely been seen.2 In this article, we present a case of scrotal KS in a HIV negative patient.\n\n2 Case report\nA 71-year old male patient admitted to the outpatient department due to black nodular lesions on the scrotum. The patient declared that these lesions were present for nearly 5 years. Past medical history revealed that he underwent left thoracotomy and upper lobectomy in 2006 for adenosquamous lung carcinoma. Then, he received a single cycle of adjuvant chemotherapy consisted of docetaxel and cisplatin. The chemotherapy was discontinued due to the side effects. No recurrence was detected regarding the lung cancer. The scrotal lesions appeared 2 months following the chemotherapy. Physical examination revealed 3 black nodules on the scrotum, each one being nearly 0.5 cm × 0.5 cm in dimension (Fig. 1). No other similar lesions were seen elsewhere. Routine laboratory tests were all normal. The anti-HIV test (chemiluminescence) was negative. He had abdominal computed tomography for the follow-up of lung cancer showing no specific abnormality unless an increase in the thickness of the stomach wall. A gastroscopy was then performed revealing no lesions. All scrotal lesions were surgically excised. The pathological investigation revealed KS of the lymphangioma-like type.\n\n3 Discussion\nIn classical KS, lesions are primarily located on the lower extremities, and the involvement of external genitalia is uncommon.3 Although cases of HIV negative patients in which the penis is primarily involved have been reported, very few cases of scrotal KS have been presented. In a recent study, only 1 patient had scrotal KS out of 32 cases with non-HIV KS.2 Also, it was unclear that this single case of scrotal KS was associated with other locations or not.2 Penile KS has been reported more extensively. Vyas et al. first reported an isolated case of scrotal KS in 1976.4 Then, only two cases of isolated scrotal KS were presented.5,6 Our case represents the 4th case up to our knowledge.\n\nThe pathogenesis of KS has still not been clearly elucidated. However, it is known that all forms of KS are associated with HHV-8 infections. A defect in immune system was almost always necessary. Therefore, KS is usually associated with HIV infection. In our case, the patient received a cycle of chemotherapy that might affect his immune system.\n\nThe lymphangioma-like type is a common morphological sub-type. While lymph edemas are commonly observed in this sub-type, no edema in the lymphs was present in our case.\n\nA Greek study reported asymptomatic stomach involvement in 82% of patients with classical KS.7 They suggest routine endoscopy for newly diagnosed KS patients. Our case had no systemic lesions on endoscopy and radiological imaging. Detailed physical examinations also revealed no other skin lesions.\n\nStudies conducted for the treatment for KS are generally performed on HIV patients. Unfortunately, there is currently no treatment method capable of eradicating HHV-8. For this reason, the main goal of KS treatment is to alleviate the symptoms of the disease, to reduce the size and number of cutaneous and visceral lesions, and to reduce and delay the progression of the disease.8 Despite the use of various local and systemic treatment methods for classical KS, there is no standard treatment procedure administered to cases with genital KS. A total of 19 cases with penile KS were reported.9 Local excision was performed on 9 patients, circumcision was performed on one patient, and radiotherapy, chemotherapy or IFN-alpha treatment in addition to local excision was performed on 3 patients. During the follow-up period, only 4 cases with local excision relapsed. Vyas et al. performed total scrotectomy and bilateral orchiectomy in their report with scrotal KS.4 We preferred local excision for our patient, since these lesions were small and stable for about 5 years. No recurrence was observed after 2 years of follow-up.\n\nIn conclusion, classical KS is generally observed in the lower extremities, it can rarely affect scrotal skin as isolated lesions. Therefore, a careful physical examination should also include scrotum for these patients.\n\nConflict of interest\nThere is no conflict of interest.\n\nFunding\nNone.\n\nEthical approval\nA written informed consent was obtained from the patient.\n\nAuthor contributions\nHamid Ozmen: data collections, writing; Dursub Baba: data collections; Coskun Kacagan: data collections; Ali Kayikci: study design, data collections; Kamil CAM: study design, writing.\n\nFig. 1 Three black nodules on the scrotum.\n==== Refs\nReferences\n1 Braun M. Classics in oncology. Idiopathic multiple pigmented sarcoma of the skin by Kaposi CA Cancer J Clin 32 1982 340 347 6812893 \n2 Rescigno P. Di Trolio R. Buonerba C. De Fata G. Federico P. Bosso D. Non-AIDS-related Kaposi's sarcoma: a single-institution experience World J Clin Oncol 10 2013 52 57 23696963 \n3 Aktas E. Güler E. Utaş S. Deniz K. Orhan O. Yıldız O.G. Penile Kaposi's sarcoma in an HIV negative male patient Turkderm 4 2 2008 131 133 \n4 Vyas S. Manabe T. Herman J.R. Newman H.R. Kaposi's sarcoma of scrotum Urology 8 1976 55 82 941364 \n5 Johnson D.E. Chica J. Rodriquez L.H. Luna M. Kaposi's sarcoma presenting as scrotal ulcerations Urology 9 June (6) 1977 686 688 883073 \n6 Serrano C. Sánchez G. del Mar Serrano M. Linares J. Dulanto C. Naranjo R. Nódulos y placas violáceas en escroto y muslo Actas Dermosifiliogr 96 2 2005 127 129 16476352 \n7 Balachandra B. Tunitsky E. Dawood S. Hings I. Marcus V.A. Classic Kaposi's sarcoma presenting first with gastrointestinal tract involvement in a HIV-negative Inuit male – a case report and review of the literature Pathol Res Pract 202 2006 623 626 16682127 \n8 Kolios G. Kaloterakis A. Filiotou A. Nakos A. Hadziyannis S. Gastroscopic findings in Mediterranean Kaposi's sarcoma (non-AIDS) Gastrointest Endosc 42 1995 336 339 8536903 \n9 Fatahzadeh M. Kaposi sarcoma: review and medical management Oral Surg Oral Med Oral Pathol Oral Radiol 113 2012 2 16 22677687\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2210-2612",
"issue": "5(12)",
"journal": "International journal of surgery case reports",
"keywords": "Case report; Kaposi's sarcoma; Scrotum",
"medline_ta": "Int J Surg Case Rep",
"mesh_terms": null,
"nlm_unique_id": "101529872",
"other_id": null,
"pages": "1086-7",
"pmc": null,
"pmid": "25460481",
"pubdate": "2014",
"publication_types": "D016428:Journal Article",
"references": "8536903;22677687;16476352;16682127;883073;6812893;23696963;945927",
"title": "Case report: HIV negative isolated scrotal Kaposi's sarcoma.",
"title_normalized": "case report hiv negative isolated scrotal kaposi s sarcoma"
} | [
{
"companynumb": "TR-SA-2014SA172405",
"fulfillexpeditecriteria": "1",
"occurcountry": "TR",
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"activesubstancename": "DOCETAXEL"
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{
"abstract": "OBJECTIVE\nHemophagocytic lymphohistiocytosis (HLH) is a disorder characterized by uncontrolled mature histiocyte proliferation, hemophagocytosis, and hypercytokinemia. We describe a previously healthy pregnant patient who presented in the third trimester of pregnancy with HLH.\n\n\nMETHODS\nA 35-year-old woman presented at 38 weeks' gestation with pyrexia, jaundice, severe anemia, elevated liver enzymes, and lactate dehydrogenase suggestive of HELLP (hemolysis, elevated liver enzyme, low platelet) syndrome. Unfortunately, her condition deteriorated and she was ventilated in the intensive care unit despite delivery of the baby and administration of dexamethasone. She developed microangiopathic hemolytic anemia, thrombocytopenia, and renal impairment suggestive of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome. However, she was refractory to plasma exchange, intravenous immunoglobulin, and broad-spectrum antibiotics. HLH was eventually diagnosed from biochemical and bone marrow findings. An extensive search for possible causes yielded negative results. She improved significantly with intravenous dexamethasone and cyclosporine A and was transferred out of the intensive care unit. Unfortunately, she developed cytomegalovirus disease 2 weeks later, which improved transiently with intravenous ganciclovir; later, however, she succumbed to multidrug-resistant nosocomial infections, rapidly progressive cytomegalovirus disease, and multiorgan failure.\n\n\nCONCLUSIONS\nThis case highlights the challenges and difficulties involved in the diagnosis and management of pregnancy-related HLH. Immunosuppressive treatment for HLH can precipitate life-threatening opportunistic infections, which need to be promptly diagnosed and treated.",
"affiliations": "Hematology Unit, Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia.;Hematology Unit, Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, 56000 Kuala Lumpur, Malaysia. Electronic address: chiehwong@ppukm.ukm.edu.my.",
"authors": "Tumian|Nor Rafeah|NR|;Wong|Chieh Lee|CL|",
"chemical_list": "D003907:Dexamethasone; D016572:Cyclosporine",
"country": "China (Republic : 1949- )",
"delete": false,
"doi": null,
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1028-4559",
"issue": "54(4)",
"journal": "Taiwanese journal of obstetrics & gynecology",
"keywords": "cytomegalovirus infection; hemophagocytic lymphohistiocytosis; hemophagocytic syndrome; pregnancy",
"medline_ta": "Taiwan J Obstet Gynecol",
"mesh_terms": "D000328:Adult; D002585:Cesarean Section; D003131:Combined Modality Therapy; D016572:Cyclosporine; D003586:Cytomegalovirus Infections; D003907:Dexamethasone; D018450:Disease Progression; D018432:Drug Resistance, Multiple; D004359:Drug Therapy, Combination; D017809:Fatal Outcome; D005260:Female; D006801:Humans; D007262:Infusions, Intravenous; D051359:Lymphohistiocytosis, Hemophagocytic; D009102:Multiple Organ Failure; D010951:Plasma Exchange; D011247:Pregnancy; D011251:Pregnancy Complications, Infectious; D011263:Pregnancy Trimester, Third; D012720:Severity of Illness Index",
"nlm_unique_id": "101213819",
"other_id": null,
"pages": "432-7",
"pmc": null,
"pmid": "26384065",
"pubdate": "2015-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D016454:Review",
"references": null,
"title": "Pregnancy-related hemophagocytic lymphohistiocytosis associated with cytomegalovirus infection: A diagnostic and therapeutic challenge.",
"title_normalized": "pregnancy related hemophagocytic lymphohistiocytosis associated with cytomegalovirus infection a diagnostic and therapeutic challenge"
} | [
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"activesubstancename": "DEXAMETHASONE"
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{
"abstract": "The question of whether systemic use of corticosteroids during the first trimester of pregnancy increases the risk of congenital malformations in people has still not been resolved. Here, we present the results of a case-control study on the relationship of corticosteroids during pregnancy and oral clefts in the newborn infant. Data are derived from the Spanish Collaborative Study of Congenital Malformations (ECEMC). Case subjects were 1,184 liveborn infants with nonsyndromic oral clefts. The results of the logistic regression analysis, show a relationship between exposure to corticosteroids during the first trimester of pregnancy and an increased risk of cleft lip (with or without cleft palate) in the newborn infants (OR = 6.55; CI = 1.44-29.76; P = 0.015), controlled for potential confounder factors, such as maternal smoking, maternal hyperthermia, first-degree malformed relatives with cleft lip with or without cleft palate, and maternal treatment with antiepileptics, benzodiazepines, metronidazole, or sex hormones during the first trimester of pregnancy. Thus, we believe that the use of corticosteroids during the first trimester of pregnancy, should be restricted to the following situations: for life-threatening situations, for those diseases without any other safe therapeutic alternative, or for those cases with replacement therapy.",
"affiliations": "ECEMC (Estudio Colaborativo Español de Malformaciones Congénitas), Facultad de Medicina, Universidad Complutense, Madrid, Spain.",
"authors": "Rodríguez-Pinilla|E|E|;Martínez-Frías|M L|ML|",
"chemical_list": "D000305:Adrenal Cortex Hormones",
"country": "United States",
"delete": false,
"doi": "10.1002/(SICI)1096-9926(199807)58:1<2::AID-TERA2>3.0.CO;2-4",
"fulltext": null,
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"issn_linking": "0040-3709",
"issue": "58(1)",
"journal": "Teratology",
"keywords": null,
"medline_ta": "Teratology",
"mesh_terms": "D000305:Adrenal Cortex Hormones; D016022:Case-Control Studies; D002971:Cleft Lip; D002972:Cleft Palate; D005260:Female; D006801:Humans; D007231:Infant, Newborn; D016015:Logistic Models; D016017:Odds Ratio; D011247:Pregnancy; D011261:Pregnancy Trimester, First; D011297:Prenatal Exposure Delayed Effects; D013030:Spain",
"nlm_unique_id": "0153257",
"other_id": null,
"pages": "2-5",
"pmc": null,
"pmid": "9699238",
"pubdate": "1998-07",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Corticosteroids during pregnancy and oral clefts: a case-control study.",
"title_normalized": "corticosteroids during pregnancy and oral clefts a case control study"
} | [
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"companynumb": "ES-PFIZER INC-2016421575",
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"activesubstancename": "HYDROCORTISONE"
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... |
{
"abstract": "BACKGROUND\nThe combination of fludarabine (Flu), high-dose cytarabine (Ara-C) and granulocyte colony-stimulating factor (G-CSF; FLAG), with anthracyclines has become standard chemotherapy for refractory acute myeloid leukemia (AML) in European children and adults. To clarify the efficacy and the safety of FLAG-idarubicin (IDA) for children prospectively, we planned a multicenter phase II study (AML-R11) by the Japanese Pediatric Leukemia/Lymphoma Study Group.\n\n\nMETHODS\nPatients with AML aged between 2 and 20 years old, who had the first bone marrow (BM) relapse or induction failure, were enrolled. The FLAG-IDA regimen consisted of Flu 30 mg/m2 for 5 days, Ara-C 2 g/m2 for 5 days, G-CSF (lenograstim) 5 μg/kg for 6 days and IDA 10 mg/m2 for 3 days. The primary endpoint was remission rate after therapy.\n\n\nRESULTS\nDue to drug supply issues, the trial was suspended after the inclusion of seven eligible patients. There were six cases of early relapse within 1 year of the first remission. All seven patients completed the therapy and no early death was observed. Hematological toxicity was common, and one patient developed grade 4 non-hematological toxicity of bacterial meningitis. Although only one patient with late relapse achieved complete remission, minimal residual disease was positive on both flow cytometry and Wilms' tumor 1 mRNA. Two patients were alive in remission following hematopoietic stem cell transplantation, whereas the other five patients died of either the disease or treatment-related causes.\n\n\nCONCLUSIONS\nFLAG-IDA might be tolerable for children with refractory AML although the efficacy should be further investigated.",
"affiliations": "Department of Pediatrics, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan.;Division of Leukemia and Lymphoma, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan.;Department of Clinical Biostatistics, Graduate School of Medicine, Kyoto University, Kyoto, Japan.;Department of Pediatrics, Mie University Graduate School of Medicine, Tsu, Mie, Japan.;Department of Pediatrics, Okayama University, Okayama, Japan.;Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.;Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.;Department of Pediatrics, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan.;Department of Pediatrics, Hirosaki University Graduate School of Medicine, Hirosaki, Japan.;Department of Pediatrics, Shiga University of Medical Science, Ohtsu, Japan.;School of Human Health Science, Faculty of Medicine, Kyoto University, Kyoto, Japan.;Department of Pediatric Hematology/Oncology, Hyougo Prefectural Kobe Children's Hospital, Kobe, Japan.;Department of Hematology/Oncology, Saitama Children's Medical Center, Saitama, Japan.;Department of Pediatrics, Kyoto Prefectural University of Medicine, Kyoto, Japan.;Department of Pediatrics, Dokkyo Medical University, Tochigi, Japan.;Department of Pediatrics, Showa University Fujigaoka Hospital, Yokohama, Japan.;Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya, Japan.;Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan.;School of Human Health Science, Faculty of Medicine, Kyoto University, Kyoto, Japan.",
"authors": "Nakayama|Hideki|H|http://orcid.org/0000-0002-1994-113X;Tomizawa|Daisuke|D|;Tanaka|Shiro|S|;Iwamoto|Shotaro|S|;Shimada|Akira|A|http://orcid.org/0000-0001-5207-3779;Saito|Akiko M|AM|;Yamashita|Yuka|Y|;Moritake|Hiroshi|H|;Terui|Kiminori|K|;Taga|Takashi|T|;Matsuo|Hidemasa|H|http://orcid.org/0000-0002-7578-006X;Kosaka|Yoshiyuki|Y|;Koh|Katsuyoshi|K|;Hosoi|Hajime|H|;Kurosawa|Hidemitsu|H|;Isoyama|Keiichi|K|;Horibe|Keizo|K|;Mizutani|Shuki|S|;Adachi|Souichi|S|",
"chemical_list": "D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D003561:Cytarabine; D016179:Granulocyte Colony-Stimulating Factor; D000078224:Lenograstim; D014740:Vidarabine; C024352:fludarabine; D015255:Idarubicin",
"country": "Australia",
"delete": false,
"doi": "10.1111/ped.13378",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1328-8067",
"issue": "59(10)",
"journal": "Pediatrics international : official journal of the Japan Pediatric Society",
"keywords": "FLAG-IDA; acute myeloid leukemia; children; minimal residual disease; relapse",
"medline_ta": "Pediatr Int",
"mesh_terms": "D000293:Adolescent; D000970:Antineoplastic Agents; D000971:Antineoplastic Combined Chemotherapy Protocols; D002648:Child; D002675:Child, Preschool; D003561:Cytarabine; D004334:Drug Administration Schedule; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor; D006801:Humans; D015255:Idarubicin; D000078224:Lenograstim; D015470:Leukemia, Myeloid, Acute; D008297:Male; D011994:Recombinant Proteins; D012008:Recurrence; D016896:Treatment Outcome; D014740:Vidarabine; D055815:Young Adult",
"nlm_unique_id": "100886002",
"other_id": null,
"pages": "1046-1052",
"pmc": null,
"pmid": "28771903",
"pubdate": "2017-10",
"publication_types": "D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study",
"references": null,
"title": "Fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia.",
"title_normalized": "fludarabine cytarabine granulocyte colony stimulating factor and idarubicin for relapsed childhood acute myeloid leukemia"
} | [
{
"companynumb": "JP-SA-2018SA072143",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "FLUDARABINE PHOSPHATE"
},
"drugadditional": "3",
... |
{
"abstract": "Despite the current knowledge of UV, there is a lack of consensus among diagnostic criteria and management. In general, antihistamine therapy is regularly used for the symptomatic management of pruritus but does not control inflammation or alter the course of the disease. Monoclonal antibodies such as omalizumab (anti-IgE) have been proposed as a potential treatment for urticarial vasculitis. A few studies have reported the benefits of omalizumab in patient-reported outcome measures (PROMs). Herein we describe a female patient with urticarial vasculitis who was treated with omalizumab. We discuss the response to treatment and possible implications of PROMs in guiding the management of the disease.\n\n\n\nWe describe the case of a 57-year-old woman with a diagnosis of urticarial vasculitis. Due to lack of response to first-line treatment and the severity of the disease, treatment with omalizumab was initiated. Omalizumab 150 mg was administered every four weeks for three months. Second-generation antihistamines were used as needed. Both CU-Q2oL and UAS 7 improved. After three-month therapy with omalizumab, disease severity improved from moderate severity (UAS7 = 19) to well controlled (UAS7 = 6). However, 5 months after the last administration of omalizumab, the patient complained of worsening symptoms and active disease with quality of life impairment. A single dose of omalizumab (150 mg) was prescribed with corticosteroids. Thereafter, the patient presented a disease activity and quality of life with a fluctuating pattern that was controlled with additional doses of omalizumab.\n\n\n\nIn chronic urticaria, patient-reported outcome measures (PROMs) are important for assessing disease status and the impact of symptoms on patients' lives. However, to our knowledge, there is no validated tool to measure such outcomes in UV patients. Although UAS7 and CU-Q2oL were not designed for UV assessment, they might be useful in the clinical setting as objective measures to determine treatment efficacy. However, some domains in the CU-Q2oL questionnaires do not correlate well with UAS7, which might serve as a relative indication to continue treatment despite disease severity improvement. Based on our observations, we believe omalizumab 150 mg might be a feasible therapeutic alternative when first-line treatment is unsuccessful.",
"affiliations": "Universidad Espíritu Santo, Km. 2.5 vía La Puntilla, 0901-952, Samborondon, Guayaquil, Ecuador. ivancherrez@gmail.com.;Universidad Espíritu Santo, Km. 2.5 vía La Puntilla, 0901-952, Samborondon, Guayaquil, Ecuador.;Universidad Espíritu Santo, Km. 2.5 vía La Puntilla, 0901-952, Samborondon, Guayaquil, Ecuador.;Universidad Espíritu Santo, Km. 2.5 vía La Puntilla, 0901-952, Samborondon, Guayaquil, Ecuador.;Respiralab, Respiralab Research Group, Guayaquil, Ecuador.",
"authors": "Cherrez-Ojeda|Ivan|I|0000-0002-1610-239X;Vanegas|Emanuel|E|;Felix|Miguel|M|;Mata|Valeria L|VL|;Cherrez|Annia|A|",
"chemical_list": "D018926:Anti-Allergic Agents; D039563:Histamine H1 Antagonists, Non-Sedating; D000069444:Omalizumab",
"country": "England",
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"doi": "10.1186/s12895-018-0077-x",
"fulltext": "\n==== Front\nBMC DermatolBMC DermatolBMC Dermatology1471-5945BioMed Central London 303592317710.1186/s12895-018-0077-xCase ReportPatient-reported outcomes in urticarial vasculitis treated with omalizumab: case report http://orcid.org/0000-0002-1610-239XCherrez-Ojeda Ivan +59345114555ivancherrez@gmail.com 12Vanegas Emanuel emnlv@hotmail.com 12Felix Miguel miguel.felixromero@gmail.com 12Mata Valeria L. valeria.matac@gmail.com 12Cherrez Annia anniacherrez@hotmail.com 231 grid.442156.0Universidad Espíritu Santo, Km. 2.5 vía La Puntilla, 0901-952, Samborondon, Guayaquil Ecuador 2 Respiralab, Respiralab Research Group, Guayaquil, Ecuador 3 Dermatology Department, University Hospital, Rostock, Germany 25 10 2018 25 10 2018 2018 18 82 3 2018 10 10 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\nDespite the current knowledge of UV, there is a lack of consensus among diagnostic criteria and management. In general, antihistamine therapy is regularly used for the symptomatic management of pruritus but does not control inflammation or alter the course of the disease. Monoclonal antibodies such as omalizumab (anti-IgE) have been proposed as a potential treatment for urticarial vasculitis. A few studies have reported the benefits of omalizumab in patient-reported outcome measures (PROMs). Herein we describe a female patient with urticarial vasculitis who was treated with omalizumab. We discuss the response to treatment and possible implications of PROMs in guiding the management of the disease.\n\nCase presentation\nWe describe the case of a 57-year-old woman with a diagnosis of urticarial vasculitis. Due to lack of response to first-line treatment and the severity of the disease, treatment with omalizumab was initiated. Omalizumab 150 mg was administered every four weeks for three months. Second-generation antihistamines were used as needed. Both CU-Q2oL and UAS 7 improved. After three-month therapy with omalizumab, disease severity improved from moderate severity (UAS7 = 19) to well controlled (UAS7 = 6). However, 5 months after the last administration of omalizumab, the patient complained of worsening symptoms and active disease with quality of life impairment. A single dose of omalizumab (150 mg) was prescribed with corticosteroids. Thereafter, the patient presented a disease activity and quality of life with a fluctuating pattern that was controlled with additional doses of omalizumab.\n\nConclusion\nIn chronic urticaria, patient-reported outcome measures (PROMs) are important for assessing disease status and the impact of symptoms on patients’ lives. However, to our knowledge, there is no validated tool to measure such outcomes in UV patients. Although UAS7 and CU-Q2oL were not designed for UV assessment, they might be useful in the clinical setting as objective measures to determine treatment efficacy. However, some domains in the CU-Q2oL questionnaires do not correlate well with UAS7, which might serve as a relative indication to continue treatment despite disease severity improvement. Based on our observations, we believe omalizumab 150 mg might be a feasible therapeutic alternative when first-line treatment is unsuccessful.\n\nKeywords\nUrticarial vasculitisPatient-reported outcomesOmalizumabissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nUrticarial vasculitis (UV) is a clinicopathological entity consisting of clinical manifestations of urticaria and histopathological evidence of small vessel cutaneous leukocytoclastic vasculitis (LCV) [1]. Clinically, lesions typically persist beyond 24 h, often resolving with faint residual hyperpigmentation. Vasculitic lesions can be pruritic in nature, but more commonly present in an asymptomatic or painful way (often with a stinging or burning sensation) [2]. Histopathological lesions consist of an inflammatory manifestation with injury to the capillaries and postcapillary venules in the skin [3]. Leukocytoclasis and fibrinoid deposits appear to be the most distinguishing features of LCV and are direct signs of vessel damage [4].\n\nUV is a relatively uncommon disease, with a prevalence ranging from 2 to 20% among chronic urticaria patients (CU) [5]. In a previous study, we found the prevalence to be approximately 10% of CU patients [6]. It is more common among women, with a peak incidence around the fourth decade of life [5]. Regarding the etiology, most cases appear to be idiopathic. UV can also be associated with connective-tissue diseases, particularly systemic lupus erythematosus (SLE) and Sjogren’s syndrome [7]. Malignancies, chronic infections, serum sickness, drugs, and sun exposure are also associated with UV [7]. Systemic manifestations of UV can include constitutional symptoms, musculoskeletal, renal, ophthalmic, pulmonary, gastrointestinal, neurologic, and even cardiovascular involvement [8].\n\nSerum complement levels are of particular importance. Patients with low complement levels usually present more systemic involvement, while normocomplementemic patients have a milder course [9]. Among the recognized syndromes of low complement levels in association with UV, are hypocomplementemic urticarial vasculitis syndrome (HUVS), and hypocomplementemic urticarial vasculitis (HUV) [5]. HUVS, also known as McDuffie syndrome, is recognized as an autoimmune disorder with at least 6 or more months of urticaria in the presence of hypocomplementemia, and various systemic manifestations (including arthritis, arthralgias, glomerulonephritis, uveitis, episcleritis, and recurrent abdominal pain) [10]. On the other hand, HUV are patients who do not meet criteria for HUVS, but still present with low complement levels. In comparison to HUVS, HUV patients present with fewer systemic manifestations [5].\n\nDespite the current knowledge of UV, there is a lack of consensus among diagnostic criteria and management. Treatment varies from patient to patient according to the disease severity and clinical presentation. In general, antihistamine therapy is regularly used for the symptomatic management of pruritus but does not control inflammation or alter the course of the disease [11]. Hydroxychloroquine (HCQ) appears to be as effective as corticosteroids among first-line therapy options [8]. The immunosuppressive agents azathioprine (AZA), mycophenolate mofetil (MMF), rituximab, or cyclophosphamide may be used in patients with relapsing or refractory disease [8]. Dapsone, colchicine, and cyclosporine have been used as therapeutic alternatives, mostly with unsatisfying results [12].\n\nMonoclonal antibodies such as omalizumab (anti-IgE) have been proposed as a potential treatment for urticarial vasculitis [13]. A few studies have reported the benefits of omalizumab in patient-reported outcome measures (PROMs) [14]. Herein we describe a female patient with urticarial vasculitis who was treated with omalizumab. We discuss the response to treatment and possible implications of PROMs in guiding the management of the disease.\n\nCase presentation\nA 57-year-old woman presented to our office with complaints of wheals, arthralgias, and a severe, generalized burning sensation on the skin. The skin lesions appeared as urticarial plaques located mainly on the trunk and proximal extremities persisting for more than 24 h after the initial appearance and leaving faint residual hyperpigmentation on the skin (Fig. 1). The patient reported approximately 6 months of relapsing and remitting symptoms. No angioedema or relevant past medical history were noted. On the basis of the previous findings, a possible diagnosis of urticarial vasculitis was suspected, and laboratory tests with a skin biopsy were requested. Laboratory tests were unremarkable; no abnormalities were noted on hemogram, acute phase reactants, thyroid function, or complement levels. Skin biopsy revealed leukocytoclastic vasculitis with perivascular infiltrates and neutrophil predominance (Fig. 2). After a careful assessment, the patient was diagnosed with normocomplementemic urticarial vasculitis.Fig. 1 Urticarial vasculitis lesions on lateral portion of right thigh. Clinical characteristics of lesions included generalized burning sensation of the skin, with plaques persisting for more than 24 h and leaving faint residual hyperpigmentation of the skin (highlighted by the arrow)\n\nFig. 2 Histopathology of urticarial vasculitis lesions showing leukocytoclastic vasculitis with perivascular infiltrates and neutrophil predominance\n\n\n\nThe patient was initially treated with a short course of oral corticosteroids (prednisone 40 mg initially for 4 days, followed by gradual tapering off for a total of 12 days), first generation H1 antihistamine (hydroxyzine 50 mg taken at night), second generation H1 antihistamine (fexofenadine 20 mg up to fourfold dosage), and hydroxychloroquine 200 mg daily for 4 months. Despite the initial treatment, the symptoms did not improve, and the UV appeared as a more active and severe disease during physical examination. In addition, the patient was disappointed with how her quality of life was markedly impaired due to her clinical condition. For this reason, Urticaria Activity Score 7 (UAS7) and Chronic Urticaria Quality of Life Questionnaire (CU-Q2oL) were assessed for the first time to have a more objective course of the disease. Her UAS7 immediately after the 4-month course of first-line therapy was 19, while CU-Q2oL showed a functioning status of 29.2, sleep of 12.5, itching/embarrassment of 25.0, mental status of 25.0, swelling/eating of 18.8, and limited appearance of 25.0. Due to the lack of response to first-line treatment and the severity of the disease, treatment with omalizumab was initiated.\n\nOmalizumab 150 mg was administered every 4 weeks for 3 months. Second-generation antihistamines were used as needed. Both CU-Q2oL and UAS 7 improved. After three-month therapy with omalizumab, disease severity improved from moderate severity (UAS7 = 19) to well controlled (UAS7 = 6). However, due to economic limitations and insurance restrictions, the patient discontinued the treatment with omalizumab. Then, 5 months after she received her third dose, the patient complained of worsening symptoms and active disease with quality of life impairment. Thus, the fourth omalizumab (150 mg) dose was prescribed with corticosteroids. Thereafter, the patient presented a disease activity and quality of life with a fluctuating pattern that was controlled with additional doses of omalizumab (5 in total), which is depicted in Fig. 3a. While follow-up is still ongoing, the patient is currently asymptomatic without any kind of medications and her mean UAS7 score after the last administration of omalizumab (ninth dose) is 4.88, which is considered a well-controlled urticaria (Fig. 3b) [15].Fig. 3 UAS7, CU-Q2oL and UCT scores over time. Data are expressed as scores in Y axis, while time is expressed in a monthly scale on X axis. (A) UAS7, CU-Q2oL and UCT scores during treatment with Omalizumab. For CU-Q2oL, each of the six domains are represented separately (functioning, sleep, itching/embarrassment, mental status, swelling/eating and limits looks). Omalizumab doses received are depicted as purple circles. (B) UAS7 scores during follow-up after treatment with Omalizumab. UAS7, Urticaria Activity Score 7; CU-Q2oL, Chronic Urticaria Quality of Life; UCT, Urticaria Control Test\n\n\n\nDiscussion\nIn chronic urticaria, patient-reported outcome measures (PROMs) are important for assessing disease status and the impact of symptoms on patients’ lives [16]. However, to our knowledge, there is no validated tool to measure such outcomes in UV patients. Although UAS7 and CU-Q2oL were not designed for UV assessment, we used these tools to measure how successful or unsuccessful the first-line therapy was in managing the disease. A modest control of disease severity was considered the major criteria for prescribing omalizumab. Both questionnaires were used to observe their fluctuations over the course of the disease, serving as guides for the management and indication of omalizumab.\n\nUnderstanding the role of omalizumab in UV remains controversial. Theoretically, omalizumab should improve any IgE-mediated condition, such as type I hypersensitivity reactions [17]. UV is mediated by a type III hypersensitivity reaction, with antigen-antibody complexes depositing at the vascular lamina. Omalizumab might not work in UV because its pharmacodynamics are incompatible with the pathogenesis of this disease [18].\n\nFew publications have reported the use of omalizumab in UV. For instance, in a publication by Fueyo-Casado et al., omalizumab was initiated in a female patient with a baseline UAS7 of 32 at 300 mg monthly for 12 months. The patient achieved remission (UAS of 0) by the fifth dose. In contrast, at a baseline UAS7 of 19, we administered half the dose monthly for the first 3 months, and UAS7 improved after this time (UAS7 = 6). As the benefits of omalizumab are considered to be dose-dependent, there was some efficacy in using half of the recommended dose. Unfortunately, the omalizumab treatment was suspended due to economic limitations, as is frequently seen with many low-income patients [19, 20]. It is interesting, however, to highlight that CU-Q2oL did not improve as well as UAS7, leading to a worse quality of life even in the presence of less severe disease after the three-week treatment.\n\nAlthough the correlation between UAS7 and CU-Q2oL was fairly good in the domains previously described, continuous administration with omalizumab at the beginning of treatment might be recommended, because 150 mg dose improves severity but seems insufficient to improve quality of life.\n\nIn another publication by Diez et al., a regimen of 150 mg every 4 weeks achieved remission in two patients, and Sussman et al. reported successful results in a patient who also achieved remission [21, 22]. It is unclear whether 150 mg or 300 mg should be used and for how long, but certainly quality of life should be considered in the initial assessment of UV.\n\nAlthough corticosteroids are the mainstay of UV treatment, we preferred omalizumab and hydroxychloroquine because corticosteroids traditionally need to be used over the long term to prevent disease relapse, leading to more adverse effects [23]. Omalizumab and hydroxychloroquine safety profiles are better than those of corticosteroids and result in fewer complications [23]. Corticosteroids were used only during periods of highly active disease. Our patient developed an exacerbation 5 months after the three-month course of omalizumab, with the highest UAS7 (28) and the greatest impairment in quality of life. The association between UAS7 and CU-Q2oL was evident during this crisis. Both greatly improved after the administration of corticosteroids and omalizumab. This combination proved useful during exacerbations.\n\nPROMs assist physicians in making inferences about changes in disease activity, response to treatment, and changes in health-related quality of life (HRQoL) [24]. Either the Dermatology Life Quality Index (DLQI) or CU-Q2oL might be used for chronic spontaneous urticaria (CSU) [25, 26]. However, neither have been validated for UV management. In a publication by Stull D. et al., CSU latent growth curve trajectories showed correlations between slopes of change in UAS7 and CU-Q2oL in clinical trials of ASTERIA I (0.90), ASTERIA II (0.89), and GLACIAL (0.92) [24]. Although we cannot directly compare our results due to methodological discrepancies, we also found a strong correlation between UAS7 and CU-Q2oL mean scores (r = .74, p = .022). This contrasts with another publication in which UAS7 was shown to only moderately correlate with the CU-Q2oL total score (r = 0.40, p < 0.0001) and with the DLQI score (r = 0.37, p < 0.0001) in CSU patients [27]. A weak significant correlation (r = 0.31, p < 0.05) between urticaria activity score values and DLQI in CU patients has also been reported [28].\n\nInterestingly, there seems to be a group of patients with relatively low UAS7 that nevertheless experience a remarkable impairment in their HRQoL [27]. This was replicated in our patient and is the reason why, in some scenarios, quality of life impairment was considered as a primary indication for omalizumab prescription independent of disease severity. Omalizumab was prescribed due to quality of life impairment on six occasions, once in the context of controlled disease and five times in mild disease assessed by UAS7. We believe that this phenomenon could be explained in part by the fact that such observation was made by analyzing quality of life as a total or average sum rather than addressing it by its axes separately as it was originally designed to be used. Certainly, discrepancy between different axes might be found. For instance, in a study of 51 CSU patients, significant correlations with UAS7 were reported for functioning (r = 0.31, p = .03), itching/embarrassment (r = 0.54, p = .001), and mental status (r = 0.28, p = .048), while those of sleep, swelling/eating, and limited appearance were not [26]. We found similar results in our patient, with stronger correlations between UAS7 and functioning (r = .84, p = .005), itching/embarrassment (r = .84, p = .005), mental status (r = .79, p = .011), and sleep (r = .72, p = .029) (Fig. 4). Correlations for swelling/eating (r = .04, p = .922) and limited appearance (r = .51, p = .165) were not statistically significant, since they did not improve as expected with treatment.Fig. 4 CU-Q2oL domains’ scores as a function of UAS7 scores. Each CU-Q2oL domain value in Y axis is expressed as a function of UAS7 on X axis, as depicted on each upper right box. All correlations were statistically significant, except for swelling/eating and limits looks. Continuous line represents the linear regression line of best fit, whilst dashed lines are confidence intervals (95%). UAS7, Urticaria Activity Score 7; CU-Q2oL, Chronic Urticaria Quality of Life; R2 linear, coefficient of determination\n\n\n\nWe would not recommend evaluating CU-C2oL as a single score since axis-per-axis evaluation might lead to a more thorough understanding of quality of life impairment. Under some circumstances, disruption in a single axis might be a sufficient indication to initiate omalizumab therapy even if the remainder axes have progressed favorably within a less active disease. Impairment in quality of life by itself might lead to significant morbidity. Patients with CSU often experience depression and anxiety, with studies showing a positive correlation between itch intensity and severity of depression [29]. Patients complain of recurrent pain syndromes, including tension headaches and fibromyalgia, while the prevalence of psychiatric disorders such as depression, hysteria, hypochondria, and post-traumatic stress disorder is high in these individuals [30–32].\n\nOf note, to prevent such comorbidities, it is essential that every prescribed therapeutic regimen be evaluated objectively with parameters of disease control. Although it is not validated for urticarial vasculitis, the Spanish version of UCT was discretely used since month 13 [33]. UCT is a validated instrument designed to assess the level of disease control in CU patients, in which a score ≥ 12 indicates well-controlled urticaria, while a score of ≤11 indicates poor disease control [34]. UCT has been shown to correlate slightly better with the total CU-Q2oL score than with UAS7 [34]. The mean score of the five UCT questionnaires answered by our patient revealed poor control. In general, UCT scores did not correlate with either UAS7 or each of the CU-Q2oL domains. However, UCT correlated strongly with the total CU-Q2oL score (r = −.95, p = .023). Although we have very limited data from this test, it was the least useful method for managing the disease.\n\nLittle is known about the role of omalizumab in UV and how treatment should be followed-up in terms of disease activity and PROMs improvement. Based on our observations, we believe omalizumab 150 mg might be a feasible therapeutic alternative when first-line treatment is unsuccessful. Omalizumab in UV has shown improvement in quality of life and disease severity without the significant adverse effects caused by first-line regimens. UAS7 and CU-Q2oL might be useful in the clinical setting as objective measures to determine treatment efficacy. However, some domains in the CU-Q2oL questionnaires do not correlate well with UAS7, which might serve as a relative indication to continue treatment despite disease severity improvement. Further studies are needed to confirm our findings.\n\nAbbreviations\nAZAAzathioprine\n\nCUChronic urticaria\n\nCU-Q2oLChronic Urticaria Quality of Life Questionnaire\n\nDLQIDermatology Life Quality Index\n\nHQCHydroxychloroquine\n\nHRQoLHealth-related quality of life\n\nLCVLeukocytoclastic vasculitis\n\nMMFMycophenolate mofetil\n\nPROMsPatient-reported outcome measures\n\nSLESystemic lupus erythematosus\n\nUAS7Urticaria activity score\n\nUCTUrticaria control test\n\nUVUrticarial vasculitis\n\nAcknowledgements\nDr. Ivan Cherrez Ojeda is a candidate at the Doctorate Program of Biomedical Research and Public Health, Universitat Autonoma de Barcelona. The authors acknowledge the guidance and knowledge imparted by the MECOR Program for this study, especially from Sonia Buist MD and Ana Menezes MD. We also want to express our gratitude to Universidad Espiritu Santo for their support.\n\nFunding\nThis study was partially supported by an unrestricted grant from the Universidad Espíritu Santo. The sponsor had no role in the design of the study or in the collection, analysis, and interpretation of data.\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors’ contributions\nCHOI, VE, FM, MV, AC developed the research question for the case report and participated in the data collection process. VE, AC interviewed the patient and oversaw the informed consent. VE, FM, MV, wrote the manuscript. CHOI, VE, FM, AC looked for grammatical and syntax errors in English. All authors approved the manuscript before submission.\n\nEthics approval and consent to participate\nNot applicable\n\nConsent for publication\nWritten informed consent was obtained from the patient for publication of this Case report and all accompanying images. A copy of the written consent is available for review by the Series Editor of this journal if requested.\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. Warin RP Urticarial vasculitis Br Med J (Clin Res Ed) 1983 286 1919 1920 10.1136/bmj.286.6382.1919 \n2. Wisnieski JJ Urticarial vasculitis Curr Opin Rheumatol 2000 12 24 31 10.1097/00002281-200001000-00005 10647951 \n3. 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Pasaoglu G Bavbek S Tugcu H Abadoglu O Misirligil Z Psychological status of patients with chronic urticaria J Dermatol 2006 33 765 771 10.1111/j.1346-8138.2006.00178.x 17073991 \n32. Chung MC Symons C Gilliam J Kaminski ER The relationship between posttraumatic stress disorder, psychiatric comorbidity, and personality traits among patients with chronic idiopathic urticaria Compr Psychiatry 2010 51 55 63 10.1016/j.comppsych.2009.02.005 19932827 \n33. Garcia-Diez I Curto-Barredo L Weller K Pujol RM Maurer M Gimenez-Arnau AM Cross-cultural adaptation of the Urticaria control test from German to Castilian Spanish Actas Dermosifiliogr 2015 106 746 752 10.1016/j.ad.2015.05.009 26164835 \n34. Weller Karsten Groffik Adriane Church Martin K. Hawro Tomasz Krause Karoline Metz Martin Martus Peter Casale Thomas B. Staubach Petra Maurer Marcus Development and validation of the Urticaria Control Test: A patient-reported outcome instrument for assessing urticaria control Journal of Allergy and Clinical Immunology 2014 133 5 1365-1372.e6 10.1016/j.jaci.2013.12.1076 24522090\n\n",
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"issn_linking": "1471-5945",
"issue": "18(1)",
"journal": "BMC dermatology",
"keywords": "Omalizumab; Patient-reported outcomes; Urticarial vasculitis",
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"mesh_terms": "D018926:Anti-Allergic Agents; D002908:Chronic Disease; D005260:Female; D039563:Histamine H1 Antagonists, Non-Sedating; D006801:Humans; D008875:Middle Aged; D000069444:Omalizumab; D000071066:Patient Reported Outcome Measures; D011537:Pruritus; D012008:Recurrence; D014581:Urticaria; D018366:Vasculitis, Leukocytoclastic, Cutaneous",
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"pubdate": "2018-10-25",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "27942350;6407634;24652205;23242113;1564151;26164835;8197313;24522090;18681869;9167337;18445192;25385679;27777182;22006145;24468258;26435858;17073991;26833304;28247460;15120147;12221865;17390766;19932827;22328958;10647951;26483177;16724624;23942323;6134548;23891451;29084635;29308115;26053294",
"title": "Patient-reported outcomes in urticarial vasculitis treated with omalizumab: case report.",
"title_normalized": "patient reported outcomes in urticarial vasculitis treated with omalizumab case report"
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"companynumb": "EC-MYLANLABS-2018M1088095",
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"occurcountry": "EC",
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"activesubstancename": "FEXOFENADINE\\FEXOFENADINE HYDROCHLORIDE"
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"abstract": "OBJECTIVE\nTo compare maternal characteristics, prenatal care, and newborn outcomes in a cohort of opioid-dependent pregnant women treated with methadone versus buprenorphine.\n\n\nMETHODS\nIn a retrospective cohort study, 609 pregnant, opioid-dependent women were treated with methadone (n = 248) or buprenorphine (n = 361) between 2000 and 2012 at a single institution.\n\n\nRESULTS\nMothers treated with buprenorphine were more likely to start medication before or earlier in pregnancy, had longer gestation, and gave birth to larger infants. Newborns of buprenorphine- versus methadone-maintained mothers required treatment for neonatal abstinence significantly less often and for a shorter duration.\n\n\nCONCLUSIONS\nThese data suggest pregnancy outcomes with buprenorphine to treat opioid dependence during pregnancy in clinical practice are as good and often better than outcomes with methadone. These results are consistent with efficacy data from randomized clinical trials and further support the use of buprenorphine for the treatment of opioid dependence during pregnancy.",
"affiliations": "From the Department of Obstetrics, Gynecology and Reproductive Sciences (MCM), Department of Pediatrics (AMJ), Department of Mathematics and Statistics (AMC), and Departments of Psychiatry and Psychology (SHH), University of Vermont, Burlington, VT.",
"authors": "Meyer|Marjorie C|MC|;Johnston|Anne M|AM|;Crocker|Abigail M|AM|;Heil|Sarah H|SH|",
"chemical_list": "D000701:Analgesics, Opioid; D002047:Buprenorphine; D008691:Methadone",
"country": "United States",
"delete": false,
"doi": "10.1097/ADM.0000000000000092",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1932-0620",
"issue": "9(2)",
"journal": "Journal of addiction medicine",
"keywords": null,
"medline_ta": "J Addict Med",
"mesh_terms": "D000328:Adult; D000701:Analgesics, Opioid; D002047:Buprenorphine; D005260:Female; D006801:Humans; D008691:Methadone; D058850:Opiate Substitution Treatment; D009293:Opioid-Related Disorders; D011247:Pregnancy; D011256:Pregnancy Outcome; D012189:Retrospective Studies; D055815:Young Adult",
"nlm_unique_id": "101306759",
"other_id": null,
"pages": "81-6",
"pmc": null,
"pmid": "25622120",
"pubdate": "2015",
"publication_types": "D003160:Comparative Study; D016428:Journal Article; D052061:Research Support, N.I.H., Extramural; D013485:Research Support, Non-U.S. Gov't",
"references": "18355989;15943939;18283247;19344048;8092377;21142534;17475739;21538146;16257138;19332991;3345396;9547764;11497536;18783498;18770079;15169566;9519499;15173491;23106923;3969327;16445556;617308",
"title": "Methadone and buprenorphine for opioid dependence during pregnancy: a retrospective cohort study.",
"title_normalized": "methadone and buprenorphine for opioid dependence during pregnancy a retrospective cohort study"
} | [
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"companynumb": "US-MALLINCKRODT-T201803767",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
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"actiondrug": "4",
"activesubstance": {
"activesubstancename": "METHADONE HYDROCHLORIDE"
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"abstract": "Gastric adenocarcinoma concurrent with metastatic neuroendocrine cancer (NEC) is rare. In the present case report, a 39-year-old male was first pathologically diagnosed by gastric endoscopy as having a highly differentiated adenocarcinoma. Next, positron emission tomography-computed tomography examination and bone marrow biopsy confirmed extensive metastasis. Subsequently, the patient underwent 6 cycles of immunotherapy (nivolumab, 160 mg) and 5 cycles of chemotherapy based on the XELOX regimen (oxaliplatin + capecitabine). Following this, the patient received the final cycles of nivolumab and XELOX; however, the patient then succumbed. Further biopsy of the metastatic collarbone lymph nodes indicated NEC. Overall, the progression-free survival was ~3.5 months, and overall survival (OS) was ~6 months. The case presented the possibility of concurrent gastric adenocarcinoma and NEC in the clinic. In addition, the efficacy of a combined regimen such as immunotherapy and chemotherapy for such disorders still requires further validation in the future.",
"affiliations": "Department of Oncology, Hainan Branch of PLA General Hospital, Sanya, Hainan 572000, P.R. China.;Department of Outpatient, Hainan Branch of PLA General Hospital, Sanya, Hainan 572000, P.R. China.;Department of Oncology, Hainan Branch of PLA General Hospital, Sanya, Hainan 572000, P.R. China.;Department of Oncology, Hainan Branch of PLA General Hospital, Sanya, Hainan 572000, P.R. China.;Department of Oncology, Hainan Branch of PLA General Hospital, Sanya, Hainan 572000, P.R. China.",
"authors": "Yan|Bing|B|;Cui|Meiqi|M|;You|Junhao|J|;Li|Fang|F|;Liu|Hui|H|",
"chemical_list": null,
"country": "England",
"delete": false,
"doi": "10.3892/mco.2018.1740",
"fulltext": "\n==== Front\nMol Clin OncolMol Clin OncolMCOMolecular and Clinical Oncology2049-94502049-9469D.A. Spandidos 10.3892/mco.2018.1740MCO-0-0-1740ArticlesGastric adenocarcinoma is concurrent with metastatic neuroendocrine cancer treated with nivolumab and chemotherapy: A case report Yan Bing 1*Cui Meiqi 2*You Junhao 1Li Fang 1Liu Hui 11 Department of Oncology, Hainan Branch of PLA General Hospital, Sanya, Hainan 572000, P.R. China2 Department of Outpatient, Hainan Branch of PLA General Hospital, Sanya, Hainan 572000, P.R. ChinaCorrespondence to: Dr Hui Liu, Department of Oncology, Hainan Branch of PLA General Hospital, 80 Jianglin Road, Sanya, Hainan 572000, P.R. China, E-mail: woshiliuhui1995@aliyun.com* Contributed equally\n\n12 2018 05 10 2018 05 10 2018 9 6 607 612 28 6 2018 21 9 2018 Copyright: © Yan et al.2018This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs 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.Gastric adenocarcinoma concurrent with metastatic neuroendocrine cancer (NEC) is rare. In the present case report, a 39-year-old male was first pathologically diagnosed by gastric endoscopy as having a highly differentiated adenocarcinoma. Next, positron emission tomography-computed tomography examination and bone marrow biopsy confirmed extensive metastasis. Subsequently, the patient underwent 6 cycles of immunotherapy (nivolumab, 160 mg) and 5 cycles of chemotherapy based on the XELOX regimen (oxaliplatin + capecitabine). Following this, the patient received the final cycles of nivolumab and XELOX; however, the patient then succumbed. Further biopsy of the metastatic collarbone lymph nodes indicated NEC. Overall, the progression-free survival was ~3.5 months, and overall survival (OS) was ~6 months. The case presented the possibility of concurrent gastric adenocarcinoma and NEC in the clinic. In addition, the efficacy of a combined regimen such as immunotherapy and chemotherapy for such disorders still requires further validation in the future.\n\ngastric adenocarcinomaneuroendocrine cancertumor markersnivolumaboxaliplatin + capecitabine\n==== Body\nIntroduction\nAlthough gastric cancer is thought to be a highly heterogeneous disease (1), adenocarcinoma is still the most frequent pathological type in clinics. Neuroendocrine cancer (NEC) in the stomach is uncommon and only accounts for approximately 0.1–0.2% of all cancers that occur in the organ (2). Concurrent occurrence of gastric adenocarcinoma and neuroendocrine cancer is rare and has only been registered in a few case reports so far.\n\nTo date, such concurrent lesions have been classified into two subgroups according to their morphological features, named the composite-type and the collision-type; in the former, both elements seem to be mixed haphazardly, while in the latter, the tumors are considered double tumors with ‘a hand in hand’ conformation (3). Based on the complex relationship of the cancers, definite pathological diagnosis of such lesions is difficult. Most of the previous cases were diagnosed by gross specimens from surgery, such as gastrectomy. In 2010, the WHO named mixed adenoneuroendocrine carcinomas (MANECs), which present neuroendocrine cells (usually over 30% of all tumor cells) mixed with nonendocrine components (usually adenocarcinoma) (4), as a new category in the list of NECs. Interestingly, some of the previous cases are likely to be reclassified into this group retrospectively.\n\nIn this study, we present a case of gastric adenocarcinoma concurrent with metastatic NEC treated by nivolumab and chemotherapy (based on the XELOX regimen). The overall survival time of the patient was approximately 6 months. Our case addresses the possibility of concurrent gastric adenocarcinoma and NEC in the clinic; however, the efficacy of a combined regimen such as immunotherapy (nivolumab, for example) and chemotherapy for such disorders still needs further validation.\n\nCase report\nA 39-year-old man was first revealed by the 13C breath test to have an H. pylori infection during a routine physical examination; however, no treatment was adopted. Six months later, he suddenly presented tarry stool after drinking and underwent a gastric endoscopy, the pathological results of which indicated a well-differentiated adenocarcinoma on the gastric corpus (Fig. 1A); further immunohistochemical staining indicated the presence of CD4 (3+), CD8 (3+), MAGEA3 (2+), NY-ESO-1 (−), and PD-L1 (−) (Fig. 1B-F). Subsequent PET-CT examination showed the following: 1). Irregular wall thickening on the distal gastric corpus and antrum, particularly the greater curvature, indicated gastric cancer with adjacent fatty infiltration, and the greater omentum, ascending and transverse colon were likely to be involved; 2). Multiple lymph node metastases were present around the left supraclavicular and neck, to the right of the diaphragmatic feet, and in the left gastric artery area, celiac axis, liver and gastric ligament, small omental bursa, mesentery, retroperitoneal abdominal aorta and inferior vena cava; 3). The right and left femoral cavity, as well as multiple bones throughout the body, presented metastatic lesions. The patient then underwent a bone marrow biopsy, which confirmed metastatic cancer, and FISH for Her-2 (negative). He then received the first cycle of nivolumab (160 mg) treatment in another hospital and came to our department. Further review of baseline images including chest, abdomen and pelvis computed tomography (CT) scans confirmed the previous imagological diagnosis (Fig. 2). Next, he received the second cycle of nivolumab and took capecitabine (1.5 g po twice per day, days 1–14 every 3 weeks) simultaneously. After that, another 3 cycles of nivolumab and XELOX (oxaliplatin 200 mg ivgtt, day 1+ capecitabine 1.5 g po twice per day, days 1–14) regimen treatments were executed; however, the intervals of the treatment plan were not executed as scheduled because of severe complications, including myelosuppression (grade 2–3 decreased platelet count and grade 1–2 anemia) and grade 1–3 hand-foot syndrome. Evaluation of the therapeutic effects was conducted by abdominal CT scan and a blood test for tumor markers as planned (Fig. 3). Stable disease (SD) and obvious progressive disease (PD) were detected after 3 and 5 cycles of treatment, respectively. He received the last 2 cycles of treatment even though the disease was considered to be PD. A further biopsy of the metastatic collarbone lymph nodes indicated neuroendocrine cancer with the following immunohistochemical staining: synaptophysin (+), CD56 (+), CK/CK7 (+), CK20 (−), Villin (−), Ki-67 (>75%) (Fig. 4). All the treatments were then ceased because of the poor performance status and severe complications; he died on December 12. Written informed consent was obtained from the patient's father.\n\nDiscussion\nGastric adenocarcinoma concurrent with metastatic NEC is a rare phenomenon. To the best of our knowledge, concurrent gastric adenocarcinoma and NEC are uncommon and have only been registered in a few case reports (Table I) (5–23). In our study, the patient was treated with nivolumab and chemotherapy. Although a transient disease regression was observed, the PFS (~3.5 months) and OS (~6 months) were still unsatisfactory; the efficacy of the combined regimen for such disorders needs further validation in the future.\n\nIn recent years, the detection of a neuroendocrine element in gastrointestinal cancers has been increasingly registered, which has often prevented concise diagnosis. In fact, the majority of previous cases (5,6,8–15,17–21,23) were diagnosed by gross specimens from surgeries such as gastrectomy because the neuroendocrine component is usually located in the mucosa, while the adenocarcinoma is seated in the deeper layers (7,14,21,24); furthermore, each of the two cancer types can occasionally present pathological evidence for the differentiation of the other (14,25–28) or the possibility of transformation from one type to the other (29). In our study, a MANEC (or, to be more precise, a high-grade MANEC by La Rosa's report) (30) likely occurred according to the new categorization by WHO in 2010, considering that some reports have indicated that gastric NEC is prone to metastasis (13) and that the cells in metastatic sites are similar to those in the primary sites (2,11). However, due to the lack of gross samples and autopsy, it is impossible to estimate the percentage of cell elements in the tumor, and thus, a definite diagnosis was difficult.\n\nTo date, consensus guidelines for the management of double or multiple original cancers have not been established. La Rosa et al (30) suggested that priority should be given to the more malignant elements in the mass. For our case, some guidelines recommended management in the same manner as for gastric adenocarcinomas (31). For example, Li et al (17) reported that the FOLFOX regimen in such cases could achieve a 12-month disease-free survival. However, as NEC is notorious for its aggressive nature, most investigators have suggested that these elements should be considered therapeutic targets (32). In 1999, Mitry et al (33) first reported the efficacy of etoposide and cisplatin regimens in a cohort of 53 neuroendocrine cancers (including 3 cases that occurred in gastric cancer); Uchiyama et al (2) introduced S-1-based regimens as adjuvant therapy for 7 cases, and the 3-year overall survival rate was 83.8%. Okita et al (34) reported that cisplatin plus irinotecan regimens received a good response in 12 cases. Notably, Ip et al (35) reported a spontaneous complete regression of gastric NEC that seemed to be mediated by cytomegalovirus-induced cross-autoimmunity. In our case, the patient was treated with the XELOX regimen based on the first pathological results, and whether replacement with schemes such as etoposide and cisplatin could have led to tumor regression is unknown because of the poor physical states and severe complications of the patient at the terminal stage.\n\nIn recent years, immunotherapy has become increasingly popular in treating cancers, but the efficacy of such therapies is still being validated. A major problem for such therapies is the lack of reliable biomarkers for patient selection and response evaluation. Predictive biomarkers such as PD-L1 were under extensive study to this end; unfortunately, although expression of PD-L1 was detected in 50% of stage II and III gastric cancers (36), it has been found to be insufficient for patient selection for immunotherapy thus far (37). A phase 1b clinical trial in 2016 first reported the application of pembrolizumab (another immunotherapy agent) for recurrent or metastatic gastric cancer (38). Subsequently, the efficacy of nivolumab in advanced gastric cancer was established in a phase 3 trial with a registered median overall survival of 5.26 months (39). Other agents targeting PD-L1 (such as avelumab) are still under clinical investigation. However, there are still no clinical trials concerning immunotherapeutic agents for concurrent or multiple cancers. In our case, the patient was treated with the nivolumab plus XELOX regime; considering the reported PFS (5.8 months) and OS (11.8 months) of single XELOX in advanced gastric cancer (40), it is difficult to conclude whether such combined therapies could help prolong the OS for such patients; however, additional clinical studies are still needed in the future.\n\nConcurrent gastric adenocarcinoma and NEC can occur in the clinic, and interpretation of the pathological results should be done cautiously in the absence of gross specimens. The efficacy of therapeutic strategies such as immunotherapy and chemotherapy still requires further validation.\n\nAcknowledgements\nNot applicable.\n\nFunding\nThe present study was supported by the Natural Science Foundation of China (grant no. 81503391), Natural Science Foundation Project of Hainan (grant no. 817352) and Medical and Health Science Innovation Project of Sanya (grant no. 2016YW08).\n\nAvailability of data and materials\nAll data generated or analyzed during this study are included in this published article.\n\nAuthors' contributions\nBY and MC performed the case study, collected the data and images of the case and produced the draft of the manuscript. JY, FL and HL critically analyzed the manuscript for important intellectual content. All authors read and approved the final manuscript.\n\nEthics approval and consent to participate\nThe present study was approved by the Medical Ethics Committee of the Hainan Branch of PLA General Hospital. Written informed consent was obtained from the patient's father.\n\nPatient consent for publication\nWritten informed consent was obtained from the patient's father.\n\nCompeting interests\nThe authors declare that they have no competing interests.\n\nFigure 1. Histological results of H&E staining and immunohistochemistry by gastric endoscopy. (A) Well-differentiated adenocarcinoma from the superficial mucous membrane layer of the gastric corpus (H&E: magnification, ×100). (B) CD4 membrane-positive cells clustered in the tumor (Magnification, ×200). (C) CD8 membrane-positive cells could also be seen in the tumor, but the area was smaller than that observed for CD4 (magnification, ×200). (D) MAGEA3 staining was diffusely positive in nearly all tumor cells. (E) NY-ESO-1 and (F) PD-L1 staining was negative in all tumor cells (magnification, ×200). H&E, hematoxylin and eosin; CD, cluster of differentiation; MAGEA3, melanoma antigen family member A3; NY-ESO-1, New York esophageal squamous cell carcinoma 1; PD-L1, programmed cell death 1 ligand 1.\n\nFigure 2. CT scan of the lesions previously reported by positron emission tomography-CT. (A) Abdominal enhanced CT indicates irregular wall thickening on the distal gastric corpus and antrum with heterogeneous enhancement, accompanied by multiple lymph node metastasis (white arrows). (B) Pelvic CT with bone window reveals extensive centrum and pelvic metastasis as well as marrow invasion (white arrows). CT, computed tomography.\n\nFigure 3. Variation in tumor markers during the course of treatment. Following 4 cycles of treatment, the levels of CA199, CA724, CEA and CA125 decreased markedly, and the image examination indicated a stable disease; however, an evident progressive disease could be detected following this, and CA199 and CA724 increased markedly. CA, carbohydrate antigen; CEA, carcinoembryonic antigen; Nivo, nivolumab; XELOX, oxaliplatin + capecitabine.\n\nFigure 4. Histological results from biopsy specimens from metastatic collarbone lymph nodes (H&E staining and immunohistochemistry). (A) Many poorly differentiated neuroendocrine cancer cells were clustered in the sample (H&E: magnification, ×10). (B-G) The cancer cells were diffusely positive for (B) Syn, (C) cluster of differentiation-56, (D) CK and (E) CK7, and were negative for (F) CK20 and (G) Vim (all, magnification, ×20). (H) The cancer cells presented high proliferative capacity, and Ki-67 was diffusely positive with an index >75% (magnification, ×20). H&E, hematoxylin and eosin; CK, creatine kniase; Syn, synaptophysin; Vim, vimentin.\n\nTable I. Case reports of concurrent gastric adenocarcinoma and neuroendocrine cancer.\n\nAuthor, year\tGender\tAge, years\tFinal pathological findings\tPositive markers for NEC\tTreatment\tOverall survival time\t(Refs.)\t\nOkamoto et al, 2003\tFemale\t78\tPoorly differentiated adenocarcinoma+NEC+hepatoid adenocarcinoma\tCgA\tGastrectomy\t4 years and 6 months\t(5)\t\nYasuda et al, 2006\tFemale\t74\tPoorly differentiated adenocarcinoma+NEC\tCgA, NSE\tGastrectomy+chemotherapy (cisplatin+5-Fu)\t1 year and 10 months\t(6)\t\nPark et al, 2007\tMale\t48\tWell differentiated adenocarcinoma+NEC\t–\tGastrectomy+chemotherapy (cisplatin+etoposide, TS-1)\t>5 years 3 months\t(7)\t\nKim et al, 2009\tMale\t77\tPoorly differentiated adenocarcinoma+NEC+hepatoid adenocarcinoma\tCgA, Syn\tGastrectomy\t91 days\t(8)\t\nJung et al, 2009\tMale\t59\tAdenocarcinoma+large cell NEC\tCD56\tGastrectomy\tNot reported\t(9)\t\nMrόz et al, 2009\tMale\t56\tPoorly differentiated adenocarcinoma+NEC\tCgA, Syn, Ki-67(70%)\tGastrectomy+adjuvant chemotherapy\tNot reported\t(10)\t\nJang et al, 2010\tMale\t50\tWell differentiated+large cell NEC\tCgA, Syn, NSE\tGastrectomy\tNot reported\t(11)\t\nCho et al, 2010\tMale\t67\tAdenocarcinoma+large cell NEC\t–\tGastrectomy\tNot reported\t(12)\t\nTerada et al, 2011\tMale\t76\tAdenocarcinoma+large cell NEC\tCK, Syn, CgA, PDGF, Ki-67 (90%)\tGastrectomy+adjuvant chemotherapy\tNot reported\t(13)\t\nMiguchi et al, 2012\tMale\t72\tModerately differentiated adenocarcinoma+NEC\tCgA, Syn, NSE, Ki-67 (95%)\tGastrectomy+adjuvant chemotherapy (S-1)\tNot reported\t(14)\t\nNakayama et al, 2012\tMale\t74\tPoorly differentiated adenocarcinoma+NEC\tSyn, CD56\tEndoscopic examination\t~2 years\t(15)\t\nLee et al, 2013\tMale\t70\tWell differentiated adenocarcinoma+NEC\tCgA, Syn, CD56\tEndoscopic submucosal dissection\tNot reported\t(16)\t\nLi et al, 2014\tMale\t56\tModerately differentiated adenocarcinoma+NEC\tCgA, Syn, Vim, TTF-1, CD117, Ki67 (80%)\tGastrectomy+adjuvant chemotherapy (FOLFOX)\tNot reported\t(17)\t\nLipi et al, 2014\tMale\t50\tAdenocarcinoma+NEC+hepatoid adenocarcinoma\tAE1/AE3, CgA, Syn\tGastrectomy+adjuvant chemotherapy (cisplatin+etoposide)\tNot reported\t(18)\t\nZhang et al, 2014\tMale\t68\tAdenocarcinoma+NEC+squamous cell carcinoma\tCgA, Syn, Ki-67(70%)\tGastrectomy\tNot reported\t(19)\t\nPayet et al, 2015\tMale\t71\tAdenocarcinoma+large-cell NEC\tSyn, AE1/AE3\tGastrectomy\tNot reported\t(20)\t\nAoyagi et al, 2016\tMale\t76\tPoorly differentiated adenocarcinoma+signet ring cell carcinoma+NEC\tSyn, CD56, Ki-67(23.1%)\tGastrectomy+adjuvant chemotherapy (tegafur-uracil)\t72 months\t(21)\t\nMitchell et al, 2015\tMale\t70\tModerately differentiated adenocarcinoma+NEC\tAE1/AE3, NSE, Ki-67(<2%)\tGastrectomy\tNot reported\t(22)\t\nMainali et al, 2017\tMale\t67\tWell differentiated adenocarcinoma+NEC\t–\tGastrectomy\tNot reported\t(23)\t\nCgA, Chromogranin A; NSE, neuron-specific enolase; Syn, synaptophysin; Vim, vimentin; TTF-1, thyroid transcription-1; NEC, neuroendocrine cancer.\n==== Refs\nReferences\n1 Shah MA Ajani JA Gastric cancer-an enigmatic and heterogeneous disease JAMA 303 1753 1754 2010 10.1001/jama.2010.553 20442394 \n2 Uchiyama C Tamura S Nakatsuka S Takeno A Miki H Kanemura T Nakahira S Suzuki R Nakata K Takeda Y Kato T Immunohistochemical consistency between primary tumors and lymph node metastases of gastric neuroendocrine carcinoma World J Surg Oncol 10 115 2012 10.1186/1477-7819-10-115 22726317 \n3 Fukui H Takada M Chiba T Kashiwagi R Sakane M Tabata F Kuroda Y Ueda Y Kawamata H Imura J Fujimori T Concurrent occurrence of gastric adenocarcinoma and duodenal neuroendocrine cell carcinoma: A composite tumour or collision tumours? Gut 48 853 856 2001 10.1136/gut.48.6.853 11358908 \n4 Kim BS Park YS Yook JH Kim BS Comparison of the prognostic values of the 2010 WHO classification, AJCC 7th edition and ENETS classification of gastric neuroendocrine tumors Medicine (Baltimore) 95 e3977 2016 10.1097/MD.0000000000003977 27472674 \n5 Okamoto T Ogasahara K Fujiki M Takagi H Ikeda H Makino T Moriga T Kawamoto K Sano K Yoshida Y Primary coexistent neuroendocrine carcinoma, hepatoid adenocarcinoma, and tubular adenocarcinoma of the stomach with focal trophoblastic differentiation in metastatic lymph nodes J Gastroenterol 38 608 610 2003 10.1007/s00535-003-1128-5 12858843 \n6 Yasuda K Fujiwara H Nomura H Sogo Y Sakai K Teramura K A case of neuroendocrine cell carcinoma and poorly differentiated adenocarcinoma of the stomach in synchronous multiple cancer Jpn J Gastroenterol Surg 39 446 451 2006 10.5833/jjgs.39.446 \n7 Park BS Jo TY Seo HI Kim HS Kim DH Jeon TY Kim DH Sim MS Kim JY Gastric collision tumor (adenocarcinoma and neuroendocrine carcinoma) diagnosed as a advanced gastric cancer J Korean Surg Soc 73 173 177 2007 \n8 Kim A Kim SW Song SK Bae YK Gastric adenocarcinoma with coexistent hepatoid adenocarcinoma and neuroendocrine carcinoma: A case report Korean J Pathol 43 79 82 2009 10.4132/KoreanJPathol.2009.43.1.79 \n9 Jung JH Kim YC Kim JH Chung HS Cheung DY Kim JI Park SH Kim JK A case of a gastric composite tumor with an adenocarcinoma and a large cell neuroendocrine carcinoma Korean J Gastrointest Endosc 39 93 96 2009 \n10 Mrόz A Kiedrowski M Malinowska M Sopyło R Collision tumour of the stomach-adenocarcinoma and neuroendocrine carcinoma: Case report and review of the literature Pol J Pathol 2 94 97 2009 \n11 Jang KY Moon WS Lee H Kim CY Park HS Gastric collision tumor of large cell neuroendocrine carcinoma and adenocarcinoma-a case report Pathol Res Pract 206 387 390 2010 10.1016/j.prp.2009.09.003 19945227 \n12 Cho KH Chang YW Sohn SD Hwangbo Y Shim J Jang JY Kim HJ Kim BH Metastatic large cell neuroendocrine carcinoma combined with gastric adenocarcinoma Korean J Gastrointest Endosc 41 94 97 2010 \n13 Terada T Maruo H Simultaneous large cell neuroendocrine carcinoma and adenocarcinoma of the stomach World J Gastroenterol 17 4831 4834 2011 10.3748/wjg.v17.i43.4831 22147986 \n14 Miguchi M Iseki M Shimatani K Advanced gastric neuroendocrine carcinoma with an adenocarcinoma component Case Rep Gastroenterol 6 52 57 2012 10.1159/000336320 22423239 \n15 Nakayama Y Higure A Shibao K Sato N Matayoshi N Yamaguchi K Synchronous occurrence of early neuroendocrine carcinoma and tubular adenocarcinoma in the stomach Clin J Gastroenterol 5 307 311 2012 10.1007/s12328-012-0320-7 26182399 \n16 Lee JH Kim HW Kang DH Choi CW Park SB Kim SH A gastric composite tumor with an adenocarcinoma and a neuroendocrine carcinoma: A case report Clin Endosc 46 280 283 2013 10.5946/ce.2013.46.3.280 23767040 \n17 Li S Cao X Jiang C Wang Q Combined neuroendocrine carcinoma and adenocarcinoma in the stomach: A case report Oncol Lett 7 953 955 2014 10.3892/ol.2014.1825 24944649 \n18 Lipi L Sachdev R Gautam D Singh J Mohapatra I Triple composite tumor of stomach: A rare combination of alpha fetoprotein positive hepatoid adenocarcinoma, tubular adenocarcinoma and large cell neuroendocrine carcinoma Indian J Pathol Microbiol 57 98 100 2014 10.4103/0377-4929.130912 24739843 \n19 Zhang W Xiao W Ma H Sun M Chen H Zheng S Neuroendocrine liver metastasis in gastric mixed adenoneuroendocrine carcinoma with trilineage cell differentiation: A case report Int J Clin Exp Pathol 7 6333 6338 2014 25337287 \n20 Payet E Pilco PI Montes J Cordero-Morales A Savitzky MJ Stenning-Persivale K Collision tumour of large-cell neuroendocrine carcinoma and adenocarcinoma in the stomach: A case report Ecancermedicalscience 10 616 2016 10.3332/ecancer.2016.616 26913067 \n21 Aoyagi K Kizaki J Isobe T Akaqi Y A case of gastric cancer with neuroendocrine carcinoma, signet ring cell carcinoma components, and intramural metastases Am J Case Rep 17 274 279 2016 10.12659/AJCR.896625 27102318 \n22 Mitchell MS Walinchus-Foster L Thomas L Shi Q Nagori M Khan W Mirza W Cortes M Masalmeh OA Zerti H Mohamed A Synchronous adenocarcinoma and neuroendocrine tumors of the stomach Am J Cancer Case Rep 4 125 128 2016 \n23 Mainali N Nepal N Kumar CP Sinha A Rajbanshi S Rauniyar S Yadav A Co-existence of gastric adenocarcinoma and neuroendocrine carcinoma: A rare entity J Pathol Nepal 7 1221 1223 2017 10.3126/jpn.v7i2.18030 \n24 Nishikura K Watanabe H Iwafuchi M Fujiwara T Kojima K Ajioka Y Carcinogenesis of gastric endocrine cell carcinoma: Analysis of histopathology and p53 gene alteration Gastric Cancer 6 203 209 2003 10.1007/s10120-003-0249-0 14716513 \n25 Kim JJ Kim JY Hur H Cho YK Han SU Clinicopathologic significance of gastric adenocarcinoma with neuroendocrine features J Gastric Cancer 11 195 199 2011 10.5230/jgc.2011.11.4.195 22324009 \n26 Zhang T Su D Mao Z Guo X Wang L Bai L Prognostic role of neuroendocrine cell differentiation in human gastric carcinoma Int J Clin Exp Med 8 7837 7842 2015 26221337 \n27 Bakkelund K Fossmark R Nordrum I Waldum H Signet ring cells in gastric carcinomas are derived from neuroendocrine cells J Histochem Cytochem 54 615 621 2006 10.1369/jhc.5A6806.2005 16344325 \n28 Yamazaki K A gastric carcinosarcoma with neuroendocrine cell differentiation and undifferentiated spindle-shaped sarcoma component possibly progressing from the conventional tubular adenocarcinoma; an immunohistochemical and ultrastructural study Virchows Arch 442 77 81 2003 12536318 \n29 Lim SU Seo SS Yoon JY Cho DH Bae SY Bae WK Shim HJ Cho SH Chung IJ A case of gastric adenocarcinoma developed in neuroendocrine carcinoma after chemotherapy Chonnam Med J 44 188 193 2008 10.4068/cmj.2008.44.3.188 \n30 La Rosa S Marando A Sessa F Capella C Mixed adenoneuroendocrine carcinomas (MANECs) of the gastrointestinal tract: An update Cancers (Basel) 4 11 30 2012 10.3390/cancers4010011 24213223 \n31 Sato Y Hashimoto S Mizuno K Takeuchi M Terai S Management of gastric and duodenal neuroendocrine tumors World J Gastroenterol 22 6817 6828 2016 10.3748/wjg.v22.i30.6817 27570419 \n32 Fukuda T Ohnishi Y Nishimaki T Ohtani H Tachikawa S Early gastric cancer of the small cell type Am J Gastroenterol 83 1176 1179 1988 2844080 \n33 Mitry E Baudin E Ducreux M Sabourin JC Rufié P Aparicio T Aparicio T Lasser P Elias D Duvillard P Treatment of poorly differentiated neuroendocrine tumours with etoposide and cisplatin Br J Cancer 81 1351 1355 1999 10.1038/sj.bjc.6690325 10604732 \n34 Okita NT Kato K Takahari D Hirashima Y Nakajima TE Matsubara J Hamaguchi T Yamada Y Shimada Y Taniguchi H Shirao K Neuroendocrine tumors of the stomach: Chemotherapy with cisplatin plus irinotecan is effective for gastric poorly-differentiated neuroendocrine carcinoma Gastric Cancer 14 161 165 2011 10.1007/s10120-011-0025-5 21327441 \n35 Ip YT Pong WM Kao SS Chan JK Spontaneous complete regression of gastric large-cell neuroendocrine carcinoma: Mediated by cytomegalovirus-induced cross-autoimmunity? Int J Surg Pathol 19 355 358 2011 10.1177/1066896911404412 21665860 \n36 Zhang L Qiu M Jin Y Ji J Li B Wang X Yan S Xu R Yang D Programmed cell death ligand 1 (PD-L1) expression on gastric cancer and its relationship with clinicopathologic factors Int J Clin Exp Pathol 8 11084 11091 2015 26617827 \n37 Gibney GT Weiner LM Atkins MB Predictive biomarkers for checkpoint inhibitor-based immunotherapy Lancet Oncol 17 e542 e551 2016 10.1016/S1470-2045(16)30406-5 27924752 \n38 Muro K Chung HC Shankaran V Geva R Catenacci D Gupta S Eder JP Golan T Le DT Burtness B Pembrolizumab for patients with PD-L1-positive advanced gastric cancer (KEYNOTE-012): A multicentre, open-label, phase 1b trial Lancet Oncol 17 717 726 2016 10.1016/S1470-2045(16)00175-3 27157491 \n39 Kang YK Boku N Satoh T Ryu MH Chao Y Kato K Chung HC Chen JS Muro K Kang WK Nivolumab in patients with advanced gastric or gastro-oesophageal junction cancer refractory to, or intolerant of, at least two previous chemotherapy regimens (ONO-4538-12, ATTRACTION-2): A randomised, double-blind, placebo-controlled, phase 3 trial Lancet 390 2461 2471 2017 10.1016/S0140-6736(17)31827-5 28993052 \n40 Park YH Lee JL Ryoo BY Ryu MH Yang SH Kim BS Shin DB Chang HM Kim TW Yuh YJ Kang YK Capecitabine in combination with Oxaliplatin (XELOX) as a first-line therapy for advanced gastric cancer Cancer Chemother Pharmacol 61 623 629 2008 10.1007/s00280-007-0515-7 17522863\n\n",
"fulltext_license": "CC BY-NC-ND",
"issn_linking": "2049-9450",
"issue": "9(6)",
"journal": "Molecular and clinical oncology",
"keywords": "gastric adenocarcinoma; neuroendocrine cancer; nivolumab; oxaliplatin + capecitabine; tumor markers",
"medline_ta": "Mol Clin Oncol",
"mesh_terms": null,
"nlm_unique_id": "101613422",
"other_id": null,
"pages": "607-612",
"pmc": null,
"pmid": "30546888",
"pubdate": "2018-12",
"publication_types": "D016428:Journal Article",
"references": "27157491;26617827;21327441;20442394;22726317;28993052;27570419;12536318;24944649;24213223;23767040;2844080;16344325;26913067;27472674;17522863;19945227;25337287;22324009;21665860;27924752;22147986;19886184;11358908;10604732;22423239;12858843;26221337;26182399;27102318;24739843;14716513",
"title": "Gastric adenocarcinoma is concurrent with metastatic neuroendocrine cancer treated with nivolumab and chemotherapy: A case report.",
"title_normalized": "gastric adenocarcinoma is concurrent with metastatic neuroendocrine cancer treated with nivolumab and chemotherapy a case report"
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"abstract": "Here we present the first reported case of a noninvasive Rhizopus fungal ball confined to the bladder of a patient with poorly controlled diabetes and right flank pain. The patient developed bilateral hydronephrosis after several hospital admissions for urinary tract infections with multiple failed courses of antibiotics. During cystoscopy to replace a ureteral stent, he was found to harbor a fungal ball in the bladder that was removed and grew Rhizopus in culture. Patient received treatment with amphotericin B and transitioned to long-term posaconazole therapy. This case highlights the importance of considering fungal agents in urinary tract infections, especially in persistent or refractory cases, and the role of the clinical microbiology laboratory in correct identification of the infectious source.",
"affiliations": "Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN.;Department of Medicine, University of Minnesota Medical School, Minneapolis, MN.;Department of Medicine, University of Minnesota Medical School, Minneapolis, MN.;Department of Medicine, University of Minnesota Medical School, Minneapolis, MN.;Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN.;Department of Laboratory Medicine and Pathology, University of Minnesota Medical School, Minneapolis, MN.",
"authors": "Barnes|Aaron M T|AMT|;Crespo-Diaz|Ruben J|RJ|;Cohenour|Justin|J|;Kirsch|Jonathan D|JD|;Arbefeville|Sophie|S|;Ferrieri|Patricia|P|",
"chemical_list": "D000935:Antifungal Agents; D000666:Amphotericin B",
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"doi": "10.1093/labmed/lmx060",
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"issn_linking": "0007-5027",
"issue": "49(1)",
"journal": "Laboratory medicine",
"keywords": "Rhizopus; fungal ball; mucorales; mucormycosis",
"medline_ta": "Lab Med",
"mesh_terms": "D000666:Amphotericin B; D000935:Antifungal Agents; D003558:Cystoscopy; D048909:Diabetes Complications; D006801:Humans; D008297:Male; D008875:Middle Aged; D009091:Mucormycosis; D012233:Rhizopus; D001743:Urinary Bladder; D001745:Urinary Bladder Diseases",
"nlm_unique_id": "0250641",
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"pubdate": "2017-12-22",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "A Noninvasive Rhizopus Infection With a Bladder Fungal Ball in a Patient With Poorly Controlled Diabetes Mellitus.",
"title_normalized": "a noninvasive rhizopus infection with a bladder fungal ball in a patient with poorly controlled diabetes mellitus"
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"abstract": "OBJECTIVE\nThe purpose of this report is to demonstrate a rare clinical manifestation of apraxia eyelid opening related to a basal ganglia lesion.\n\n\nMETHODS\nIn this study, we report a 91-year-old woman suffering from difficulty in eyelid opening after being treated for myocardial ischemia with dual antiplatelet medications. She could open her eyelid with fingers touching her forehead. Brain computed tomography revealed a right putamen hemorrhage. Surface electromyography revealed persistent frontalis muscle contraction during relaxation of orbicularis oculi muscles. Apraxia of eyelid opening was diagnosed. Her eyelid symptom resolved 2 months later.\n\n\nCONCLUSIONS\nApraxia of eyelid opening may be caused by subcortical hemorrhage of the basal ganglia. In addition to the primary motor cortex and supplemental motor area, the basal ganglia may also play a role in eyelid opening.",
"affiliations": "Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan.",
"authors": "Lin|Yi-Hui|YH|;Liou|Li-Min|LM|;Lai|Chiou-Lian|CL|;Chang|Yang-Pei|YP|",
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"fulltext": "\n==== Front\nNeuropsychiatr Dis TreatNeuropsychiatr Dis TreatNeuropsychiatric Disease and TreatmentNeuropsychiatric Disease and Treatment1176-63281178-2021Dove Medical Press 10.2147/NDT.S50974ndt-9-1495Case ReportRight putamen hemorrhage manifesting as apraxia of eyelid opening Lin Yi-Hui 1Liou Li-Min 23Lai Chiou-Lian 12Chang Yang-Pei 121 Department of Neurology, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan2 Department of Neurology, Faculty of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan3 Department of Neurology, Kaohsiung Municipal Hsiao-Kang Hospital, Kaohsiung Medical University, Kaohsiung, TaiwanCorrespondence: Yang-Pei Chang, Department of Neurology, Kaohsiung Medical University Hospital, 100 Zihyou 1st Rd, Sanmin District, Kaohsiung City 807, Taiwan, Tel +886 7 312 1101 ext 5851, Fax +886 7 316 2158, Email cyp905@gmail.com2013 2013 26 9 2013 9 1495 1497 © 2013 Lin et al. This work is published by Dove Medical Press Ltd, and licensed under Creative Commons Attribution – Non Commercial (unported, v3.0) License2013The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Ltd, provided the work is properly attributed.Purpose\nThe purpose of this report is to demonstrate a rare clinical manifestation of apraxia eyelid opening related to a basal ganglia lesion.\n\nCase report\nIn this study, we report a 91-year-old woman suffering from difficulty in eyelid opening after being treated for myocardial ischemia with dual antiplatelet medications. She could open her eyelid with fingers touching her forehead. Brain computed tomography revealed a right putamen hemorrhage. Surface electromyography revealed persistent frontalis muscle contraction during relaxation of orbicularis oculi muscles. Apraxia of eyelid opening was diagnosed. Her eyelid symptom resolved 2 months later.\n\nConclusion\nApraxia of eyelid opening may be caused by subcortical hemorrhage of the basal ganglia. In addition to the primary motor cortex and supplemental motor area, the basal ganglia may also play a role in eyelid opening.\n\nKeywords\nintracranial hemorrhagebasal gangliaorbicularis oculi musclefrontalis muscle\n==== Body\nIntroduction\nApraxia of eyelid opening (AEO) is a syndrome that manifests as the inability to open the eyes at will. Patients usually try to open their eyes with their hands or by contracting the frontalis muscles in the absence of any significant evidence of orbicularis oculi contraction, such as lowering of the brow beneath the orbital rim (Charcot sign).1,2 This syndrome is often found in patients with progressive supranuclear palsy, Parkinson’s disease, atypical parkinsonism, and blepharospasm,2,3 but is rarely seen as the initial presentation of an acute cerebrovascular event.4–8 Herein, we report the case of a patient with AEO in which the AEO was an initial clinical symptom of right putamen hemorrhage.\n\nCase presentation\nA 91-year-old right-handed woman with a history of hypertension was admitted to the medical ward due to pneumonia. She was independent in daily life and without a documented neurological deficit.\n\nOne day following admission, a sudden onset of chest discomfort was noted and non-ST elevated myocardial infarction was diagnosed. She was transferred to the intensive care unit, where clopidogrel and aspirin were used continually, followed by heparinization for 3 days. After 7 days of this dual antiplatelet therapy, she was found to have an acute onset of difficulty in opening her eyes. A nasogastric (NG) tube was put in place to avoid choking and because she could not walk steadily. A neurologist was consulted for the eye-opening problem.\n\nThe neurological exam revealed she had difficulty in bilateral eyelid opening, left central facial palsy, mild dysarthria, and left-side hemiparesis. Pursuit and saccadic eye movements were intact. Her eye opening was especially difficult after closing her eyes tight, but she could open her eyelid after a light touch to her forehead. No ptosis or blepharospasm was noted. Brain computed tomography scans revealed an acute hemorrhage at the right putamen (Figure 1) and surface electromyography revealed persistent contraction of the frontalis muscle and relaxation of the orbicularis oculi muscles on trying to open the eyes (Figure 2). AEO was suspected.\n\nHer eyelid opening and dysphagia had not improved 2 weeks after the hemorrhage. Half a Sinemet® (carbidopa-levodopa, 25/100 mg) tablet (Merck & Co., Inc, Whitehouse Station, NJ, USA) was given twice daily for 6 weeks. Her NG tube was removed 1 month later. Her eyelid problem had subsided after 2 months of hemorrhage being identified, while brain computed tomography scans revealed that the hemorrhage had resolved.\n\nDiscussion\nThe case described here had AEO as the initial presentation of right putamen hemorrhage without other extrapyramidal symptoms suggestive of Parkinson’s disease, progressive supranuclear palsy, or cortico-basal degeneration. As it is well known that a unilateral basal ganglia lesion can cause bilateral AEO, here we discuss the possible mechanism of this symptom in our patient.\n\nVoluntary eye opening is controlled by the corticobulbar tract from the primary motor cortex (M1) and motor-related cortical areas, including the supplementary motor area (SMA) or premotor cortex. The basal ganglia may play a role in the regulation of the eye-opening system in the SMA through the thalamus.9 In terms of basal ganglia dysfunction, regulation may be impaired in Parkinson’s disease or other diseases with parkinsonian features and AEO. On the basis of pharmacological evidence, the role of basal ganglia dysfunction in AEO has been further clarified,10 even in Parkinson’s disease patients receiving deep brain stimulation at the bilateral subthalamic nucleus.11 Thus, the AEO in our patient may support the theory of a basal ganglia abnormality producing AEO.\n\nIn our case, we suggest that the right hemispheric lesion may have caused the AEO. A few reports have suggested that a right cerebral hemispheric lesion would be more likely to cause AEO because the right cerebral hemisphere controls the bilateral levator palpebrae superioris.5–8 In contrast, other reports have shown that a dominant hemisphere lesion caused AEO.4,7 As for the laterality of AEO, more evidence is still required to reach a conclusion about this.\n\nDual antiplatelet therapy of aspirin and clopidogrel has been proven to be associated with significantly reduced major atherothrombotic events and an increased risk of moderate and severe bleeding.12 Indeed, gastrointestinal bleeding and intracranial hemorrhage are two of the most common bleeds associated with dual antiplatelet therapy. Since AEO is an uncommon initial presentation of intracranial hemorrhage, special caution should be taken and further brain imaging performed during dual antiplatelet treatment for atherothrombotic events.\n\nConclusion\nOur patient experienced eyelid-opening apraxia secondary to an isolated right putamen hemorrhage, which is suggestive of the essential role of the basal ganglia in eyelid opening.\n\nDisclosure\n\nThe authors declare no conflicts of interest in this work.\n\nFigure 1 Brain computed tomography scans showing acute hemorrhage at the right putamen.\n\nFigure 2 Surface electromyography was recorded at the bilateral eyelids: (A) right frontalis and orbicularis oculi muscles; (B) left frontalis and orbicularis oculi muscles. Persistent contraction of the frontalis muscle was observed, while there was rare contraction of the orbicularis oculi muscle when the patient tried to open her eyes.\n==== Refs\nReferences\n1 Zadikoff C Lang AE Apraxia in movement disorders Brain 2005 128 Pt 7 1480 1497 15930045 \n2 Miller NR Newman NJ The Essentials: Walsh and Hoyt’s Clinical Neuro-Ophthalmology 5th ed Baltimore, MD Williams & Wilkins 1999 \n3 Hallett M Evinger C Jankovic J Stacy M BEBRF International Workshop Update on blepharospasm: report from the BEBRF International Workshop Neurology 2008 71 16 1275 1282 18852443 \n4 Kaiboriboon K Oliveira GR Leira EC Apraxia of eyelid opening secondary to a dominant hemispheric infarction J Neurol 2002 249 3 341 342 11993536 \n5 Algoed L Janssens J Vanhooren G Apraxia of eyelid opening secondary to right frontal infarction Acta Neurol Belg 1992 92 4 228 233 1441901 \n6 Johnston JC Rosenbaum DM Picone CM Grotta JC Apraxia of eyelid opening secondary to right hemisphere infarction Ann Neurol 1989 25 6 622 624 2742362 \n7 Hirose M Mochizuki H Honma M Kobayashi T Nishizawa M Ugawa Y Apraxia of lid opening due to a small lesion in basal ganglia: two case reports J Neurol Neurosurg Psychiatry 2010 81 12 1406 1407 20547609 \n8 Lee SS Lee HS Can subcortical infarction cause apraxia of eyelid opening? J Clin Neurosci 2011 18 10 1399 1400 21778059 \n9 Costa J Valls-Solé J Valldeoriola F Rumià J Tolosa E Motor responses of muscles supplied by cranial nerves to subthalamic nucleus deep brain stimuli Brain 2007 130 Pt 1 245 255 17151002 \n10 Lee KC Finley R Miller B Apraxia of lid opening: dose-dependent response to carbidopa-levodopa Pharmacotherapy 2004 24 3 401 403 15040654 \n11 Umemura A Toyoda T Yamamoto K Oka Y Ishii F Yamada K Apraxia of eyelid opening after subthalamic deep brain stimulation may be caused by reduction of levodopa Parkinsonism Relat Disord 2008 14 8 655 657 18316231 \n12 Bhatt DL Fox KA Hacke W CHARISMA Investigators Clopidogrel and aspirin versus aspirin alone for the prevention of atherothrombotic events N Engl J Med 2006 354 16 1706 1717 16531616\n\n",
"fulltext_license": "CC BY-NC",
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"issue": "9()",
"journal": "Neuropsychiatric disease and treatment",
"keywords": "basal ganglia; frontalis muscle; intracranial hemorrhage; orbicularis oculi muscle",
"medline_ta": "Neuropsychiatr Dis Treat",
"mesh_terms": null,
"nlm_unique_id": "101240304",
"other_id": null,
"pages": "1495-7",
"pmc": null,
"pmid": "24109186",
"pubdate": "2013",
"publication_types": "D002363:Case Reports",
"references": "2742362;16531616;1441901;15040654;20547609;11993536;18852443;15930045;21778059;17151002;18316231",
"title": "Right putamen hemorrhage manifesting as apraxia of eyelid opening.",
"title_normalized": "right putamen hemorrhage manifesting as apraxia of eyelid opening"
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"abstract": "BACKGROUND\nBrain metastasis during pregnancy is a rare occurrence. In particular, there have only been three prior cases regarding breast cancer metastasis. We report a patient with breast cancer metastasis to the brain during pregnancy and review the literature.\n\n\nMETHODS\nThe patient was a 35-year-old female with a history of breast cancer (estrogen receptor/progesterone receptor negative, human epidermal growth factor receptor 2/neu positive, status post-neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab therapy, status post-bilateral mastectomies), and prior right frontal brain metastases (status post-resection, capecitabine/lapatinib/temozolomide therapy, and cyberknife treatment). Patient was found to be pregnant at 9 weeks' gestation while on chemotherapy; the patient elected to continue with the pregnancy and chemotherapy was discontinued. At 14 weeks' gestation, she returned with recurrent right frontal disease. She was taken for a craniotomy at 16 weeks' gestation, which confirmed metastases. Six weeks later, patient returned with worsening headaches and fatigue, with more recurrent right frontal disease. She was started on decadron and chemotherapy (5-fluorouracil, adriamycin, and cyclophosphamide). Serial magnetic resonance imaging (MRI) demonstrated enlarging right frontal lesions. She underwent a craniotomy at 27 weeks' gestation, and chemotherapy was discontinued promptly. Starting at 30 weeks' gestation, she received whole brain radiation for 2 weeks. Subsequently, she delivered a baby girl via cesarean section at 32 weeks' gestation. At 6 weeks follow-up, an MRI brain demonstrated no new intracranial disease, with stable postoperative findings.\n\n\nCONCLUSIONS\nThere is a lack of guidelines and clinical consensus on medical and surgical treatment for breast cancer metastases in pregnant patients. Treatment usually varies based upon underlying tumor burden, location, gestational age of the fetus, and patient's preference and symptomatology.",
"affiliations": "Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.;Department of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.",
"authors": "Sharma|Ashish|A|;Nguyen|Ha Son|HS|;Lozen|Andrew|A|;Sharma|Abhishiek|A|;Mueller|Wade|W|",
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"doi": "10.4103/2152-7806.189730",
"fulltext": "\n==== Front\nSurg Neurol IntSurg Neurol IntSNISurgical Neurology International2229-50972152-7806Medknow Publications & Media Pvt Ltd India SNI-7-60310.4103/2152-7806.189730Surgical Neurology International: Neuro-OncologyBrain metastases from breast cancer during pregnancy Sharma Ashish ashishsharma@mcw.eduNguyen Ha Son hsnguyen@mcw.edu*Lozen Andrew alozen@mcw.eduSharma Abhishiek absharma@mcw.eduMueller Wade wmueller@mcw.eduDepartment of Neurosurgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA* Corresponding author\n2016 01 9 2016 7 Suppl 23 SNI: Neuro-Oncology, a supplement to Surgical Neurology InternationalS603 S606 07 6 2016 14 6 2016 Copyright: © 2016 Surgical Neurology International2016This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Background:\nBrain metastasis during pregnancy is a rare occurrence. In particular, there have only been three prior cases regarding breast cancer metastasis. We report a patient with breast cancer metastasis to the brain during pregnancy and review the literature.\n\nCase Description:\nThe patient was a 35-year-old female with a history of breast cancer (estrogen receptor/progesterone receptor negative, human epidermal growth factor receptor 2/neu positive, status post-neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab therapy, status post-bilateral mastectomies), and prior right frontal brain metastases (status post-resection, capecitabine/lapatinib/temozolomide therapy, and cyberknife treatment). Patient was found to be pregnant at 9 weeks’ gestation while on chemotherapy; the patient elected to continue with the pregnancy and chemotherapy was discontinued. At 14 weeks’ gestation, she returned with recurrent right frontal disease. She was taken for a craniotomy at 16 weeks’ gestation, which confirmed metastases. Six weeks later, patient returned with worsening headaches and fatigue, with more recurrent right frontal disease. She was started on decadron and chemotherapy (5-fluorouracil, adriamycin, and cyclophosphamide). Serial magnetic resonance imaging (MRI) demonstrated enlarging right frontal lesions. She underwent a craniotomy at 27 weeks’ gestation, and chemotherapy was discontinued promptly. Starting at 30 weeks’ gestation, she received whole brain radiation for 2 weeks. Subsequently, she delivered a baby girl via cesarean section at 32 weeks’ gestation. At 6 weeks follow-up, an MRI brain demonstrated no new intracranial disease, with stable postoperative findings.\n\nConclusion:\nThere is a lack of guidelines and clinical consensus on medical and surgical treatment for breast cancer metastases in pregnant patients. Treatment usually varies based upon underlying tumor burden, location, gestational age of the fetus, and patient's preference and symptomatology.\n\nBrain metastasesbrain surgerybreast cancer\n==== Body\nBACKGROUND\nBrain metastasis during pregnancy is a rare occurrence. In particular, there have only been three prior cases regarding breast cancer metastasis. Not surprisingly, pregnancy complicates the management of brain metastases. We report a patient with breast cancer metastasis to the brain during pregnancy and review the literature.\n\nCASE PRESENTATION\nThe patient was a 35-year-old female who had a history of breast cancer (invasive ductal carcinoma of the left breast, estrogen receptor (ER)/progesterone (PR) negative, human epidermal growth factor receptor 2 (HER2)/neu positive, status post-neoadjuvant docetaxel/carboplatin/trastuzumab/pertuzumab therapy (TCH-P therapy), status post-bilateral mastectomies and left axillary lymph node dissection), with a prior right frontal brain metastases (status post-gross total resection, capecitabine/lapatinib/temozolomide therapy (TTX therapy), and cyberknife treatment). Patient was found pregnant at 9 weeks’ gestation; despite potential complications with the fetus during TTX therapy, patient elected to continue with the pregnancy; TTX therapy was discontinued. At 14 weeks’ gestation, she returned with headaches. Imaging showed recurrent right frontal dural-based lesion with significant surrounding vasogenic edema [Figure 1]. Magnetic resonance imaging (MRI) of the spine was negative. She was taken for a craniotomy at 16 weeks’ gestation, which again confirmed metastatic adenocarcinoma.\n\nFigure 1 Axial magnetic resonance T1 (left) and fluid-attenuated inversion recovery demonstrates right frontal dural-based lesion\n\nSix weeks later, patient returned with worsening headaches and fatigue. CT head showed recurring disease in the right frontal lobe [Figure 2a]. She was started on decadron and chemotherapy (5-fluorouracil, adriamycin, and cyclophosphamide). Serial MRI demonstrated enlarging right frontal lesions [Figure 2b and c]. She underwent a craniotomy at 27 weeks’ gestation, and chemotherapy was discontinued promptly. Starting at 30 weeks’ gestation, she received whole brain radiation (10 fractions, each at 3000 cGy) for 2 weeks. Subsequently, she delivered a baby girl via cesarean section at 32 weeks’ gestation; at the same time, patient had an elective bilateral tubal ligation. Overall, her pregnancy was complicated by intrauterine growth restriction, with estimated gestation weight at 6th percentile. She was getting weekly biophysical profiles/umbilical arterial Doppler which had been reassuring; in addition, she had a normal fetal echocardiogram at 20 weeks’ gestation. At 6 weeks follow-up, an MRI brain demonstrated no new intracranial disease, with stable postoperative findings [Figure 3].\n\nFigure 2 Axial computed tomography of the head (a), and serial fluid-attenuated inversion recovery (b, c) demonstrate progressive growth of recurrent right frontal lesion, with midline shift\n\nFigure 3 Axial magnetic resonance fluid-attenuated inversion recovery (left) and T1 with contrast demonstrate no residual or recurrent disease\n\nDISCUSSION\nThe literature is limited regarding intracranial neoplasms during pregnancy. The estimated incidence is 15 per 100,000.[57] Common lesions include primary tumors, typically gliomas, pituitary adenoma, and meningiomas.[51215] Brain metastasis during pregnancy is rather rare, where choriocarcinoma is the most common pathology.[513] Overall, the management of intracranial neoplasms can be challenging. Patients may opt for less aggressive treatment or to postpone treatment in order to decrease risk to the fetus while others may opt to terminate the pregnancy and proceed with full therapy. Future fertility may also be compromised, which remains an important consideration. Management needs to be tailored for each patient with interdisciplinary cooperation.\n\nBreast cancer is the most common malignancy during pregnancy.[2] Of the reported cases, up to 3.8% exhibit metastatic disease.[5] Brain metastasis during pregnancy, however, has been rare and has only been reported in three other instances.[5810] These are summarized in Table 1. Mandrawa et al.[8] reported the case of a 25-year-old female who underwent craniotomies at 23 weeks’ gestation and 25 weeks’ gestation for brain metastases; patient took ongoing trastuzumab; forceps-assisted delivery occurred at 37 weeks’ gestation; baby continued to do well up to 28 months follow-up. Gupta et al.[5] presented the case of a 24-year-old female, diagnosed with intracranial metastases at 22 weeks’ gestation, who received whole brain radiation and dexamethasone; patient underwent a cesarean section at 38 weeks; baby continued to do well at 6 months follow-up. Okuda et al.[10] noted a 35-year-old female who underwent a craniotomy for a metastases at 18 weeks’ gestation, however, symptoms worsened, necessitating a termination of pregnancy at 21 weeks’ gestation, followed by aggressive whole brain radiation and adjuvant chemotherapy.\n\nTable 1 Review of literature\n\nChemotherapy for the treatment of breast cancer during pregnancy appears to be well-tolerated by the fetus; a large series reported 104 cases where chemotherapy was given starting at a mean gestational age of 20.4 weeks; the malformation rate of exposed neonates was not significantly different than the general population.[2] Radiation to the brain may be feasible during pregnancy, if adjusted accordingly. Mazonakis et al.[9] demonstrated that, for an isocentric dose of 65 Gy, the radiation dose to the fetus does not exceed 100 mGy, a limit where risks toward the fetus are effectively marginalized.[14] According to a meta-analysis by Cohen-Kerem et al.,[4] non-obstetric surgery during pregnancy does not heighten the risk of birth defects, even during the first trimester. On the other hand, scant data exists regarding craniotomies for tumor resection.[36] The American College of Obstetrics and Gynecology endorses fetal ultrasound and Doppler before and after the procedure and states that known anesthesia has not been linked to teratogenic effects at any gestational age.[1] Overall, pregnancy-associated breast cancer is more advanced and aggressive at diagnosis than breast cancer during non-pregnancy; on the other hand, patients who become pregnant after breast cancer do not appear to have worse outcomes than patients who do not become pregnant.[11]\n\nOur patient is the fourth case of breast cancer metastases to the brain. She was able to undergo two craniotomies, at 16 weeks’ gestation and at 27 week's gestation, without surgical complications. Her baby was delivered at 32 weeks’ gestation; though the patient exhibited low gestational weight, the patient exhibited no malformation.\n\nCONCLUSION\nThere is a lack of guidelines and clinical consensus on medical and surgical treatment for breast cancer metastases in pregnant patients. Treatment usually varies based upon underlying tumor burden, location, gestational age of the fetus, and patient's preference and symptomatology. In this patient, our treatment rationale was based upon prolonging the gestational age and attempted gross total-resection of the metastases.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n\nhttp://surgicalneurologyint.com/Brain-metastases-from-breast-cancer-during-pregnancy/\n==== Refs\nREFERENCES\n1 ACOG Committee on Obstetric Practice. ACOG Committee Opinion No.474: Nonobstetric Surgery During Pregnancy Obstet Gynecol 2011 117 420 1 21252774 \n2 Cardonick E Dougherty R Grana G Gilmandyar D Ghaffar S Usmani A Breast cancer during pregnancy: Maternal and fetal outcomes Cancer J 2010 16 76 82 20164696 \n3 Cohen-Gadol AA Friedman JA Friedman JD Tubbs RS Munis JR Meyer FB Neurosurgical management of intracranial lesions in the pregnant patient: A 36-year institutional experience and review of the literature J Neurosurg 2009 111 1150 7 19408979 \n4 Cohen-Kerem R Railton C Oren D Lishner M Koren G Pregnancy outcome following non-obstetric surgical intervention Am J Surg 2005 190 467 73 16105538 \n5 Gupta S Jain P McDunn S Breast cancer with brain metastases in pregnancy J Community Support Oncol 2014 12 378 80 25853260 \n6 Johnson N Sermer M Lausman A Maxwell C Obstetric outcomes of women with intracranial neoplasms Int J Gynaecol Obstet 2009 105 56 9 19155008 \n7 Lew PS Tan WC Tan WK Tan HK Dilemmas in management of brain tumours in pregnancy Ann Acad Med 2010 39 64 5 \n8 Mandrawa CL Stewart J Fabinyi GC Walker SP A case study of trastuzumab treatment for metastatic breast cancer in pregnancy: Fetal risks and management of cerebral metastases Aust N Z J Obstet Gynaecol 2011 51 372 6 21806575 \n9 Mazonakis M Damilakis J Theoharopoulos N Varveris H Gourtsoyiannis N Brain radiotherapy during pregnancy: An analysis of conceptus dose using anthropomorphic phantoms Br J Radiol 1999 72 274 8 10396218 \n10 Okuda T Yamamoto S Matsuo S Kataoka H Kitawaki J Metastasis of Pregnancy-Associated Breast Cancer (Suspected to Be Hereditary Breast and Ovarian Cancer) to the Brain, Diagnosed at 18 Weeks’ Gestation: A Case Report and Review of the Literature Case Rep Obstet Gynecol 2016 2016 9813253 \n11 Raphael J Trudeau M Chan K Outcome of patients with pregnancy during or after breast cancer: A review of the recent literature Curr Oncol 2015 22 Suppl 1 S8 18 25848342 \n12 Ravindra VM Braca JA 3rd Jensen RL Duckworth EA Management of intracranial pathology during pregnancy: Case example and review of management strategies Surg Neurol Int 2015 6 43 25883835 \n13 Stevenson CB Thompson RC The clinical management of intracranial neoplasms in pregnancy Clin Obstet Gynecol 2005 48 24 37 15725854 \n14 Stovall M Blackwell CR Cundiff J Novack DH Palta JR Wagner LK Fetal dose from radiotherapy with photon beams: Report of AAPM Radiation Therapy Committee Task Group No.36 Med Phys 1995 22 63 82 7715571 \n15 Verheecke M Halaska MJ Lok CA Ottevanger PB Fruscio R Dahl-Steffensen K Primary brain tumours, meningiomas and brain metastases in pregnancy: Report on 27 cases and review of literature Eur J Cancer 2014 50 1462 71 24636876\n\n",
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"issn_linking": "2152-7806",
"issue": "7(Suppl 23)",
"journal": "Surgical neurology international",
"keywords": "Brain metastases; brain surgery; breast cancer",
"medline_ta": "Surg Neurol Int",
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"nlm_unique_id": "101535836",
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"pages": "S603-6",
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"pubdate": "2016",
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"references": "16105538;21806575;19408979;20164696;25848342;24636876;25853260;21252774;20126819;7715571;25883835;15725854;26981296;10396218;19155008",
"title": "Brain metastases from breast cancer during pregnancy.",
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"abstract": "Parathyroid carcinoma (PC) is an orphan malignancy accounting for only ~1% of all cases with primary hyperparathyroidism. The localization of recurrent PC is of critical importance and can be exceedingly difficult to diagnose and sometimes futile when common sites of recurrence in the neck and chest cannot be confirmed. Here, we present the diagnostic workup, molecular analysis and multimodal therapy of a 46-year old woman with the extraordinary manifestation of abdominal lymph node metastases 12 years after primary diagnosis of PC. The patient was referred to our endocrine tumor center in 2016 with the aim to localize the tumor causative of symptomatic biochemical recurrence. In view of the extensive previous workup we decided to perform [18F]FDG-PET-CT. A pathological lymph node in the liver hilus showed slightly increased FDG-uptake and hence was suspected as site of recurrence. Selective venous sampling confirmed increased parathyroid hormone concentration in liver veins. Abdominal lymph node metastasis was resected and histopathological examination confirmed PC. Within four months, the patient experienced biochemical recurrence and based on high tumor mutational burden detected in the surgical specimen by whole exome sequencing the patient received immunotherapy with pembrolizumab that led to a biochemical response. Subsequent to disease progression repeated abdominal lymph node resection was performed in 10/2018, 01/2019 and in 01/2020. Up to now (12/2020) the patient is biochemically free of disease. In conclusion, a multimodal diagnostic approach and therapy in an interdisciplinary setting is needed for patients with rare endocrine tumors. Molecular analyses may inform additional treatment options including checkpoint inhibitors such as pembrolizumab.",
"affiliations": "Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.;Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany.;Institute of Pathology, University of Würzburg, Würzburg, Germany.;Department of Nuclear Medicine, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.;Department of Diagnostic and Interventional Radiology, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.;Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.;Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.;Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.;Computational Oncology, Molecular Diagnostics Program, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany.;Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.;Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany.;National Center for Tumor Diseases (NCT Heidelberg), Division of Translational Medical Oncology German Cancer Research Center (DKFZ), University Hospital Heidelberg, Heidelberg, Germany.;Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, University of Würzburg, Würzburg, Germany.;Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany.",
"authors": "Lenschow|Christina|C|;Fuss|Carmina Teresa|CT|;Kircher|Stefan|S|;Buck|Andreas|A|;Kickuth|Ralph|R|;Reibetanz|Joachim|J|;Wiegering|Armin|A|;Stenzinger|Albrecht|A|;Hübschmann|Daniel|D|;Germer|Christoph Thomas|CT|;Fassnacht|Martin|M|;Fröhling|Stefan|S|;Schlegel|Nicolas|N|;Kroiss|Matthias|M|",
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"doi": "10.3389/fendo.2021.643328",
"fulltext": "\n==== Front\nFront Endocrinol (Lausanne)\nFront Endocrinol (Lausanne)\nFront. Endocrinol.\nFrontiers in Endocrinology\n1664-2392\nFrontiers Media S.A.\n\n10.3389/fendo.2021.643328\nEndocrinology\nCase Report\nCase Report: Abdominal Lymph Node Metastases of Parathyroid Carcinoma: Diagnostic Workup, Molecular Diagnosis, and Clinical Management\nLenschow Christina 1 *\n\nFuss Carmina Teresa 2\nKircher Stefan 3\nBuck Andreas 4\nKickuth Ralph 5\nReibetanz Joachim 1\nWiegering Armin 1\nStenzinger Albrecht 6 7\nHübschmann Daniel 8\nGermer Christoph Thomas 1\nFassnacht Martin 2 9\n\nFröhling Stefan 10\nSchlegel Nicolas 1\n\nKroiss Matthias 2 9 11\n1 Department of General, Visceral, Transplant, Vascular and Pediatric Surgery, University Hospital Würzburg, University of Würzburg, Würzburg, Germany\n2 Department of Internal Medicine I, Division of Endocrinology and Diabetes, University Hospital, University of Würzburg, Würzburg, Germany\n3 Institute of Pathology, University of Würzburg, Würzburg, Germany\n4 Department of Nuclear Medicine, University Hospital Würzburg, University of Würzburg, Würzburg, Germany\n5 Department of Diagnostic and Interventional Radiology, University Hospital Würzburg, University of Würzburg, Würzburg, Germany\n6 Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany\n7 Germany and German Cancer Consortium (DKTK), Heidelberg Partner Site, Heidelberg, Germany\n8 Computational Oncology, Molecular Diagnostics Program, NCT Heidelberg and Heidelberg University Hospital, Heidelberg, Germany\n9 Comprehensive Cancer Center Mainfranken, University of Würzburg, Würzburg, Germany\n10 National Center for Tumor Diseases (NCT Heidelberg), Division of Translational Medical Oncology German Cancer Research Center (DKFZ), University Hospital Heidelberg, Heidelberg, Germany\n11 Department of Medicine IV, University Hospital Munich, Ludwig-Maximilians-Universität München, Munich, Germany\nEdited by: Enzo Lalli, UMR7275 Institut de pharmacologie moléculaire et cellulaire (IPMC), France\n\nReviewed by: Alfredo Campenni’, University of Messina, Italy; Christian Albert Koch, Fox Chase Cancer Center, United States\n\n*Correspondence: Christina Lenschow, Lenschow_C@ukw.de\nThis article was submitted to Cancer Endocrinology, a section of the journal Frontiers in Endocrinology\n\n23 3 2021\n2021\n12 64332817 12 2020\n04 2 2021\nCopyright © 2021 Lenschow, Fuss, Kircher, Buck, Kickuth, Reibetanz, Wiegering, Stenzinger, Hübschmann, Germer, Fassnacht, Fröhling, Schlegel and Kroiss\n2021\nLenschow, Fuss, Kircher, Buck, Kickuth, Reibetanz, Wiegering, Stenzinger, Hübschmann, Germer, Fassnacht, Fröhling, Schlegel and Kroiss\nThis is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.\nParathyroid carcinoma (PC) is an orphan malignancy accounting for only ~1% of all cases with primary hyperparathyroidism. The localization of recurrent PC is of critical importance and can be exceedingly difficult to diagnose and sometimes futile when common sites of recurrence in the neck and chest cannot be confirmed. Here, we present the diagnostic workup, molecular analysis and multimodal therapy of a 46-year old woman with the extraordinary manifestation of abdominal lymph node metastases 12 years after primary diagnosis of PC. The patient was referred to our endocrine tumor center in 2016 with the aim to localize the tumor causative of symptomatic biochemical recurrence. In view of the extensive previous workup we decided to perform [18F]FDG-PET-CT. A pathological lymph node in the liver hilus showed slightly increased FDG-uptake and hence was suspected as site of recurrence. Selective venous sampling confirmed increased parathyroid hormone concentration in liver veins. Abdominal lymph node metastasis was resected and histopathological examination confirmed PC. Within four months, the patient experienced biochemical recurrence and based on high tumor mutational burden detected in the surgical specimen by whole exome sequencing the patient received immunotherapy with pembrolizumab that led to a biochemical response. Subsequent to disease progression repeated abdominal lymph node resection was performed in 10/2018, 01/2019 and in 01/2020. Up to now (12/2020) the patient is biochemically free of disease. In conclusion, a multimodal diagnostic approach and therapy in an interdisciplinary setting is needed for patients with rare endocrine tumors. Molecular analyses may inform additional treatment options including checkpoint inhibitors such as pembrolizumab.\n\nparathyroid carcinoma\nabdominal lymph node metastases\nmolecular diagnostics\nrepeated surgery\n[18F]FDG-PET-CT\nimmune check inhibitor\npembrolizumab\n==== Body\nIntroduction\n\nParathyroid carcinoma PC is an orphan malignancy occurring in approximately 1%–5% (United States, Europe, Japan) of all patients with primary hyperparathyroidism (pHPT) (1–5). The main pre-operative challenge of PC is to raise the suspicion of malignant disease at diagnosis since clinical outcome and prognosis are largely dependent on the extent of primary surgery. Despite the combination of multiple diagnostic modalities, this rare tumor is often difficult to diagnose preoperatively (6–9). Moreover, diagnosis of malignancy is made in only 15% of the fast-frozen sections. So, in the vast majority of cases, only the final histology or a relapse provides the diagnosis (10).\n\nThe high rate of relapse is another considerable problem in PC patients. We have recently published a comprehensive clinical characterization of 83 PC cases and have demonstrated that within a median interval of 48 months 38.6% of cases relapsed (7). However, in case of biochemical recurrence, the precise localization of cancerous tissue is mandatory to enable surgical treatment. The calcimimetic drug cinacalcet is approved to control serum calcium and may be used in case of unsuccessful localization and/or advanced, non-resectable disease. Systemic antitumoral therapy has remained anecdotal (11).\n\nTo date, only very few cases of PC with abdominal tumor localization (peripancreatic lymph nodes: n=1, liver n= 6) have been described (12–14).\n\nHere, we present the complex diagnostic workup and multimodal therapy in a 46-year old woman with the uncommon manifestation of abdominal metastases of PC.\n\nCase Description\n\nA 46-year old woman was referred to our endocrine tumor center in 2016 with the aim to localize the tumor causative of biochemical recurrence.\n\nPrimary surgery due to pHPT had been performed in 2004. Intraoperatively, PC was suspected and en-bloc-resection (hemithyroidectomy, parathyroidectomy and central lymph node dissection of the left side) was performed. PC was confirmed histopathologically and resection margins were free of tumor (R0). The patient experienced a permanent recurrent laryngeal nerve palsy at the left side as complication of the surgical procedure. She underwent postoperative adjuvant external beam radiation of the thyroid region at a total dose of 50.4 Gy. The patient was subsequently free of disease for 12 years.\n\nIn 2016, the patient experienced symptoms similar to those at initial diagnosis with thirst, fatigue and visual flashes. Serum calcium was elevated up to 3.4 mmol/L [reference range: 2.0–2.7mmol/L] and parathyroid hormone (PTH) was increased to 203 pg/mL [10–65pg/ml]. Medication with cinacalcet was initiated. Within the three subsequent months, the patient underwent cervical ultrasonography, CT and MRI of the neck and chest, [99mTc] Sestamibi-SPECT/CT, as well as [11C]methionine-PET-CT. None of these imaging modalities localized tumor recurrence. Additionally, the patient underwent re-exploration of the right neck and lymph node dissection of the right cervical lymph nodes. Histopathology was negative for PC and hypercalcemia persisted postoperatively.\n\nSubsequently the patient presented herself at our institution. In view of the extensive previous workup we decided to perform [18F]FDG-PET-CT. Surprisingly, a pathological lymph node (17x24 mm) within the liver hilus showed slightly increased FDG-uptake ( Figures 1A, B ). Due to the unusual localization we questioned relationship with the recurrence of PC and performed selective PTH venous sampling that included the entire neck region, but also sampling from the liver veins in addition to V. cava inferior sampling ( Figure 1C ). Highest PTH was measured in the right V. hepatica with 758 pg/ml and a ratio of 1.3 compared to V. cava inferior. After laparotomy and preparation of the liver hilus, the lymph node was resected with intact capsule without any signs of infiltration (R0) in January 2017. Inspection revealed no further lymph node manifestations ( Figures 1D, E ). Intraoperative PTH dropped from 841 ng/L to 387ng/L The peri-and postoperative course was without any complications. The histological assessment of the resected tissue confirmed lymph node metastasis with blood vessel infiltration (V1) of PC ( Figure 1F ). Histological and immunohistochemical analyses were both consistent with parathyroid carcinoma (positivity for PTH, loss of parafibromin). Furthermore, we stained the lymph node sample for PD-L1 (antibody 28-8). In the tumor cell there was no specific membrane-bound positivity (TC Score 0; Cologne -Score for NSCLS) (15). No tumor associated PD-L1 positivity in the background inflammatory infiltrate was observed. Moreover, we analyzed the DNA-Mismatch-Repair-Protein MLH1, MSH2, MSHG, and PMS2. The results showed no evidence of microsatellite instability. In summary, this was a lymph node metastases of a PD-L1-negative, microsatellite stable parathyroid carcinoma.\n\nFigure 1 CT Imaging (A), [18F]FDG-PET-CT (B), Venous sampling V. hepatica (C), intraoperative localization (D), Resected lymph node (E), histological result at time of diagnosis recurrence (F), White arrow marks the lymph node metastases in the hilus of the liver.\n\nAfter resection, Calcium decreased steadily from 3.4 mmol/L to 2.3 mmol/L. Cinacalcet was discontinued.\n\nSystemic Treatment\n\nUnfortunately, few days after discharge, PTH level and Calcium level increased slowly again requiring the use of cinacalcet. The medication was increased to a daily cumulative dose of 150 mg in the following weeks. Four months after resection, PTH rose to 912 ng/L and additionally, denosumab was required to adequately control serum calcium levels (2.6 mmol/l).\n\nAbdominal ultrasonography indicated recurrent lymph node metastases in the hepatic hilus ( Figure 2A ) which was confirmed by [18F]FDG-PET-CT.\n\nFigure 2 Abdominal ultrasonography (A) [18F]FDG-PET-CT (B), photography surgery 10/2018, Lymph node metastases in situ (C) (white arrows mark the tumor), and the tumor localization in an anatomical drawing (D). CD, cystic duct; CBD, common bile duct; CHD, common hepatic duct.\n\nThe patient was included in NCT/DKTK MASTER (Molecularly Aided Stratification for Tumor Eradication Research), a multicenter, prospective observational study that is based on a common workflow for diagnostics, therapeutic decision making, and structured follow-up in patients with rare tumors failing standard treatment. The formalin-fixed paraffin embedded lymph node tissue obtained at surgery was utilized for whole exome sequencing and 412 single nucleotide variants (SNV) and 2 insertions/deletions (indels) were identified.\n\nBecause of the rapid recurrence in the same location, the fact that PTH levels had not returned to normal levels after resection of the previous metastases and in view of controlled serum calcium (2.6 mmol/L) only with 150 mg cinacalcet, we decided to initiate therapy with pembrolizumab on a compassionate use basis at 200 mg every three weeks. Pembrolizumab treatment was started in 09/2017 at a PTH serum concentration of 1,906 ng/L ( Figure 3F ). After four cycles of therapy, PTH dropped significantly (11/2017) to 613 ng/L and [18F]FDG-PET-CT showed stable disease four months later. Pembrolizumab was continued for six infusions every three weeks until [18F]FDG-PET-CT detected a lymph node bulk adjacent to the gallbladder ( Figure 2B ) in 07/2018. After evaluation of resectability, re-laparotomy was performed (10/2018) and the lymph node conglomerate of 3.4x2.0x3.2cm in lymph node station 12 was resected. There were no clinical signs of extra nodal tumor infiltration ( Figures 2C, D ). Intraoperative PTH dropped from 2864 ng/L to 64.3ng/L. Histology confirmed a conglomerate of lymph node metastases of the PC up to 3.8 cm in size exhibiting the same features as the initial specimen. The postoperative course of the patient was unremarkable. In the following months, the patient’s serum calcium and PTH levels increased slowly. The patient was normocalcaemic on intermittent medication with denosumab and had stable PTH levels between 197 und 332 pg/L until 06/2019. At this time a progress of increased serum calcium levels (2.8 mmol/L) and PTH (418 ng/L) was detected. A [18F]FDG-PET-CT was performed and showed a new lymph node recurrence near the diaphragm ( Figures 3A–D ). This lymph node was resected as well as a lymph node dorsal of the V. cava inferior in 01/2020 ( Figure 3E ). PTH dropped intraoperatively to 15.8 ng/L (preoperative: 1,831 ng/L). Due to postoperative hypocalcemia, the patient received decostriol (1,25-dihydroxycholecalciferol) at a dose of 0.5 µg twice a day and up to 3 g calcium P.O. per day which could be discontinued during the following 8 weeks. Until 10/2020 the patient was biochemically free of recurrence (serum calcium 2.4 mmol/L, PTH 42.7 pg/ml) without any medication. The whole course of PTH is shown in Figure 3F . Interdisciplinary discussion recommended watchful waiting and restaging in case of biochemical progression.\n\nFigure 3 CT Imaging (A, C), 12/2019), [18F]FDG-PET-CT (B, D), (white arrows mark the tumor), photography surgery 01/2020 E; K, Kidney; VC, Vena cava; AG, adrenal gland; PTH course is shown as time scale from the beginning of treatment in our hospital 2016 up to 2020. In this period, we performed three abdominal surgeries (red arrow) and the beginning of therapy within Pembrolizumab (green arrow) (F).\n\nDiscussion\n\nThe diagnostic workup and site directed therapy in case of recurrent PC remains challenging. Distant metastases and especially abdominal localization of PC, as presented in this case report, are highly uncommon (7). The review of the literature revealed case reports of distant metastases, specifically abdominal and brain metastases (12–14) ( Table 1 ). Interdisciplinary management is crucial to enable focused surgical treatment and adequate medical treatment (16). In this case report, we presented an example for an interdisciplinary workflow in a patient with abdominal recurrent PC 12 years after primary diagnosis.\n\nTable 1 Unusual localizations of distant PC recurrence in the literature.\n\nFirst Authors\tPublication\nYear\tPatients\n(n=)\tSites of Distant Metastases (DM)\tFinding Modality\nof DM\tTreatment of DM\tOutcome\tFollow up\n(years)\t\nManente et al.\t1987\t1\tLymph node Pancreas region\tNot Reported\tResection\tDeath\t1\t\nQiu Zhong-ling et al.\t2013\t5\tLiver\tCT n=5\tRFA /EB n=1\tAlive n=3\t0.5-9\t\nBiopsy n= 3\tPR n=3\tDeath n=2\t\t\n99mTC-MIBI n=1\tUnknown=1\t\t\n3\tBrain\tMRI n=2\tPR\tAlive n= 2\t5.5-9\t\nCT n=1\t\tUnknown n=1\t2.5\t\nTsoli et al.\t2017\t1\tBrain\tMRI\tResection, RTx\tDeath\t2\t\nAsare et al.\t2019\t2\tLiver\tUnkown\tCTx\tAlive n=1\tUnkown\t\nDeath n=1\tn=6\t\nDistant metastases were only considered, if they were localized extracervical, extrathoracic and were not localized in bones. RFA, radiofrequency ablation; EB, embolization; PR, palliative resection; CTx, chemotherapy; RTx, Radiotherapy.\n\n[18F]FDG-PET-CT and Selective Venous Sampling Improves Localization Diagnostics\n\nAfter biochemical recurrence in our patient, tumor localization was not possible by various imaging techniques. However, [18F]FDG-PET-CT was able to visualize the unusual localization of abdominal recurrence. In several a case series, [18F]FDG-PET-CT has been shown to effectively localize PC manifestation sites at initial diagnosis, follow-up or recurrence (17). In the current literature, [18F]choline-PET-CT was compared in small series with [18F]FDG-PET-CT. In 2 cases [18F]FDG-PET-CT detected tumor manifestations in the liver and bone lesions in the pelvis, which was missed by [18F]FDG-PET-CT. The authors of that study discussed that the differences in choline and FDG uptake could be the differences in tumor proliferation and differentiation (18). Another case report demonstrated that [18F]FDG-PET-CT and [18F]choline-PET-CT are feasible, in (recurrent) PC (19). In summary, as long as there is no standardized diagnostic work-up especially in recurrent PC, whole body functional imaging should be considered for detecting uncommon tumor localization and to avoid repeated cervical surgery.\n\nFurthermore, in our case the selective venous sampling was additionally performed to confirm this uncommon localization. Therefore, selective venous sampling was able to support the localization diagnostics and consecutively, the focused surgical approach we then performed.\n\nMolecular Informed Systemic Treatment\n\nOverall, only few reports have characterized the molecular landscape of PC. Using exome sequencing, Yu et al. (20) in a series of seven cases found an average of 51 somatic variants. This is in stark contrast to the findings in our patient who had high tumor mutational burden (TMBh). TMBh is increasingly recognized as a marker of response to immunotherapy (21) and related to the accumulation of tumoral neoantigens which increase the likelihood of response to inhibition of immune checkpoint molecules.\n\nMolecular guided systemic treatment with pembrolizumab led to stable disease as best response on imaging and a marked clinical and biochemical benefit with a stabilization of serum calcium and drop of PTH for 9 months. Our case demonstrates that in rare tumors, molecular analysis may be useful to detect druggable targets. So far, no case of successful treatment of PC with immune checkpoint inhibitors has been described.\n\nTargeted Surgical Resection Permitted Long-Term Disease Control\n\nAfter the first two resections of parathyroid metastases, calcium normalization has been achieved. The patient was subsequently clinically and biochemically disease free for 9 months (at last observation 10/2020). Repeated surgery was able to control serum calcium supporting that every effort should be made to localize the disease and evaluate resectability (16, 17). It must be noted that our previous case series suggests that more extended primary surgery (parathyroidectomy and hemithyroidectomy) may be beneficial in lowering the rate of recurrence in general although it is unclear whether this is also true for the very rare distant metastases (7).\n\nPatients Perspective\n\nOur patient has been alive with a “chronic” disease over a long duration which required medical treatment for long periods of time. Uncertainty about prognosis, eventual diagnostic success and risk of surgery have contributed to the disease burden. The present outcome with biochemical remission has significantly improved the well-being of the patient.\n\nConclusion\n\nBecause manifestation of recurrent PC outside of the neck and chest is possible, whole body imaging for tumor localization is useful to allow for focused repeat surgery. The course of the disease in our patient with a recurrence after 12 years after primary surgery suggests that the tumor evaded immune recognition at a certain time point during disease progression which may also explain the unusual systemic spread of the disease. It is tempting to speculate that pembrolizumab treatment inhibited further progression of disease rendering surgical removal effective in a neo-adjuvant manner. A multimodal diagnostic approach and therapy in an interdisciplinary setting is needed for patients with rare endocrine tumors.\n\nData Availability Statement\n\nThe original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding author.\n\nEthics Statement\n\nWritten informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.\n\nAuthor Contributions\n\nCL, NS, and MK designed the study. AB and RK performed diagnostic imaging and procedures. JR and AW performed surgical procedures. CG supervised all surgical procedures. SK examined all histopathological samples. AS, DH, and SF performed whole exome sequencing. CL, CF, and MK provided data. CL and MK analyzed the data. CL, MF, NS, CG, AS, DH, SF, and MK interpreted the data. CL and MK wrote a manuscript draft. All authors contributed to the article and approved the submitted version.\n\nFunding\n\nThis publication was supported by the Open Access Publication Fund of the University of Wuerzburg.\n\nConflict of Interest\n\nThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\n\nSupplementary Material\n\nThe Supplementary Material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fendo.2021.643328/full#supplementary-material\n\nClick here for additional data file.\n==== Refs\nReferences\n\n1 Ryhanen EM Leijon H Metso S Eloranta E Korsoff P Ahtiainen P . A nationwide study on parathyroid carcinoma. Acta Oncol (2017) 56 (7 ):991–1003. 10.1080/0284186X.2017.1306103 28362521\n2 Obara T Fujimoto Y . Diagnosis and treatment of patients with parathyroid carcinoma: an update and review. World J Surg (1991) 15 (6 ):738–44. 10.1007/BF01665308\n3 Lee PK Jarosek SL Virnig BA Evasovich M Tuttle TM . Trends in the incidence and treatment of parathyroid cancer in the United States. Cancer (2007) 109 (9 ):1736–41. 10.1002/cncr.22599\n4 Cetani F Pardi E Marcocci C . Parathyroid Carcinoma. Front Horm Res (2019) 51 :63–76. 10.1159/000491039 30641523\n5 Harari A Waring A Fernandez-Ranvier G Hwang J Suh I Mitmaker E . Parathyroid carcinoma: a 43-year outcome and survival analysis. J Clin Endocrinol Metab (2011) 96 (12 ):3679–86. 10.1210/jc.2011-1571\n6 Witteveen JE Haak HR Kievit J Morreau H Romijn JA Hamdy MA . Challenges and pitfalls in the management of parathyroid carcinoma: 17-year follow-up of a case and review of the literature. Horm Cancer (2010) 1 (4 ):205–14. 10.1007/s12672-010-0042-6\n7 Lenschow C Schragle S Kircher S Lorenz K Machens A Dralle H . Clinical Presentation, Treatment, and Outcome of Parathyroid Carcinoma: Results of the NEKAR Retrospective International Multicenter Study. Ann Surg (2020). 10.2139/ssrn.3541131\n8 Cetani F Pardi E Marcocci C . Update on parathyroid carcinoma. J Endocrinol Invest (2016) 39 (6 ):595–606. 10.1007/s40618-016-0447-3 27001435\n9 Campenni A Ruggeri RM Sindoni A Giovinazzo S Calbo E Ieni A . Parathyroid carcinoma presenting as normocalcemic hyperparathyroidism. J Bone Miner Metab (2012) 30 (3 ):367–72. 10.1007/s00774-011-0344-y\n10 Wang P Xue S Wang S Lv Z Meng X Wang G . Clinical characteristics and treatment outcomes of parathyroid carcinoma: A retrospective review of 234 cases. Oncol Lett (2017) 14 (6 ):7276–82. 10.3892/ol.2017.7076\n11 Machado NN Wilhelm SM . Parathyroid Cancer: A Review. Cancers (Basel) (2019) 11 (11 ):1676. 10.3390/cancers11111676\n12 Manente P Cecchettin M Infantolino D Foscolo G Conte N . Apparently nonfunctioning metastases of parathyroid carcinoma. Tumori (1987) 73 (2 ):191–3. 10.1177/030089168707300218\n13 Qiu ZL Wu CG Zhu RS Xue YL Luo QY . Unusual case of solitary functioning bone metastasis from a “parathyroid adenoma”: imagiologic diagnosis and treatment with percutaneous vertebroplasty–case report and literature review. J Clin Endocrinol Metab (2013) 98 (9 ):3555–61. 10.1210/jc.2013-2014\n14 WEEKLY clinicopathological exercises; parathyroid carcinoma with hyperparathyroidism and with metastases to liver. N Engl J Med (1953) 248 (10 ):426–32. 10.1056/NEJM195303052481007\n15 Lloyd RV Osamura RY Klöppel G Rosai J . WHO classification of tumours of endocrine organs by International Agency for Research. In: Lloyd RV , editor. Cancer, 4th ed, vol. 10 th . World Health Organization (WHO, Genf, Switzerland (2017).\n16 Storvall S Ryhanen E Bensch FV Heiskanen I Kytola S Ebeling T . Recurrent Metastasized Parathyroid Carcinoma-Long-Term Remission After Combined Treatments With Surgery, Radiotherapy, Cinacalcet, Zoledronic Acid, and Temozolomide. JBMR Plus (2019) 3 (4 ):e10114. 10.1002/jbm4.10114 31044184\n17 Evangelista L Sorgato N Torresan F Boschin IM Pennelli G Saladini G . FDG-PET/CT and parathyroid carcinoma: Review of literature and illustrative case series. World J Clin Oncol (2011) 2 (10 ):348–54. 10.5306/wjco.v2.i10.348\n18 Deandreis D Terroir M Al Ghuzlan A Berdelou A Lacroix L Bidault F . (1)(8)Fluorocholine PET/CT in parathyroid carcinoma: a new tool for disease staging? Eur J Nucl Med Mol Imaging (2015) 42 (12 ):1941–2. 10.1007/s00259-015-3130-6\n19 Hatzl M Roper-Kelmayr JC Fellner FA Gabriel M . 18F-Fluorocholine, 18F-FDG, and 18F-Fluoroethyl Tyrosine PET/CT in Parathyroid Cancer. Clin Nucl Med (2017) 42 (6 ):448–50. 10.1097/RLU.0000000000001652\n20 Yu W McPherson JR Stevenson M van Eijk R Heng HL Newey P . Whole-exome sequencing studies of parathyroid carcinomas reveal novel PRUNE2 mutations, distinctive mutational spectra related to APOBEC-catalyzed DNA mutagenesis and mutational enrichment in kinases associated with cell migration and invasion. J Clin Endocrinol Metab (2015) 100 (2 ):E360–4. 10.1210/jc.2014-3238\n21 Passaro A Stenzinger A Peters S . Tumor Mutational Burden as a Pan-cancer Biomarker for Immunotherapy: The Limits and Potential for Convergence. Cancer Cell (2020) 38 (5 ):624–5. 10.1016/j.ccell.2020.10.019\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1664-2392",
"issue": "12()",
"journal": "Frontiers in endocrinology",
"keywords": "[18F]FDG-PET-CT; abdominal lymph node metastases; immune check inhibitor; molecular diagnostics; parathyroid carcinoma; pembrolizumab; repeated surgery",
"medline_ta": "Front Endocrinol (Lausanne)",
"mesh_terms": null,
"nlm_unique_id": "101555782",
"other_id": null,
"pages": "643328",
"pmc": null,
"pmid": "33833736",
"pubdate": "2021",
"publication_types": "D002363:Case Reports; D013485:Research Support, Non-U.S. Gov't",
"references": "23861459;32649472;17372919;21937626;30641523;1767540;13025711;31044184;22022662;31661917;29344163;21258429;22246083;28362521;26253272;27001435;28394837;3576716;33171127;25387265",
"title": "Case Report: Abdominal Lymph Node Metastases of Parathyroid Carcinoma: Diagnostic Workup, Molecular Diagnosis, and Clinical Management.",
"title_normalized": "case report abdominal lymph node metastases of parathyroid carcinoma diagnostic workup molecular diagnosis and clinical management"
} | [
{
"companynumb": "DE-AMGEN-DEUSP2021126917",
"fulfillexpeditecriteria": "1",
"occurcountry": "DE",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "CINACALCET HYDROCHLORIDE"
},
"drugadditional":... |
{
"abstract": "BACKGROUND\nComorbidities can impose diagnostic and treatment challenges in patients with multiple sclerosis (MS). Sickle cell disease (SCD) and MS are both inflammatory diseases featuring immune system dysregulation, and the reciprocal interaction of these diseases deserves investigation.\n\n\nRESULTS\nWe present the case of a 28-year-old woman with SCD who developed a sickle cell crisis and acute chest syndrome during corticosteroid treatment for a first MS attack. We then provide a review of the literature on co-management of SCD and MS. In patients with SCD experiencing an acute MS exacerbation, pre-treatment with red blood cell exchange transfusion before corticosteroids may reduce adverse vaso-occlusive events. Plasma exchange may also be considered. Finally, we discuss innovative pre-clinical research that suggests that natalizumab or dimethyl fumarate may ameliorate SCD symptoms while preventing MS relapses; human trials, however, are needed.\n\n\nCONCLUSIONS\nThe co-occurrence of inflammatory disorders, in this case MS and SCD, requires providers to appropriately manage each condition with consideration of the other. Future studies may generate shared avenues for treatment.",
"affiliations": "Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, NY, USA.;NewYork-Presbyterian Brooklyn Methodist Hospital, Department of Hematology and Oncology, Brooklyn, NY, USA.;Icahn School of Medicine at Mount Sinai, Department of Neurology, New York, NY, USA. Electronic address: Anusha.Yeshokumar@mssm.edu.",
"authors": "Kerpen|Kate|K|;Baptiste|Ayanna|A|;Yeshokumar|Anusha K|AK|",
"chemical_list": null,
"country": "Netherlands",
"delete": false,
"doi": "10.1016/j.msard.2020.102427",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2211-0348",
"issue": "45()",
"journal": "Multiple sclerosis and related disorders",
"keywords": "African american; Anemia; Blood transfusion; Comorbidity; Multiple sclerosis; Plasma exchange; Sickle Cell",
"medline_ta": "Mult Scler Relat Disord",
"mesh_terms": "D056586:Acute Chest Syndrome; D000328:Adult; D000755:Anemia, Sickle Cell; D005260:Female; D006801:Humans; D009103:Multiple Sclerosis",
"nlm_unique_id": "101580247",
"other_id": null,
"pages": "102427",
"pmc": null,
"pmid": "32841868",
"pubdate": "2020-10",
"publication_types": "D002363:Case Reports; D016421:Editorial; D016454:Review",
"references": null,
"title": "Multiple sclerosis in a young woman with sickle cell disease.",
"title_normalized": "multiple sclerosis in a young woman with sickle cell disease"
} | [
{
"companynumb": "US-TEVA-2020-US-1842126",
"fulfillexpeditecriteria": "1",
"occurcountry": "US",
"patient": {
"drug": [
{
"actiondrug": "1",
"activesubstance": {
"activesubstancename": "METHYLPREDNISOLONE"
},
"drugadditional": "1",
... |
{
"abstract": "BACKGROUND\nCryptococcosis is a fungal infection caused by the yeast-like encapsulated basidiomycetous fungus of the Cryptococcus neoformans (C. neoformans) species complex. These fungi are ubiquitous in soil and bird droppings, and infection by them is an important global health concern, particularly in immunosuppressed patients, such as organ transplant recipients and those infected by the human immunodeficiency virus. The fungus usually enters the body through the respiratory tract, but extremely rare cases of infection acquired by transplantation of solid organs have been reported.\n\n\nMETHODS\nWe report a case of disseminated cryptococcosis in a liver transplant recipient, diagnosed 2 wk after the procedure. The patient initially presented with fever, hyponatremia and elevated transaminase levels, manifesting intense headache after a few days. Blood cultures were positive for C. neoformans. Liver biopsy showed numerous fungal elements surrounded by gelatinous matrix and sparse granulomatous formations. Magnetic resonance imaging of the brain showed multiple small lesions with low signal in T2, peripheric enhancement and edematous halo, diffuse through the parenchyma but more concentrated in the subcortical regions. Treatment with amphotericin B for 3 wk, followed by maintenance therapy with fluconazole, led to complete resolution of the symptoms. The recipients of both kidneys from the same donor also developed disseminated cryptococcosis, confirming the transplant as the source of infection. The organ donor lived in a rural area, surrounded by tropical rainforest, and had negative blood cultures prior to organ procurement.\n\n\nCONCLUSIONS\nThis case highlights the risk of transmission of fungal diseases, specifically of C. neoformans, through liver graft during liver transplantation.",
"affiliations": "Department of Liver Transplantation, Instituto de Cardiologia do Distrito Federal, Brasilia 70673900, Brazil. gustferr@ufmg.br.;Department of Liver Transplantation, Instituto de Cardiologia do Distrito Federal, Brasilia 70673900, Brazil.;Department of Liver Transplantation, Instituto de Cardiologia do Distrito Federal, Brasilia 70673900, Brazil.;Department of Liver Transplantation, Instituto de Cardiologia do Distrito Federal, Brasilia 70673900, Brazil.;Department of Liver Transplantation, Instituto de Cardiologia do Distrito Federal, Brasilia 70673900, Brazil.;Department of Liver Transplantation, Instituto de Cardiologia do Distrito Federal, Brasilia 70673900, Brazil.;Department of Liver Transplantation, Instituto de Cardiologia do Distrito Federal, Brasilia 70673900, Brazil.",
"authors": "Ferreira|Gustavo de Sousa Arantes|GSA|;Watanabe|Andre Luis Conde|ALC|;Trevizoli|Natalia de Carvalho|NC|;Jorge|Fernando Marcus Felippe|FMF|;Couto|Carolina de Fatima|CF|;de Campos|Priscila Brizolla|PB|;Caja|Gabriel Oliveira Nunes|GON|",
"chemical_list": null,
"country": "United States",
"delete": false,
"doi": "10.4254/wjh.v12.i5.253",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "12(5)",
"journal": "World journal of hepatology",
"keywords": "Case report; Cryptococcosis; Cryptococcus neoformans; Fungal infection; Immunosuppression; Liver transplantation",
"medline_ta": "World J Hepatol",
"mesh_terms": null,
"nlm_unique_id": "101532469",
"other_id": null,
"pages": "253-261",
"pmc": null,
"pmid": "32547692",
"pubdate": "2020-05-27",
"publication_types": "D002363:Case Reports",
"references": "30508502;8965683;20100136;10770733;20373460;15984941;4934356;27766797;28904437;18756456;18171241;16160511;16619158;21220771;25747471;26019853;11384512;25063020;28562416;30866766;20879857;345120;22015465;14762626;18070977;27742281;20061921;8394951;9503557;28173801;18840080;19009203;19538493;19148422;19210677;26504469;30900315;26897067;24375706;12201357;28480277;16443429;23550668;23901902",
"title": "Transmission of cryptococcosis by liver transplantation: A case report and review of literature.",
"title_normalized": "transmission of cryptococcosis by liver transplantation a case report and review of literature"
} | [
{
"companynumb": "BR-ACCORD-186799",
"fulfillexpeditecriteria": "1",
"occurcountry": "BR",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PREDNISONE"
},
"drugadditional": "3",
"druga... |
{
"abstract": "Background Health records can be used to measure medicine use and health outcomes. The public subsidy of lenalidomide in Australia was based on two phase III trials showing improved survival. Objective To use hospital pharmacy information management systems to determine survival outcomes for lenalidomide as a second line treatment in relapsed or refractory multiple myeloma (RRMM) patients. Setting Five public hospitals in Queensland, Australia. Method We extracted data on medicine use and survival for RRMM patients planned to start lenalidomide from pharmacy management and pathology databases. Descriptive statistical analyses (Kaplan-Meier curves) were used to calculate overall survival. Main outcome measure Overall survival. Results There were 136 patients who received at least one lenalidomide dose and 2234 cycles were ordered. The median age was 69 years and 54% were male. Two lenalidomide containing protocols were considered: 90% of patients had lenalidomide plus dexamethasone; 18% had lenalidomide plus dexamethasone with cyclophosphamide. The median starting lenalidomide dose was 20 mg (range 4.3-25 mg) on days 1-21 of a 28-day cycle. Median time on treatment 9.4 months (range 0.5-71.7 months). Median overall survival was 45.4 months (range 12.0-70.5 months). Conclusion The median survival in our study compared favourably to clinical trials. Patients and clinicians can be reassured that outcomes in this clinical setting are as good as those observed in trials.",
"affiliations": "School of Pharmacy, University of Queensland, Woolloongabba, QLD, Australia.;Charm Implementation Manager, Icon Cancer Care Head Office, 293 Vulture St, South Brisbane, QLD, 4101, Australia.;Princess Alexandra Hospital Cancer Services, 199 Ipswich Rd, Woolloongabba, QLD, 4102, Australia.;Department of Haematology, Princess Alexandra Hospital, 199 Ipswich Rd, Woolloongabba, QLD, 4102, Australia.;School of Pharmacy, University of Queensland, Woolloongabba, QLD, Australia. s.hollingworth@uq.edu.au.",
"authors": "Sharkey|Megan M|MM|;McKavanagh|Daniel|D|;Walpole|Euan|E|;Mollee|Peter|P|;Hollingworth|Samantha A|SA|",
"chemical_list": "D007155:Immunologic Factors; D013792:Thalidomide; D000077269:Lenalidomide",
"country": "Netherlands",
"delete": false,
"doi": "10.1007/s11096-017-0480-0",
"fulltext": null,
"fulltext_license": null,
"issn_linking": null,
"issue": "39(4)",
"journal": "International journal of clinical pharmacy",
"keywords": "Australia; Lenalidomide; Multiple myeloma; Pharmacy information system; Refractory; Relapsed; Survival",
"medline_ta": "Int J Clin Pharm",
"mesh_terms": "D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia; D055695:Electronic Prescribing; D005260:Female; D006801:Humans; D007155:Immunologic Factors; D000077269:Lenalidomide; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma; D010607:Pharmacy Service, Hospital; D011793:Queensland; D012189:Retrospective Studies; D015996:Survival Rate; D013792:Thalidomide; D016896:Treatment Outcome",
"nlm_unique_id": "101554912",
"other_id": null,
"pages": "836-843",
"pmc": null,
"pmid": "28573439",
"pubdate": "2017-08",
"publication_types": "D016428:Journal Article; D016448:Multicenter Study",
"references": "23879201;18799726;24974802;22572968;21680536;23816163;25385278;20371448;23114547;24026427;26715547;21892856;23803862;18032763;24724748;17160081;27365091;21360065;24419113;19302559;24177258;18032762;26438514;26141212",
"title": "Using pharmacy management systems for research: survival outcomes for lenalidomide in multiple myeloma in the clinical setting.",
"title_normalized": "using pharmacy management systems for research survival outcomes for lenalidomide in multiple myeloma in the clinical setting"
} | [
{
"companynumb": "AU-CELGENEUS-AUT-20170602121",
"fulfillexpeditecriteria": "1",
"occurcountry": "AU",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "LENALIDOMIDE"
},
"drugadditional": null,
... |
{
"abstract": "A 21-year-old Chinese man who took an overdose of acetaminophen was hospitalized. His medical history was significant for glucose-6-phosphate dehydrogenase (G6PD) deficiency. On admission, physical examination was unremarkable and laboratory results were within normal limits. During his hospitalization, the patient experienced a decrease in hemoglobin concentration of almost 4 g/dl and an increase in unconjugated bilirubin consistent with the development of hemolysis. Acetaminophen was the most likely cause of the hemolysis. Clinicians must be aware of this potential complication after acetaminophen overdose in G6PD-deficient patients.",
"affiliations": "Department of Pharmacy, National University of Singapore, Republic of Singapore. phages@nus.edu.sg",
"authors": "Sklar|Grant E|GE|",
"chemical_list": "D018712:Analgesics, Non-Narcotic; D006454:Hemoglobins; D000082:Acetaminophen",
"country": "United States",
"delete": false,
"doi": "10.1592/phco.22.8.656.33216",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0277-0008",
"issue": "22(5)",
"journal": "Pharmacotherapy",
"keywords": null,
"medline_ta": "Pharmacotherapy",
"mesh_terms": "D000082:Acetaminophen; D000328:Adult; D018712:Analgesics, Non-Narcotic; D001772:Blood Cell Count; D005955:Glucosephosphate Dehydrogenase Deficiency; D006454:Hemoglobins; D006461:Hemolysis; D006801:Humans; D008297:Male",
"nlm_unique_id": "8111305",
"other_id": null,
"pages": "656-8",
"pmc": null,
"pmid": "12013368",
"pubdate": "2002-05",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Hemolysis as a potential complication of acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency.",
"title_normalized": "hemolysis as a potential complication of acetaminophen overdose in a patient with glucose 6 phosphate dehydrogenase deficiency"
} | [
{
"companynumb": "SG-RANBAXY-2014R1-91334",
"fulfillexpeditecriteria": "1",
"occurcountry": "SG",
"patient": {
"drug": [
{
"actiondrug": "6",
"activesubstance": {
"activesubstancename": "ACETAMINOPHEN"
},
"drugadditional": null,
... |
{
"abstract": "OBJECTIVE\nThe primary objective of this study was to evaluate the safety and tolerability of carboplatin plus pemetrexed for elderly patients (≥75 years) with chemotherapy-naïve advanced non-squamous non-small cell lung cancer.\n\n\nMETHODS\nPatients received escalated doses of carboplatin at an area under the concentration-time curve of 4 (Level 1) or 5 (Level 2) plus pemetrexed (500 mg/m(2)) every 3 weeks for a maximum of six cycles. Dose escalation was decided according to whether dose-limiting toxicity occurred in the first cycle of chemotherapy.\n\n\nRESULTS\nA total of 20 patients (6 at Level 1, 14 at Level 2) were enrolled. No dose-limiting toxicities were observed in patients at Level 1 or the first six patients at Level 2, and therefore the combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was considered to be the recommended dose. Among a total of 14 patients in Level 2, only 1 patient experienced dose-limiting toxicity: Grade 3 febrile neutropenia and urticaria. The major toxicities were neutropenia, thrombocytopenia and anemia. Liver dysfunction, fatigue and anorexia were also common, but generally manageable. Six patients showed partial responses, giving the overall response rate of 30%. The median progression-free survival period was 4.8 months (95% confidence interval 2.9-6.7 months).\n\n\nCONCLUSIONS\nThe combination of carboplatin at an area under the concentration-time curve of 5 plus pemetrexed at 500 mg/m(2) was determined as the recommended dose in chemotherapy-naïve elderly patients (≥75 years) with advanced non-squamous non-small cell lung cancer, in view of overall safety and tolerability.",
"affiliations": "*Division of Respirology, Neurology, and Rheumatology, Department of Internal Medicine, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka 830-0011, Japan. kayamada@med.kurume-u.ac.jp.",
"authors": "Takeoka|Hiroaki|H|;Yamada|Kazuhiko|K|;Azuma|Koichi|K|;Zaizen|Yoshiaki|Y|;Yamashita|Fumie|F|;Yoshida|Tsukasa|T|;Naito|Yoshiko|Y|;Okayama|Yusuke|Y|;Miyamoto|Maki|M|;Hoshino|Tomoaki|T|",
"chemical_list": "D005971:Glutamates; D000068437:Pemetrexed; D006147:Guanine; D016190:Carboplatin",
"country": "England",
"delete": false,
"doi": "10.1093/jjco/hyu030",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "0368-2811",
"issue": "44(5)",
"journal": "Japanese journal of clinical oncology",
"keywords": "carboplatin; elderly; non-small cell lung cancer; pemetrexed",
"medline_ta": "Jpn J Clin Oncol",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000740:Anemia; D000855:Anorexia; D000971:Antineoplastic Combined Chemotherapy Protocols; D019540:Area Under Curve; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D018572:Disease-Free Survival; D004334:Drug Administration Schedule; D005221:Fatigue; D005260:Female; D005971:Glutamates; D006147:Guanine; D048550:Hepatic Insufficiency; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D009503:Neutropenia; D000068437:Pemetrexed; D013921:Thrombocytopenia; D016896:Treatment Outcome",
"nlm_unique_id": "0313225",
"other_id": null,
"pages": "472-8",
"pmc": null,
"pmid": "24688087",
"pubdate": "2014-05",
"publication_types": "D017426:Clinical Trial, Phase I; D016428:Journal Article",
"references": null,
"title": "Phase I study of carboplatin combined with pemetrexed for elderly patients with advanced non-squamous non-small cell lung cancer.",
"title_normalized": "phase i study of carboplatin combined with pemetrexed for elderly patients with advanced non squamous non small cell lung cancer"
} | [
{
"companynumb": "JP-MYLANLABS-2016M1043248",
"fulfillexpeditecriteria": "1",
"occurcountry": "JP",
"patient": {
"drug": [
{
"actiondrug": "5",
"activesubstance": {
"activesubstancename": "PEMETREXED"
},
"drugadditional": "3",
... |
{
"abstract": "Prostaglandin E (PGE) is the preferred agent for second-trimester pregnancy termination. Hypotension, bradycardia, ventricular arrhythmias, myocardial infarction, cardiac arrest and death associated with PGE have been reported. A case of acute myocardial infarction due to coronary vasospasm induced by PGE is described in the present report. The diagnosis was confirmed by electrocardiography and coronary angiography.",
"affiliations": "Department of Internal Medicine, Kangnam Sacred Heart Hospital, Hallym University Meidcal Center, Seoul, Republic of Korea.",
"authors": "Sung|Chong Won|CW|;Jung|Jae-Hun|JH|;Lee|Sang-Hak|SH|;Lee|Kyung Min|KM|;Ahn|Byung Moo|BM|;Choi|Seonghoon|S|;Cho|Jung Rae|JR|;Lee|Nanho|N|;Lee|Keun-Young|KY|",
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"issue": "25(10)",
"journal": "The Canadian journal of cardiology",
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"medline_ta": "Can J Cardiol",
"mesh_terms": "D000282:Administration, Intravaginal; D000328:Adult; D000527:Alprostadil; D017023:Coronary Angiography; D003329:Coronary Vasospasm; D004562:Electrocardiography; D005260:Female; D006801:Humans; D009203:Myocardial Infarction; D011247:Pregnancy; D011249:Pregnancy Complications, Cardiovascular; D011256:Pregnancy Outcome; D014665:Vasodilator Agents",
"nlm_unique_id": "8510280",
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"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Acute myocardial infarction due to vasospasm induced by prostaglandin.",
"title_normalized": "acute myocardial infarction due to vasospasm induced by prostaglandin"
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"abstract": "Peritonitis is the most common complication of peritoneal dialysis (PD). Staphylococcus epidermidis (S. epi), a common skin organism, is the microorganism that is identified is the majority of episodes of peritonitis. The PD catheter breaks the natural skin barrier and allows a periluminal migration of bacteria from the skin surface into the sterile peritoneal cavity. Exit site care is routinely performed to decrease the colony counts of microorganisms on the skin surrounding the PD catheter. Research data is limited to support any of the currently used protocols for exit site care. This study compared the effect of two antiseptic agents, povidone-iodine (P-I) and chlorhexidine gluconate (CG), on S. epi colony forming units (cfu) at the PD catheter exit site over a 24 hour period. Because the distribution of the research data was markedly non-normal, a descriptive approach was used to interpret the data. Results showed that there was no difference between P-I and CG immediately after exit site care. All patients had zero growth at Time I. One trend that emerged was that at 24 hours after exit site care with P-I, more patients (54%) had S. epi cfu than did patients (15%) cleaned with CG.",
"affiliations": "Baptist Hospital, Nashville, TN.",
"authors": "Shelton|D M|DM|",
"chemical_list": "D011206:Povidone-Iodine; C010882:chlorhexidine gluconate; D002710:Chlorhexidine",
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"journal": "Advances in peritoneal dialysis. Conference on Peritoneal Dialysis",
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"medline_ta": "Adv Perit Dial",
"mesh_terms": "D000328:Adult; D000368:Aged; D002710:Chlorhexidine; D015169:Colony Count, Microbial; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010530:Peritoneal Dialysis; D010538:Peritonitis; D011206:Povidone-Iodine; D011446:Prospective Studies; D012867:Skin; D013212:Staphylococcus epidermidis",
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"title": "A comparison of the effects of two antiseptic agents on Staphylococcus epidermidis colony forming units at the peritoneal dialysis catheter exit site.",
"title_normalized": "a comparison of the effects of two antiseptic agents on staphylococcus epidermidis colony forming units at the peritoneal dialysis catheter exit site"
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"companynumb": "US-BECTON DICKINSON-2018BDN00292",
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"abstract": "We present a case study of a 67-year-old man who presented with a new onset of recurrent tonic-clonic seizures. He had tested positive to gamma-aminobutyric acid B receptor antibodies in his blood and cerebrospinal fluid, and subsequent CT imaging and transrectal biopsy confirmed the presence of a locally advanced mixed small cell and Gleason 9 adenocarcinoma of the prostate. His seizures remained resistant to treatment with multiple antiepileptic drugs, including sodium valproate, clobazam, topiramate, carbamazepine, phenytoin and lacosamide. He progressed to status epilepticus, which required intravenous immunoglobulin and steroids, followed by plasma exchange 1 week later. The status epilepticus was refractory and required multiple admissions to the intensive care unit.",
"affiliations": "Department of Internal Medicine and Clinical Epidemiology, Princess Alexandra Hospital Health Service District, Brisbane, Queensland, Australia chriskwan88@gmail.com.;Department of Neurology and Stroke, Princess Alexandra Hospital Health Service District, Brisbane, Queensland, Australia.;Department of Neurology and Stroke, Princess Alexandra Hospital Health Service District, Brisbane, Queensland, Australia.",
"authors": "Kwan|Christopher|C|http://orcid.org/0000-0002-3775-4370;Sia|Aaron|A|;O'Gorman|Cullen|C|",
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"doi": "10.1136/bcr-2020-238172",
"fulltext": "\n==== Front\nBMJ Case Rep\nBMJ Case Rep\nbmjcr\nbmjcasereports\nBMJ Case Reports\n1757-790X BMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR \n\nbcr-2020-238172\n10.1136/bcr-2020-238172\nCase Report\n1506\n200\n209\n1333\n293\nStatus epilepticus from GABABR antibody positive encephalitis due to de novo mixed small cell and adenocarcinoma of the prostate\nhttp://orcid.org/0000-0002-3775-4370Kwan Christopher 1 Sia Aaron 2 O'Gorman Cullen 2 1 Department of Internal Medicine and Clinical Epidemiology, Princess Alexandra Hospital Health Service District, Brisbane, Queensland, Australia\n2 Department of Neurology and Stroke, Princess Alexandra Hospital Health Service District, Brisbane, Queensland, Australia\nCorrespondence to Dr Christopher Kwan; chriskwan88@gmail.com\n2020 \n30 11 2020 \n30 11 2020 \n13 11 e23817222 10 2020 © BMJ Publishing Group Limited 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.2020http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.We present a case study of a 67-year-old man who presented with a new onset of recurrent tonic-clonic seizures. He had tested positive to gamma-aminobutyric acid B receptor antibodies in his blood and cerebrospinal fluid, and subsequent CT imaging and transrectal biopsy confirmed the presence of a locally advanced mixed small cell and Gleason 9 adenocarcinoma of the prostate. His seizures remained resistant to treatment with multiple antiepileptic drugs, including sodium valproate, clobazam, topiramate, carbamazepine, phenytoin and lacosamide. He progressed to status epilepticus, which required intravenous immunoglobulin and steroids, followed by plasma exchange 1 week later. The status epilepticus was refractory and required multiple admissions to the intensive care unit.\n\nepilepsy and seizuresprostate cancerspecial-featureunlocked\n==== Body\nBackground\nThe management of seizures in the setting of paraneoplastic syndrome remains difficult and is dependent on treatment of the underlying malignancy. This case study outlines the presentation, diagnosis and subsequent management of a patient admitted under the Department of Neurology and Stroke at Princess Alexandra Hospital.\n\nCase presentation\nA 67-year-old man presented in December 2019 with a new onset of recurrent tonic-clonic seizures. This was associated with postictal confusion but no baseline changes to cognition. This was not associated with aura. He had no weakness, sensory or visual changes. There was no history of any fevers, rigours, travel or sick contacts. There was no history of weight loss, night sweats. He denied any respiratory symptoms including chronic cough or haemoptysis, and denied any urological symptoms including haematuria or changes in urinary flow.\n\nHis medical history was significant for type 2 diabetes mellitus, hypertension and having a 45-pack year smoking history (quit 25 years ago). His medications on admission included lisinopril 20 mg two times per day, metformin extended release 1.5 g at night and gliclazide modified release 30 mg daily. He otherwise was independent with all activities of daily living, lived with his wife and only occasionally consumed alcohol. There was no family or personal history of neurological disorders (including seizure disorders) or developmental issues.\n\nOn examination, all his vital observations were normal. He had a Glasgow Coma Score of 15 on arrival and looked well with a normal body habitus. He had a normal neurological examination with a normal cranial nerve, upper and lower limb motor, cerebellar and sensory examinations. His cardiovascular, respiratory and abdominal examinations were all normal.\n\nInvestigations\nHis full blood count and biochemistry—including serum creatinine and estimated glomerularfiltration rate—were normal. His first electroencephalogram (EEG) was normal. MRI scan of his brain was normal. Due to his smoking history, antineuronal antibodies were tested in his blood and cerebrospinal fluid (CSF), which subsequently tested positive to gamma-aminobutyric acid B receptor (GABABR) antibodies without the presence of malignant cells or infection in CSF.\n\nSubsequent screening for occult malignancies included CT scans of his chest, abdomen and pelvis, which revealed the presence of a soft tissue density bulkiness of the right seminal vesicle and prostatomegaly of 48×32 mm in size (see figure 1). There was locoregional invasion into the right seminal vesicle and locoregional lymphadenopathy (involving at least five nodes). There were no other lesions of note. Transrectal biopsy was performed, which confirmed the diagnosis of mixed small cell and Gleason 9 adenocarcinoma of the prostate.\n\nFigure 1 CT imaging of prostate lesion.\n\nDue to ongoing seizures and development of status epilepticus, repeat EEG was requested and found evidence of severe encephalopathy with cortical dysfunction in the left temporal and central regions.\n\nDifferential diagnosis\nThe differential diagnoses for the seizure disorder included new primary epilepsy, or secondary seizure disorder in the setting of infection (including central nervous system (CNS) infections), and malignancy, specifically small cell lung cancer (SCLC).\n\nFive days after initial admission, GABABR antibodies were detected; CT scans were completed on day 6 with subsequent transrectal biopsy completed on day 13 which confirmed the overall diagnosis of GABABR antibody encephalitis secondary to mixed small cell and Gleason 9 adenocarcinoma of the prostate.\n\nTreatment\nThe patient was given 500 mg levetiracetam two times per day but developed status epilepticus on day 7, requiring a dose increase of levetiracetam to 1000 mg two times per day intravenously and 2.5 mg midazolam intravenously. He was subsequently transferred to neurology high dependency unit (HDU) for monitoring due to slow recovery. A drug-related rash was found on day 10, so levetiracetam was changed over to valproate 400 mg two times per day. During the 3 months of hospitalisation, the patient had recurrent seizures despite the addition and titration of multiple antiepileptics, with his most recent antiepileptic regimen now consisting of valproate 500 mg two times per day, clobazam 10 mg at night, topiramate 100 mg daily, carbamazepine 200 mg in the morning and 400 mg at night, phenytoin 300 mg daily and lacosamide 200 mg two times per day. He also had several episodes of status epilepticus, each requiring 2 mg doses of midazolam; he also required two admissions to intensive care unit (ICU) with 800 mg phenobarbitone infusion being required for the first admission.\n\nDue to recurrent seizures in the setting of encephalitis, 5 days of 1 g intravenous methylprednisolone was given, with weaning down to oral 50 mg prednisolone afterwards and initiation of trimethoprim–sulfamethoxazole due to immunosuppression. Due to lack of neurological improvement, 5 days of 30 g intravenous immunoglobulin (IVIG) (with subsequent 30 g monthly IVIG) and then 5 days of 3.5 L plasma exchange were completed once in each of his ICU admissions.\n\nThe prostate malignancy was managed by Medical Oncology and cisplatin and etoposide were initiated on day 15. The malignancy was not amenable to surgery as per the urology department. Radiation Oncology was consulted, though radiotherapy could not be performed due to persistent seizures.\n\nOutcome and follow-up\nUnfortunately, this patient’s neurological function did not recover and he passed away.\n\nDiscussion\nGABABR antibody-associated encephalitis is a rare form of autoimmune encephalitis, representing 5% of all cases of autoimmune encephalitis.\n\nGABABR are G-protein-coupled receptors that are composed of two subunits—GABAB1 and GABAB2.1 GABABR mediate presynaptic inhibition via the activation of G-protein-coupled inward rectifying potassium channels and inhibition of calcium channels, and attenuate presynaptic firing frequencies.1 GABABR interacts alongside other ion channels and synaptic receptors (such as excitatory glutamate NMDA and AMPA receptors) to influence synaptic plasticity; this is involved with memory, learning and cognition.1–3 The highest concentration of GABABR is in the hippocampus, thalamus and cerebellum.2 4 In animal models, disruption of GABABR is associated with seizures and cognitive impairment, which is similar to the effects of GABABR antibodies.2 5\n\nThe first cases of GABABR antibody-related encephalitis were identified by Lancaster et al between 2006 and 2009 via a HEK293 cell-based assay performed on patients with suspected paraneoplastic encephalitis.6 Seizures are the most common presentation of GABABR antibody-associated encephalitis, seen in 80% of cases.2 7 Other symptoms include cognitive impairment, hallucinations, ataxia and opsoclonus-myoclonus.8 Fifty per cent are associated with malignancy—usually SCLC or pulmonary neuroendocrine tumour—although our patient was found to have a small cell prostate cancer (SCPC).2 9–11 EEG abnormalities are evident in approximately 90.9% of cases, typically presenting with generalised or local and low-amplitude slow-wave activity. 18.2% may present with concurrent temporal epileptiform discharges, as was evident with our patient. In 36.4% of cases, MRI brain scans may show increased signals restricted to the medial temporal lobes, hippocampus and para-hippocampal gyrus on MRI fluid-attenuated inversion recovery (FLAIR) or T2-weighted imaging with one diffusion restriction, though our patient had a normal MRI brain scan. Nonetheless, autoimmune encephalitides in general are uncommon, and it is suggested by Graus et al that patients should be considered for a diagnosis of autoimmune encephalitis if all three of the following criteria are met: (1) subacute onset (rapid progression <3 months) of working memory deficits (short-term memory loss), altered mental status (defined as decreased or altered level of consciousness, lethargy or personality change) or psychiatric symptoms; (2) at least one of the following features: new focal CNS findings, seizures not explained by a previously known seizure disorder, CSF pleocytosis (>5 white cell count per mm3), MRI features suggestive of encephalitis (brain MRI hyperintense signal on T2-weighted FLAIR sequences highly restricted to one or both medial temporal lobes (limbic encephalitis), or in multifocal areas involving grey matter, white matter or both, compatible with demyelination or inflammation and (3) reasonable exclusion of alternative causes.12\n\nSCPC is rare at initial diagnosis (≤2% of cases). SCPC is more likely to emerge in men with previous androgen deprivation therapy for prostate adenocarcinoma and rarely occurs de novo as in our patient.13 It has an aggressive tumour biology that is associated with rapid development of visceral metastases and bulky tumour masses.14 15 SCPC is characterised by small cell neuroendocrine morphology with the secretion of neuroendocrine tumour markers such as neuron-specific enolase and chromogranin A.14 15 These tumours grow independently from the androgen receptor axis and are thus usually resistant to androgen deprivation therapy.14 SCPC has a poor prognosis and most patients are deceased within 1 year.16\n\nThe management of GABABR antibody-associated encephalitis is dependent on the prompt management of seizures and other neurological symptoms, and the treatment of underlying malignancies. There are no specific guidelines that determine the optimal choices of antiepileptics for GABABR antibody-associated encephalitis or other paraneoplastic encephalitides, but antiepileptic management should be aggressive.17 Depending on clinical outcomes, most patients will not require long-term antiepileptics.17 Our patient, however, has required multiple antiepileptics and is still having seizures and cognitive impairment. There are no controlled studies relating to optimal use of immunotherapy in patients with GABABR antibody-associated encephalitis though usually the encephalitis responds well to treatment.7 Overall treatment response is based on clinical evaluation as antibody titres often do not correlate with disease activity.18 When treating for SCPC, the National Comprehensive Cancer Network suggests a combination of etoposide with cisplatin or carboplatin in patients with pure small cell carcinoma of the prostate or combination of docetaxel and carboplatin.19 A single-arm phase II study investigated the use of carboplatin plus docetaxel in combination with prednisone in 113 patients with SCPC. After progression on carboplatin plus doctetaxel, patients were treated with cisplatin and etoposide. Median overall survival of the cohort was 16 months (95% CI 13.6 to 19.0), and the proportion of patients who were progression free after four cycles of carboplatin plus docetaxel and subsequent treatment with cisplatin plus etoposide (N=71) was 65.4% and 33.8%, respectively.19 20 Androgen deprivation is usually ineffective for SCPCs.19\n\nThis case highlights the difficulties in seizure management in patients who develop GABABR antibody-associated encephalitis. Four different long-term antiepileptics were prescribed, which did not successfully reduce seizure burden. Another source of difficulty was the limited oncological treatment options available for this patient and the patient only received cisplatin and etoposide. Additionally, the patient’s cancer was not amenable to surgical management. He also was not neurologically stable enough to undergo radiotherapy. The case was also unusual in that SCPCs usually arise after androgen deprivation therapy for use of primary prostate adenocarcinoma, but this patient had de novo disease that was associated with paraneoplastic syndrome.\n\nLearning points\nSeizures secondary to paraneoplastic phenomena are difficult to treat and require a combined approach of antiepileptic therapy, immunosuppression and treatment of underlying malignancy.\n\nGABABR antibodies usually occur secondary to small cell lung cancers but can occur secondary to other small cell cancers in other sites.\n\nPrimary small cell prostate cancers (SCPCs) are rare and usually occur after androgen deprivation therapy for primary prostate adenocarcinoma as opposed to de novo disease.\n\nTreatment options for SCPC are limited and prognosis is poor.\n\nContributors: Supervised by CoG. Patient under the care of CoG. Report written by CK, AS and CoG.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Next of kin consent obtained.\n\nProvenance and peer review: Not commissioned; externally peer reviewed.\n==== Refs\nReferences\n1 Chalifoux JR , Carter AG \nGABAB receptor modulation of synaptic function\n. Curr Opin Neurobiol \n2011 ;21 :339 –44\n. 10.1016/j.conb.2011.02.004 21376567 \n2 Qiao S , Zhang Y-X , Zhang B-J , et al \nClinical, imaging, and follow-up observations of patients with anti-GABAb>Bb> receptor encephalitis\n. Int J Neurosci \n2017 ;127 :379 –85\n. 10.1080/00207454.2016.1176922 27066808 \n3 Ulrich D , Bettler B \nGABA(B) receptors: synaptic functions and mechanisms of diversity\n. Curr Opin Neurobiol \n2007 ;17 :298 –303\n. 10.1016/j.conb.2007.04.001 17433877 \n4 Benarroch EE \nGABAB receptors: structure, functions, and clinical implications\n. Neurology \n2012 ;78 :578 –84\n. 10.1212/WNL.0b013e318247cd03 22351795 \n5 Cortez MA , McKerlie C , Snead OC \nA model of atypical absence seizures: EEG, pharmacology, and developmental characterization\n. Neurology \n2001 ;56 :341 –9\n. 10.1212/WNL.56.3.341 11171899 \n6 Lancaster E , Lai M , Peng X , et al \nAntibodies to the GABA(B) receptor in limbic encephalitis with seizures: case series and characterisation of the antigen\n. Lancet Neurol \n2010 ;9 :67 –76\n. 10.1016/S1474-4422(09)70324-2 19962348 \n7 Ramanathan S , Mohammad SS , Brilot F , et al \nAutoimmune encephalitis: recent updates and emerging challenges\n. J Clin Neurosci \n2014 ;21 :722 –30\n. 10.1016/j.jocn.2013.07.017 24246947 \n8 Kruer MC , Hoeftberger R , Lim KY , et al \nAggressive course in encephalitis with opsoclonus, ataxia, chorea, and seizures: the first pediatric case of γ-aminobutyric acid type B receptor autoimmunity\n. JAMA Neurol \n2014 ;71 :620 –3\n. 10.1001/jamaneurol.2013.4786 24590315 \n9 Höftberger R , Titulaer MJ , Sabater L , et al \nEncephalitis and GABAB receptor antibodies: novel findings in a new case series of 20 patients\n. Neurology \n2013 ;81 :1500 –6\n. 10.1212/WNL.0b013e3182a9585f 24068784 \n10 Dalmau J , Rosenfeld MR \nAutoimmune encephalitis update\n. Neuro Oncol \n2014 ;16 :771 –8\n. 10.1093/neuonc/nou030 24637228 \n11 Leypoldt F , Armangue T , Dalmau J \nAutoimmune encephalopathies\n. Ann N Y Acad Sci \n2015 ;1338 :94 –114\n. 10.1111/nyas.12553 25315420 \n12 Graus F , Titulaer MJ , Balu R , et al \nA clinical approach to diagnosis of autoimmune encephalitis\n. Lancet Neurol \n2016 ;15 :391 –404\n. 10.1016/S1474-4422(15)00401-9 26906964 \n13 Zekeridou A , Majed M , Heliopoulos I , et al \nParaneoplastic autoimmunity and small-cell lung cancer: neurological and serological accompaniments\n. Thorac Cancer \n2019 ;10 :1001 –4\n. 10.1111/1759-7714.13009 30810271 \n14 Beltran H , Tagawa ST , Park K , et al \nChallenges in recognizing treatment-related neuroendocrine prostate cancer\n. J Clin Oncol \n2012 ;30 :e386 –9\n. 10.1200/JCO.2011.41.5166 23169519 \n15 Suzuki K , Terakawa T , Kimbara S , et al \nAmrubicin for patients with platinum-refractory small-cell prostate cancer: two case reports\n. Clin Genitourin Cancer \n2020 ;18 :e324 –9\n. 10.1016/j.clgc.2019.12.017 32005612 \n16 Palmgren JS , Karavadia SS , Wakefield MR \nUnusual and underappreciated: small cell carcinoma of the prostate\n. Semin Oncol \n2007 ;34 :22 –9\n. 10.1053/j.seminoncol.2006.10.026 17270662 \n17 de Bruijn MAAM , van Sonderen A , van Coevorden-Hameete MH , et al \nEvaluation of seizure treatment in anti-LGI1, anti-NMDAR, and anti-GABAb>Bb>R encephalitis\n. Neurology \n2019 ;92 :e2185 –96\n. 10.1212/WNL.0000000000007475 30979857 \n18 Dutra LA , Abrantes F , Toso FF , et al \nAutoimmune encephalitis: a review of diagnosis and treatment\n. Arq Neuropsiquiatr \n2018 ;76 :41 –9\n. 10.1590/0004-282x20170176 29364393 \n19 Aggarwal R , Zhang T , Small EJ , et al \nNeuroendocrine prostate cancer: subtypes, biology, and clinical outcomes\n. J Natl Compr Canc Netw \n2014 ;12 :719 –26\n. 10.6004/jnccn.2014.0073 24812138 \n20 Aparicio AM , Harzstark AL , Corn PG , et al \nPlatinum-based chemotherapy for variant castrate-resistant prostate cancer\n. Clin Cancer Res \n2013 ;19 :3621 –30\n. 10.1158/1078-0432.CCR-12-3791 23649003\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "1757-790X",
"issue": "13(11)",
"journal": "BMJ case reports",
"keywords": "epilepsy and seizures; prostate cancer",
"medline_ta": "BMJ Case Rep",
"mesh_terms": "D000230:Adenocarcinoma; D000368:Aged; D000927:Anticonvulsants; D018288:Carcinoma, Small Cell; D003937:Diagnosis, Differential; D004660:Encephalitis; D017809:Fatal Outcome; D006801:Humans; D008297:Male; D016609:Neoplasms, Second Primary; D011471:Prostatic Neoplasms; D018080:Receptors, GABA-B; D012640:Seizures; D013226:Status Epilepticus",
"nlm_unique_id": "101526291",
"other_id": null,
"pages": null,
"pmc": null,
"pmid": "33257388",
"pubdate": "2020-11-30",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": "23649003;11171899;30810271;27066808;23169519;17270662;19962348;25315420;29364393;24812138;24068784;24637228;24590315;32005612;30979857;21376567;17433877;22351795;26906964;24246947",
"title": "Status epilepticus from GABABR antibody positive encephalitis due to de novo mixed small cell and adenocarcinoma of the prostate.",
"title_normalized": "status epilepticus from gababr antibody positive encephalitis due to de novo mixed small cell and adenocarcinoma of the prostate"
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"abstract": "BACKGROUND\nDespite newer treatment modalities, few patients with non-small cell lung cancer in stages IIIB and IV survive the median of one year. We present four patients with non-small cell lung cancer treated with an adjuvant therapy with cascade primed immune cells. The in vitro stimulated expression of cancer information on the patients' monocytes matures and activates T lymphocytes to destroy cancer cells. The cascade primed immune cell therapy significantly improved the quality of life and the lifespan of all four patients; thus far, three patients survived 40, 55 and 120 months, respectively; and one patient died 39 months after diagnosis.\n\n\nMETHODS\nPatient 1, stage IV (T4N2M1): The adenocarcinoma of the 67-year-old German Caucasian man infiltrated into the mediastinal lymph nodes and iliosacral bones. Chemotherapy modalities were started immediately after diagnosis of cancer, and cascade primed immune cell therapy one year later. The patient survived 39 months.Patient 2, stage IV (T3N3M1a): The 62-year-old German Caucasian woman presented with adenocarcinoma of the lower lobe with infiltrated lymph nodes of the mediastinum and malignant pleural effusion. Chemotherapy, radiation and the cascade primed immune cell therapy were administered together. The patient is still alive after 40 months.Patient 3, stage IIIB (T4N1-2M0): The 75-year-old German Caucasian woman presented with an undifferentiated tumor and a separate tumor nodule in the ipsilateral lobe. The patient received only cascade primed immune cell therapy after tumor resection and has survived for the last 55 months.Patient 4, pancoast tumor (IIIB, T3N3M0): The 77-year-old German Caucasian man presented with an undifferentiated tumor that infiltrated the lymph nodes, the clavicle, one rib and the plexus brachialis. In addition to chemotherapy and radiation, cascade primed immune cells were administered every weekday for one year. After four months, no living tumor cell was detected in the resected lung, the lymph nodes or the bone material. The patient is still alive after 120 months.\n\n\nCONCLUSIONS\nThe novel adoptive cell therapy with cascade primed immune cells significantly increased the survival rate and maintained the quality of life for four patients with non-small cell lung cancer in stages IIIB and IV. Our findings indicate that tumor resection, chemotherapy and radiation appear to support the cascade primed immune cell therapy.",
"affiliations": "Immunotherapy Research Center, Pettenkoferstrasse 8, 80336 München, Germany. professor-wank@muenchen-mail.de.",
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"fulltext": "\n==== Front\nJ Med Case RepJ Med Case RepJournal of Medical Case Reports1752-1947BioMed Central 1752-1947-7-2662433062710.1186/1752-1947-7-266Case ReportProlongation of life by adoptive cell therapy with cascade primed immune cells in four patients with non-small cell lung cancer stages IIIB and IV and a pancoast tumor: a case series Laumbacher Barbara 1barbara.laumbacher@muenchen-mail.deGu Songhai 1songhaigu@googlemail.comWank Rudolf 1professor-wank@muenchen-mail.de1 Immunotherapy Research Center, Pettenkoferstrasse 8, 80336 München, Germany2013 11 12 2013 7 266 266 11 1 2013 31 5 2013 Copyright © 2013 Laumbacher et al.; licensee BioMed Central Ltd.2013Laumbacher 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\nDespite newer treatment modalities, few patients with non-small cell lung cancer in stages IIIB and IV survive the median of one year. We present four patients with non-small cell lung cancer treated with an adjuvant therapy with cascade primed immune cells. The in vitro stimulated expression of cancer information on the patients’ monocytes matures and activates T lymphocytes to destroy cancer cells. The cascade primed immune cell therapy significantly improved the quality of life and the lifespan of all four patients; thus far, three patients survived 40, 55 and 120 months, respectively; and one patient died 39 months after diagnosis.\n\nCase presentation\nPatient 1, stage IV (T4N2M1): The adenocarcinoma of the 67-year-old German Caucasian man infiltrated into the mediastinal lymph nodes and iliosacral bones. Chemotherapy modalities were started immediately after diagnosis of cancer, and cascade primed immune cell therapy one year later. The patient survived 39 months.\n\nPatient 2, stage IV (T3N3M1a): The 62-year-old German Caucasian woman presented with adenocarcinoma of the lower lobe with infiltrated lymph nodes of the mediastinum and malignant pleural effusion. Chemotherapy, radiation and the cascade primed immune cell therapy were administered together. The patient is still alive after 40 months.\n\nPatient 3, stage IIIB (T4N1-2M0): The 75-year-old German Caucasian woman presented with an undifferentiated tumor and a separate tumor nodule in the ipsilateral lobe. The patient received only cascade primed immune cell therapy after tumor resection and has survived for the last 55 months.\n\nPatient 4, pancoast tumor (IIIB, T3N3M0): The 77-year-old German Caucasian man presented with an undifferentiated tumor that infiltrated the lymph nodes, the clavicle, one rib and the plexus brachialis. In addition to chemotherapy and radiation, cascade primed immune cells were administered every weekday for one year. After four months, no living tumor cell was detected in the resected lung, the lymph nodes or the bone material. The patient is still alive after 120 months.\n\nConclusions\nThe novel adoptive cell therapy with cascade primed immune cells significantly increased the survival rate and maintained the quality of life for four patients with non-small cell lung cancer in stages IIIB and IV. Our findings indicate that tumor resection, chemotherapy and radiation appear to support the cascade primed immune cell therapy.\n==== Body\nIntroduction\nThe interest in adoptive cell therapy (ACT) is continuously growing for three reasons. First, Rosenberg et al. reported convincing clinical results of ACT in patients with tumor-infiltrating lymphocytes (TIL) who were treated for melanoma [1]; and Takayama et al. reported their findings for the treatment of liver cancer [2]. Second, in solid cancers, particularly in non-small cell lung cancer (NSCLC), chemotherapy and radiation as well as newer modalities achieve only a modest prolongation of survival time. Third, this modest prolongation of survival is accompanied by severe side effects that often heavily affect the quality of the patient’s shortened life. In ACT, two strategies are most often used to stimulate and armour autologous immune cells against cancer cells. One strategy is the in vitro activation of T lymphocytes, which is based on the fact that the T cells in malignant tumors recognize the cancer cells but they do not destroy the cancer. As described by Rosenberg et al., such TIL have been isolated, resuscitated and amplified in vitro and subsequently infused into the patients [1]. Another strategy employs the patient’s dendritic cells, which are prepared in vitro with different methods to express cancer peptides that can activate the naïve/resting T lymphocytes in vivo[3]. The cascade primed immune (CAPRI) cell method uses elements of both strategies.\n\nAntigen-presenting cells (APC) internalize, process and present foreign and autologous proteins; however, until recently, it was not considered that APC could supply information about autologous cancer proteins. If T lymphocytes were activated with OKT3 antibodies in peripheral blood mononuclear cell (PBMC) bulk cultures, they stimulate the processing and the presentation of tumor-immunogenic information. These stimulated monocytes could mature autologous naïve/resting lymphocytes to cytotoxic effector cells. In another published study, we demonstrated that activated monocytes differentiated naïve/resting T lymphocytes to potent cancer-destructing effector T cells in vitro, which significantly prolonged the lifespan of patients with breast cancer [4]. In this study, we describe the successful life prolongation of four patients with NSCLC in stages IIIB and IV, who were treated with the CAPRI cells in combination with surgical intervention and/or chemotherapy and radiation.\n\nAll steps of the cell preparations, including the final therapy (the treatment attempts), were controlled by a medical doctor (RW). In Germany, treatment attempts with new modalities are permitted if they are performed on the authority of a medical doctor [4]. An institutional review was not required. Patients were informed about the experimental nature of the approach, and the ethics recommendations of Helsinki along with subsequent amendments of Tokyo 1975, Hong Kong 1989 and Somerset West 1996 were followed.\n\nCase presentation\nPatient 1\nOncological diagnosis\nThe 67-year-old German Caucasian man presented with a tumor of the upper lung lobe that infiltrated the mediastinum and the mediastinal lymph nodes, and with metastases of the iliosacral bones. Evaluations of the tumor size (T4), regional lymph node involvement (N2) and distant metastases (M1) (T4N2M1) led to a diagnosis of NSCLC in stage IV. A histological analysis revealed adenocarcinoma. Locoregional progress was seen 10 months after diagnosis (AD), malignant pleural effusion 12 months AD, locoregional progress and suspicion of brain metastases 20 months AD, tumor infiltration of the thorax walls and malignant pleural effusion 32 months AD.\n\nTherapy\nTherapy was started immediately with injections of the biphosphonate zoledronate and a combined chemotherapy with paclitaxel, carboplatin and sorafenib (Figure 1). The combined modality was stopped two months AD because of diarrhea, vomiting, progressive weakness and tumor growth. Sorafenib was continued and stopped 10 months AD because the disease progressed. Docetaxel was started 12 months AD and stopped 15 months AD because of paravasate application and leg edema despite a marginal tumor reduction. Pemetrexed was started 20 months AD and stopped after one round because of the same side effects. Two brain metastases were irradiated with the gamma knife (20Gy/22Gy) two weeks later. Treatment with the tyrosine kinase inhibitor erlotinib was started 21 months AD and stopped after six months because of leg edema, nose bleeding and peripheral neuropathies. The latter condition was treated with gabapentin unsuccessfully. A malignant pleural effusion was drained 25 months AD; irradiation of the right spina iliaca superior (35Gy) and an infusion of two red cell concentrates were conducted because of chemotherapy-associated anemia 29 months AD. A therapy with vinorelbine was started 32 months AD and continued until 34 months AD (Figure 1).\n\nFigure 1 Survival time and therapeutic modalities of four patients with non-small cell lung cancer. Shown are months of survival after diagnosis and therapeutic modalities in chronological order. CAPRI, cascade primed immune.\n\nACT with the CAPRI cells started 12 months AD. Three months after the CAPRI cell therapy, a marginal reduction of the tumor was noticed in the computed tomography (CT) scan. The patient survived 39 months; over a period of 26 months he received, twice weekly, 268 injections comprising 60 to 80 million CAPRI cells, two-thirds intravenously, one-third intracutaneously. The cell donations were occasionally interrupted for a week during the patient’s hospitalization. The CAPRI cell therapy was hampered not only by the low leucocyte count but also by the low quality of the immune cells. The patient survived 39 months.\n\nPatient 2\nOncological diagnosis\nThe 62-year-old German Caucasian woman presented with a nonresectable adenocarcinoma of the right lower lobe with infiltrated lymph nodes of the mediastinum and malignant pleural effusion, staged by tumor size and dissemination (T3N3M1a) as IV.\n\nThe first CT scan 12 months AD showed a stable disease; a positron emission tomography/computed tomography (PET/CT) scan 20 months AD exhibited a marginal but definite progression of the disease, disintegration of the central lymph nodes without enlargement, pleural effusion but no distant metastases. A PET/CT scan 26 months AD, performed because of swallowing difficulties, revealed an enlarged lymph node that had caused a severe obstruction of the esophagus, which required treatment with a stent. A histological analysis revealed tumor infiltration, which had caused the lymph node enlargement. Neither a second radiation nor chemotherapy was performed.\n\nTherapy\nThe patient received a combined treatment of radiation and chemotherapy for three months starting two weeks AD. Four cycles of cisplatin and pemetrexed were administered together with a total of 64Gy.\n\nACT with the CAPRI cells started after radiation and chemotherapy, that is, three months AD (Figure 2). In the first six months, the patient received 40 to 60 million CAPRI cells twice weekly; after improvement of the cell count, the patient received 80 million CAPRI cells twice weekly, two-thirds intravenously, one-third intracutaneously, with a total of 260 injections over a period of 35 months. The growing pleural effusion, diagnosed by PET/CT scan 26 months AD, was first treated for several months with thoracentesis and later successfully combined with thoracic CAPRI cell injections eight times using 100 to 300 million immune cells. After the first thoracic injection of 300 million CAPRI cells, the patient felt very weak and had a low-grade fever for two days. Consequently, the dose of CAPRI cells was reduced to 100 million, which was well tolerated. The patient is still alive after 40 months (Figure 2).\n\nFigure 2 Survival time and therapeutic modalities of a 62-year-old German Caucasian woman with non-small cell lung cancer. Shown are months of survival after diagnosis and therapeutic modalities in chronological order. CAPRI, cascade primed immune; PET/CT, positron emission tomography/computed tomography.\n\nPatient 3\nOncological diagnosis\nThe 75-year-old German Caucasian woman presented with an undifferentiated tumor ‘resembling’ a squamous cell carcinoma of the upper lobe and a separate tumor nodule in the ipsilateral tumor lobe (T4N1-2M0, stage IIIB). The PET/CT scan restaging each year had shown no suspicious growth of the tumor until now.\n\nTherapy\nThe patient refused chemotherapy or radiation but agreed to surgery. The upper lobe was resected two months AD, the middle lobe was resected six months AD because of an aspergilloma.\n\nACT with CAPRI cells was begun after the tumor resection (two months AD); the patient received 152 injections of the CAPRI cells; during the first year, she received 60 to 80 million CAPRI cells twice weekly, subsequently once a week.\n\nThe patient is in good condition and has survived for the last 55 months (Figure 3).\n\nFigure 3 Survival time and therapeutic modalities of a 75-year-old German Caucasian woman with non-small cell lung cancer. Shown are months of survival after diagnosis and therapeutic modalities in chronological order. CAPRI, cascade primed immune.\n\nPatient 4\nOncological diagnosis\nThe 77-year-old German Caucasian man presented with a large cell undifferentiated pancoast tumor (IIIB, T3N3M0) of the left upper lobe that infiltrated the lymph nodes, the clavicle, the first rib and the plexus brachialis; no distant metastasis was found. A PET/CT scan was performed every three months in the first year AD, in the second year every six months and subsequently each year. No 18F-FDG uptake was seen in the examinations after surgery. Before the PET/CT scan, the CAPRI cell therapy had to be interrupted for two weeks to avoid unspecific uptake of 18F-FDG by CAPRI cells in the tumor region.\n\nTherapy\nOver the course of five months, the patient received the maximum radiation dose of 70Gy in combination with 25 rounds of cisplatin. In the subsequent surgery six months AD, the upper lobe, the first rib, the clavicle and a portion of the pleura were resected, but it was not possible to remove the portions of the tumor that enveloped the plexus brachialis.\n\nACT with 100 to 120 million CAPRI cells was administered every weekday until surgery, one third intracutaneously, two-thirds intravenously. Because the tumor could not be completely removed, the CAPRI cell therapy was continued for an entire year with the same frequency and intensity. No negative side effects were observed despite the large amounts of activated immune cells. The patient received, in the first year, 223 injections of CAPRI cells; he still receives 20 to 40 million of CAPRI cells one to two times per week, with interruptions for excursions and other endeavors. For several years after the surgery, the patient has enjoyed playing golf and is still alive after 120 months (Figure 4).\n\nFigure 4 Survival time and therapeutic modalities of a 77-year-old German Caucasian man with non-small cell lung cancer. Shown are months of survival after diagnosis and therapeutic modalities in chronological order. CAPRI, cascade primed immune.\n\nDiscussion\nThe therapy of patients with NSCLC in stages IIIB and IV remains unsatisfactory, despite improvements with combined radiation and chemotherapy and newer modalities. We report the successful adjuvant treatment with the CAPRI cells for four patients in stages IIIB and IV. All four patients surpassed the median survival time of nine to 13 months [5,6]. The patient in stage IV died 39 months AD; the other patients have survived up to the time of this publication 40, 55, and 120 months, respectively. The patients reported that they were able to resume their normal activities, such as long walks, bicycling or playing golf after they had received the CAPRI cell injections (patients 2, 3 and 4). An adverse effect was observed in patient 2 after the thoracic injection of 300 million CAPRI cells. She responded with fever and tiredness for two days. The thoracic administration of lower cell numbers, that is, 100 million CAPRI cells, was well tolerated.\n\nThe preparation of CAPRI cells differs from other ACT methods and has been previously described [4]. The immune cells are isolated from the peripheral blood. The T lymphocytes are activated in vitro with the monoclonal antibody CD3, in the presence of other immune cells, especially monocytes. The activated T lymphocytes stimulate monocytes to present the phagocytozed tumor material. It is very important to add ‘new’ unstimulated T lymphocytes to the stimulated monocytes because CD3-activated T lymphocytes internalize the antigen-T-cell receptor and cannot recognize the cancer-relevant information of monocytes. Using proper timing in the activation steps yields the CAPRI cells after 24 hours. These CAPRI cells recognize and destroy cancer cells and are ready to be injected into patients. However, in the majority of the cases, larger numbers of CAPRI cells are needed; the CAPRI cells are cultured for one week. The addition of the cytokine interleukin-2 induces cell division and an increase in the number of CAPRI cells. The CAPRI cells can be produced for cancer patients without loss of time because no tumor-immunogenic peptides need to be identified, which must be inoculated into APC. Furthermore, the T lymphocytes can be used from the peripheral blood and can be easily expanded. The T lymphocytes from the blood are not damaged by the tumor environment as in the case of TIL. Finally, we have tested many different types of cancer and found that the monocytes of other cancers also present tumor-immunogenic determinants [4].\n\nThe point of time for isolating the immune cells for the preparation of the CAPRI cells influences the efficiency of the CAPRI cells. For the success of ACT, it is important to isolate the immune cells before they are damaged by radiation and chemotherapy. In patients 1 and 2, the immune cells were isolated after completion of the first rounds of chemotherapy and radiation; that is, the immune cells and/or their precursors in the bone marrow were exposed to chemotherapeutical reagents and/or radiation therapy. Another influential factor is the presence of a large tumor mass; in patients 1 and 2, the tumor could not be removed or reduced by surgery. A larger tumor mass had to be attacked by the immune cells. Understandably, it is not possible to derive strong conclusions from four patients. We do not know whether patient 1 would have survived longer if the immune cells were isolated from his blood before chemotherapy. Although patient 1 was the only one with distant metastasis, it is worthy of note that the median survival of NSCLC patients with stage IV seems to differ only minimally from patients with stage IIIB [5,6]. In patient 2 (stage IIIB), chemotherapy and radiation preceded the immune cell isolation. The tumor could not be resected. Although the patient shows a prolonged survival time of 40 months with a stabilization of the disease, including a marginal tumor reduction, a local regrowth of the tumor was recognized in the PET/CT scan in the 36th month. In contrast, patient 3 (stage IIIB) and patient 4 (pancoast tumor) are still in complete remission 55 and 120 months AD without signs of recurrence. Patient 3 had decided to undergo only surgery, in addition to the CAPRI cell therapy, whereas patient 4 had a combined chemotherapy and radiation but his CAPRI cells were prepared from immune cells, which had been isolated before the start of chemotherapy and radiation. With all of the caveats of immunogenetic variations among these patients, variations of tumor size, tumor type and the total numbers of CAPRI cells injected in these four patients, the disease course in patients 3 and 4 suggests that there is an advantage in isolating immune cells before chemotherapy and radiation. Furthermore, the resection and reduction of the tumor, if possible, seem to be advantageous in stages IIIB and IV.\n\nAnother aspect appears in patient 4. In the resected tumor material, no living cancer cell was found after six months, neither in the tumor itself nor in the clavicle, rib or lymph nodes. This observation suggests a synergism of chemotherapy and radiation with a simultaneous CAPRI cell therapy. The halt of tumor growth by chemotherapy or radiation may support the downsizing of the tumor by the CAPRI cells. Furthermore, the inflammation caused by irradiation and chemotherapy may enhance migration to the tumor and the cytotoxic activity.\n\nConclusions\nCancer cells of the NSCLC type appear to be excellent immunogenic targets for the CAPRI cells. The inflammation caused by chemotherapy and radiation may be an additional stimulus for cytotoxic attacks by the CAPRI cells. The reduction of the cancer mass by surgery or the arrest of tumor growth by chemotherapy and radiation seems to support the tumor downsizing by the CAPRI cells. For the achievement of a synergism between the CAPRI cells and other modalities, it is important to isolate the immune cells before chemotherapy, radiation or other treatment modalities, which might damage the bone marrow and the immune cells.\n\nConsent\nWritten informed consent was obtained from each of the three surviving patients and from the wife of the deceased patient for publication of this case series and any accompanying images. A copy of the written consents are available for review by the Editor-in-Chief of this journal.\n\nEthical Approval\nIRB approval was not required as, in Germany, treatment attempts with new modalities are permitted, if they are performed on the authority of the medical doctor [4]. The authors hereby confirm that the treatment was performed solely to meet the patients’ clinical needs, at the discretion of the responsible physician (RW). Confirmation of this is available for the Editor in Chief of the journal to check.\n\nCompeting interests\nRW holds the European and international patents on the CAPRI procedure.\n\nAuthors’ contributions\nBL, SG and RW were involved in acquiring data and writing the manuscript; RW designed the concept of the treatment. All authors read and approved the final manuscript.\n==== Refs\nRosenberg SA Dudley ME Adoptive cell therapy for the treatment of patients with metastatic melanoma Curr Opin Immunol 2009 7 233 240 10.1016/j.coi.2009.03.002 19304471 \nTakayama T Sekine T Makuuchi M Yamasaki S Kosuge T Yamamoto J Shimada K Sakamoto M Hirohashi S Ohashi Y Kakizoe T Adoptive immunotherapy to lower postsurgical recurrence rates of hepatocellular carcinoma: a randomized trial Lancet 2000 7 802 807 10.1016/S0140-6736(00)02654-4 11022927 \nEngleman EG Dendritic cell-based immunotherapy Sem Oncol 2003 7 23 29 \nLaumbacher B Gu S Wank R Activated monocytes prime naïve T cells against autologous cancer: vigorous cancer destruction in vitro and in vivo Scand J Immunol 2012 7 314 328 10.1111/j.1365-3083.2011.02652.x 21995310 \nScagliotti GV Vynnychenko I Park K Ichinose Y Kubota K Blackhall F Pirker R Galiulin R Ciuleanu TE Sydorenko O Dediu M Papai-Szekely Z Banaclocha NM McCoy S Yao B Hei YJ Galimi F Spigel DR International, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small-cell lung cancer: MONET1 J Clin Oncol 2012 7 2829 2836 10.1200/JCO.2011.41.4987 22753922 \nZhu J Sharma DB Gray SW Chen AB Weeks JC Schrag D Carboplatin and paclitaxel with vs without bevacizumab in older patients with advanced non-small cell lung cancer JAMA 2012 7 1593 1601 10.1001/jama.2012.454 22511687\n\n",
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"title": "Prolongation of life by adoptive cell therapy with cascade primed immune cells in four patients with non-small cell lung cancer stages IIIB and IV and a pancoast tumor: a case series.",
"title_normalized": "prolongation of life by adoptive cell therapy with cascade primed immune cells in four patients with non small cell lung cancer stages iiib and iv and a pancoast tumor a case series"
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"abstract": "BACKGROUND\nWhile many cases of DRESS reaction to minocycline have been described, few of these involve doxycycline.\n\n\nMETHODS\nA 59-year-old woman of African origin was repatriated after a journey to Ghana for hyperthermia with infiltrated maculopapular exanthema, facial oedema (no mucosal involvement) and polyadenopathy. Laboratory tests revealed hypereosinophilia, hepatic cytolysis and mononucleosis syndrome. Cutaneous histology was non-specific. The patient had been taking doxycycline as antimalarial prophylaxis for three weeks before the onset of symptoms. DRESS to doxycycline was diagnosed. Patch-tests with doxycycline three months later proved negative. The patient's HLA phenotype was A3/A30 and B39/B42.\n\n\nCONCLUSIONS\nAn intrinsic causal relationship with doxycycline was likely in this case (I3). Although patch-test sensitivity and specificity with doxycycline remains unknown in DRESS exploration, a negative result does not necessarily rule out the diagnosis. A number of cases of DRESS to doxycycline have been described recently, possibly as a result of more frequent prescription (malarial prophylaxis, acne). Subjects of African ethnicity or having specific HLA phenotypes are at higher risk of developing drug hypersensitivity.\n\n\nCONCLUSIONS\nThis patient is the third case of DRESS to doxycycline described in the literature. The originality of this case lies in the allergological investigation using patch-tests and HLA determination.",
"affiliations": "Service de dermatologie, hôpital Purpan, CHU de Toulouse, TSA 40031, 31059 Toulouse cedex 9, France.",
"authors": "Mailhol|C|C|;Tremeau-Martinage|C|C|;Paul|C|C|;Godel|A|A|;Lamant|L|L|;Giordano-Labadie|F|F|",
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"abstract": "Ophthalmic abnormalities are amongst the 5 major criteria required for a diagnosis of Alagille syndrome (ALGS), of which embryotoxon, pseudopapilledema, and hypopigmented retinopathy are the most common. Papilledema with or without intracranial hypertension (ICHT) is rarely described. We report 9 pediatric cases of ALGS with bilateral papilledema, 5 of which were diagnosed with ICHT.\n\n\n\nThe ophthalmic data from 85 patients with clinically and/or genetically (n = 37) proven ALGS were reviewed. The study inclusion criteria were a positive diagnosis of ALGS and availability of ophthalmic follow-up data. Ophthalmic data from 40 patients after liver transplantation (LT) for other indications were also analyzed.\n\n\n\nNine (13.0%) of the 69 patients meeting the inclusion criteria had papilledema. The neurological and neuroimaging results in all 9 patients were normal. These 9 patients were categorized into 4 groups: a nontransplant group (n = 1), a group with pretransplant papilledema persistent after LT (n = 2), a group with papilledema occurring after LT with spontaneous resolution (n = 1), and a group with papilledema and signs of ICHT after LT (n = 5). The patients with ICHT were treated with steroids alone (n = 1) or with acetazolamide (n = 4). A ventriculoperitoneal shunt was placed in 2 of the 5 cases because of progressive visual loss. Pseudopapilledema was present in 10 additional patients (14.5%, 10/69). One (2.5%) of the 40 patients without ALGS developed papilledema after LT.\n\n\n\nTrue ICHT may be underdiagnosed in patients with ALGS. Our findings underscore the need for close ophthalmic follow-up before and after LT in these patients.",
"affiliations": "Pediatric Gastroenterology and Hepatology Department, Cliniques Universitaires St-Luc, Bruxelles, Belgium.;Pediatric Gastroenterology and Hepatology Department, Cliniques Universitaires St-Luc, Bruxelles, Belgium.;Pediatric Gastroenterology and Hepatology Department, Cliniques Universitaires St-Luc, Bruxelles, Belgium.;Pediatric Gastroenterology and Hepatology Department, Cliniques Universitaires St-Luc, Bruxelles, Belgium.;Pediatric Gastroenterology and Hepatology Department, Cliniques Universitaires St-Luc, Bruxelles, Belgium.;Swiss Pediatric Liver Center, Pediatric Department, Hôpitaux Universitaires de Genève, Geneva, Switzerland.;Ophthalmology Department, Cliniques Universitaires St-Luc, Bruxelles, Belgium.;Pediatric Gastroenterology and Hepatology Department, Cliniques Universitaires St-Luc, Bruxelles, Belgium.",
"authors": "Rock|Nathalie M|NM|;Demaret|Tanguy|T|;Stéphenne|Xavier|X|;Scheers|Isabelle|I|;Smets|Francoise|F|;McLin|Valérie A|VA|;Boschi|Antonella|A|;Sokal|Etienne M|EM|",
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"mesh_terms": "D016738:Alagille Syndrome; D002648:Child; D015785:Eye Diseases, Hereditary; D006801:Humans; D019586:Intracranial Hypertension; D009901:Optic Nerve Diseases; D010211:Papilledema",
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"pubdate": "2020-11",
"publication_types": "D016428:Journal Article",
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"title": "Intracranial Hypertension and Papilledema in a Large Cohort of Pediatric Patients With Alagille Syndrome.",
"title_normalized": "intracranial hypertension and papilledema in a large cohort of pediatric patients with alagille syndrome"
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"abstract": "Clear cell basal cell carcinoma (BCC) is an unusual variant of BCC. Its pathogenesis, prognosis, and optimal management remain poorly described due to its rarity. This report presents a 51-year-old man with a history of excised BCC and cutaneous squamous cell carcinomas of the face, with multiple recurrent poorly differentiated carcinomas with clear cell changes of the shoulder for which further classification using conventional histologic means was not possible. His tumor tissue was sent to Foundation Medicine for testing, which revealed a high number of pathogenic genomic alterations, including a mutation in PTCH1. He was diagnosed with dedifferentiated BCC and started on vismodegib. He developed lung metastases while receiving vismodegib, and his disease continued to progress while he was undergoing treatment in a phase I clinical trial. Given the high number of pathogenic alterations suggestive of high tumor mutational burden, immunotherapy was considered and off-label authorization was obtained for treatment with a PD-1 antibody (pembrolizumab). He had a dramatic disease response after 4 infusions of pembrolizumab. Molecular testing was instrumental in determining the correct diagnosis and formulating appropriate treatment options for this patient. Molecular profiling of metastatic BCCs and its subtypes is essential to the development of effective targeted therapies and combination approaches.",
"affiliations": "Melanoma and Skin Cancer Program, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.;Oschsner Clinical School, University of Queensland, New Orleans, Louisiana; and.;Department of Dermatology, and.;Melanoma and Skin Cancer Program, UCSF Helen Diller Family Comprehensive Cancer Center, San Francisco, California.;Department of Dermatology, and.;Department of Dermatology, and.",
"authors": "Tsai|Katy K|KK|;Khurana|Neharika|N|;McCalmont|Timothy|T|;Daud|Adil|A|;Bastian|Boris|B|;Yeh|Iwei|I|",
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"journal": "Journal of the National Comprehensive Cancer Network : JNCCN",
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"medline_ta": "J Natl Compr Canc Netw",
"mesh_terms": "D061067:Antibodies, Monoclonal, Humanized; D002277:Carcinoma; D002280:Carcinoma, Basal Cell; D006801:Humans; D007167:Immunotherapy; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D009154:Mutation; D000072081:Patched-1 Receptor; D061026:Programmed Cell Death 1 Receptor",
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"pubdate": "2019-07-01",
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"title": "PTCH1 Mutation in a Patient With Metastatic Undifferentiated Carcinoma With Clear Cell Change.",
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"abstract": "This study evaluated the safety and efficacy of nab-paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma.\nThirty-nine pretreated patients [33 with taxane-based regimens (docetaxel, cisplatin, and fluorouracil)] and 6 with combination of fluoropyrimidines plus cisplatin with locally advanced inoperable and metastatic gastric and gastroesophageal junction adenocarcinoma were treated with weekly nab-paclitaxel (150 mg/m2 d1, d8, d15 in cycles of 28 days).\nPartial response (PR) was documented in nine patients (23.1%; 95% confidence interval 10.1-37.2%), stable disease (SD) in 11 (28.2%) and disease progression in 18 (46.2%). The disease control rate (SD + PR + complete response) was 51.3%. Grade 3 and 4 neutropenia occurred in 10.2% and 5.1% of patients, respectively; grade 3 anemia in 5.1%; grade 3 neurotoxicity in 5.1%; and grade 2 pain in 5.1%. The median progression-free survival was 3.0 months (range 0.3-13.6) and the median overall survival 6.8 months (range 0.3-22).\nNab-paclitaxel as second-line treatment in locally advanced inoperable or metastatic gastric and gastroesophageal junction carcinoma is an active chemotherapy regimen with a manageable toxicity profile and merits further evaluation.",
"affiliations": "Department of Medical Oncology, IASO General Hospital, Athens (Papangiotis Katsaounis, Vassilis Georgoulias), Greece.;Department of Medical Oncology, University General Hospital of Heraklion, Crete (Athanasios Kotsakis, Filippos Koinis, Lambros Vamvbakas, Nikolaos Vardakis, Kostas Kalbakis, John Souglakos), Greece.;Department of Medical Oncology, 251 Air Force General Hospital, Athens (Nikolaos Kentepozidis, Marios Bakogeorgos), Greece.;Department of Medicine, Medical School, University of Athens, Laikon General Hospital, Athens (Aris Polyzos), Greece.;Department of Medical Oncology, 251 Air Force General Hospital, Athens (Nikolaos Kentepozidis, Marios Bakogeorgos), Greece.;Department of Medical Oncology, University General Hospital of Heraklion, Crete (Athanasios Kotsakis, Filippos Koinis, Lambros Vamvbakas, Nikolaos Vardakis, Kostas Kalbakis, John Souglakos), Greece.;Department of Medical Oncology, University General Hospital of Heraklion, Crete (Athanasios Kotsakis, Filippos Koinis, Lambros Vamvbakas, Nikolaos Vardakis, Kostas Kalbakis, John Souglakos), Greece.;Department of Medical Oncology, University General Hospital of Heraklion, Crete (Athanasios Kotsakis, Filippos Koinis, Lambros Vamvbakas, Nikolaos Vardakis, Kostas Kalbakis, John Souglakos), Greece.;Department of Medical Oncology, University General Hospital of Heraklion, Crete (Athanasios Kotsakis, Filippos Koinis, Lambros Vamvbakas, Nikolaos Vardakis, Kostas Kalbakis, John Souglakos), Greece.;Department of Medical Oncology, Bioclinic of Thessaloniki (Ioannis Boukovinas), Greece.;Department of Medical Oncology, Henry Dunant Hospital, Athens (Ioannis I. Varthalitis), Greece.;Hellenic Oncology Research Group (HORG), Athens (Efthimios Prinarakis), Greece.;Department of Medical Oncology, IASO General Hospital, Athens (Papangiotis Katsaounis, Vassilis Georgoulias), Greece.;Department of Medical Oncology, University General Hospital of Heraklion, Crete (Athanasios Kotsakis, Filippos Koinis, Lambros Vamvbakas, Nikolaos Vardakis, Kostas Kalbakis, John Souglakos), Greece.",
"authors": "Katsaounis|Panagiotis|P|;Kotsakis|Athanasios|A|;Kentepozidis|Nikolaos|N|;Polyzos|Aris|A|;Bakogeorgos|Marios|M|;Koinis|Filippos|F|;Vamvakas|Lambros|L|;Vardakis|Nikolaos|N|;Kalbakis|Kostas|K|;Boukovinas|Ioannis|I|;Varthalitis|Ioannis I|II|;Prinarakis|Efthimios|E|;Georgoulias|Vassilis|V|;Souglakos|John|J|",
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"doi": "10.20524/aog.2017.0215",
"fulltext": "\n==== Front\nAnn GastroenterolAnn GastroenterolAnnals of Gastroenterology1108-74711792-7463Hellenic Society of Gastroenterology Greece AnnGastroenterol-31-6510.20524/aog.2017.0215Original ArticleNab-paclitaxel as second-line treatment in advanced gastric cancer: a multicenter phase II study of the Hellenic Oncology Research Group Katsaounis Panagiotis aKotsakis Athanasios bKentepozidis Nikolaos cPolyzos Aris dBakogeorgos Marios cKoinis Filippos bVamvakas Lambros bVardakis Nikolaos bKalbakis Kostas bBoukovinas Ioannis eVarthalitis Ioannis I. fPrinarakis Efthimios gGeorgoulias Vassilis aSouglakos John ba Department of Medical Oncology, IASO General Hospital, Athens (Papangiotis Katsaounis, Vassilis Georgoulias), Greeceb Department of Medical Oncology, University General Hospital of Heraklion, Crete (Athanasios Kotsakis, Filippos Koinis, Lambros Vamvbakas, Nikolaos Vardakis, Kostas Kalbakis, John Souglakos), Greecec Department of Medical Oncology, 251 Air Force General Hospital, Athens (Nikolaos Kentepozidis, Marios Bakogeorgos), Greeced Department of Medicine, Medical School, University of Athens, Laikon General Hospital, Athens (Aris Polyzos), Greecee Department of Medical Oncology, Bioclinic of Thessaloniki (Ioannis Boukovinas), Greecef Department of Medical Oncology, Henry Dunant Hospital, Athens (Ioannis I. Varthalitis), Greeceg Hellenic Oncology Research Group (HORG), Athens (Efthimios Prinarakis), Greece\nCorrespondence to: John Souglakos MD, PhD, Department of Medical Oncology, University General Hospital of Heraklion, Voutes, PO Box 1352, 71110 Heraklion, Crete, Greece, e-mail: georgsec@med.uoc.grThis work was supported by a research grant from the CELGENE International Sàrl: protocol number AX-ST-PI-0057 and the Hellenic Oncology Research Group (HORG): protocol number CT/12.05.\n\nNumber of National Ethics Committee Approval: 268/8-6-2012\n\nJan-Feb 2018 27 11 2017 31 1 65 70 22 4 2017 09 10 2017 Copyright: © Hellenic Society of Gastroenterology2018This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background:\nThis study evaluated the safety and efficacy of nab-paclitaxel as second-line treatment in patients with advanced gastric adenocarcinoma.\n\nMethods:\nThirty-nine pretreated patients [33 with taxane-based regimens (docetaxel, cisplatin, and fluorouracil)] and 6 with combination of fluoropyrimidines plus cisplatin with locally advanced inoperable and metastatic gastric and gastroesophageal junction adenocarcinoma were treated with weekly nab-paclitaxel (150 mg/m2 d1, d8, d15 in cycles of 28 days).\n\nResults:\nPartial response (PR) was documented in nine patients (23.1%; 95% confidence interval 10.1-37.2%), stable disease (SD) in 11 (28.2%) and disease progression in 18 (46.2%). The disease control rate (SD + PR + complete response) was 51.3%. Grade 3 and 4 neutropenia occurred in 10.2% and 5.1% of patients, respectively; grade 3 anemia in 5.1%; grade 3 neurotoxicity in 5.1%; and grade 2 pain in 5.1%. The median progression-free survival was 3.0 months (range 0.3-13.6) and the median overall survival 6.8 months (range 0.3-22).\n\nConclusion:\nNab-paclitaxel as second-line treatment in locally advanced inoperable or metastatic gastric and gastroesophageal junction carcinoma is an active chemotherapy regimen with a manageable toxicity profile and merits further evaluation.\n\nNab-paclitaxelgastric cancersecond-line treatmentchemotherapy regimen\n==== Body\nIntroduction\nGastric and gastroesophageal junction (GEJ) adenocarcinomas constitute a major health problem worldwide, representing the third most frequent cause of cancer deaths [1]. Metastatic gastric cancer is a lethal disease, with a mean overall survival (OS) of 6-12 months and 5-year survival estimate <10% [2]. Combination chemotherapy regimens provide higher response rates than do single agents, but this translates into only modestly longer durations of disease control and survival, measured as a gain of a few weeks or months. Regimens containing docetaxel, either as monotherapy or in combination, have shown clinical activity [3]. The combination of docetaxel with cisplatin and 5-fluorouracil (5-FU), i.e. DCF regimen, results in a statistically significant improvement in response rate and survival compared to the non-docetaxel regimen (cisplatin and 5-FU alone); however, the DCF regimen is associated with increased toxicity [4,5]. In addition, the replacement of cisplatin with oxaliplatin in the r5-FU, leucovorin, oxaliplatin, and docetaxel (FLOT) regimen as weekly administration has shown comparable efficacy with more favorable toxicity results [6]. Given the encouraging results of DCF and FLOT, these regimens are usually administered nowadays in several countries as first-line treatment. On the other hand, the second-line treatment options are limited. In general, clinical trials assessing the efficacy of a variety of second-line therapy regimens have shown lower response rates and a poorer toxicity profile compared to first-line regimens [7-11]. Weekly paclitaxel [6], irinotecan as a single agent [11] or in combination with 5-FU [10] were the preferable regimens in the most part of the world. Ramucirumab is monoclonal antibody that binds to vascular endothelial growth factor receptor (VEGFR)-2, blocking receptor activation. Recently, the addition of ramucirumab to weekly paclitaxel has shown an increase in response rate, progression-free survival (PFS) and OS in a randomized prospective study [12].\n\nNab-paclitaxel is a novel nanoparticle form of paclitaxel bound with human albumin. Clinical studies with nab-paclitaxel, in patients with metastatic breast cancer, demonstrated that the lack of solvents during the preparation of nab-paclitaxel offers many advantages during intravenous administration such as: i) a higher maximum tolerated dose (300 mg/m2 vs. 175 mg/m2); ii) no premedication with corticosteroids; iii) no need for special filters, used for solvent-based paclitaxel; and iv) an increased infusion rate.\n\nIn a phase III study of patients with metastatic breast cancer, nab-paclitaxel demonstrated superior efficacy, with higher response rates, a longer time to progression (TTP), and higher OS in comparison to solvent-based paclitaxel [13]. Based on these favorable pharmacologic characteristics of nab-paclitaxel, the gastrointestinal working group of the Hellenic Oncology Research Group (HORG) designed a phase II study in which nab-paclitaxel was administered as salvage second-line treatment in patients with advanced gastric and GEJ adenocarcinomas.\n\nPatients and methods\nPatient eligibility\nPatients with histologically or cytologically confirmed inoperable locally advanced, recurrent or metastatic gastric or GEJ adenocarcinomas, with documented disease progression after first-line systemic treatment, were enrolled in the study. Additional inclusion criteria included bidimensional measurable disease, age >18 years, ECOG performance status (PS) of 0-2, adequate bone marrow, liver and renal function, a life expectancy of at least 3 months and written informed consent. Exclusion criteria included a locally advanced carcinoma of the stomach and GEJ not corresponding to local disease, active gastrointestinal hemorrhage, obstruction, known brain metastases, active infection, clinically significant cardiovascular disease, pregnancy and lactation, as well as psychiatric disorders.\n\nThe study was approved by the National Drug Administration, the National Ethics Committee, as well as the Ethics Committees of the participating institutions.\n\nPatient evaluation\nPre-treatment evaluation included a complete medical history, physical examination and blood pressure measurement; a complete blood count (CBC) with differential and platelet count; standard biochemical profile; electrocardiogram (ECG); chest X-rays; and computed tomography scans of the chest and abdomen. Brain and bone scintigraphy were performed only in patients with suspicious symptoms. During treatment, a CBC was performed weekly, while in case of grade 3 and 4 neutropenia and thrombocytopenia the CBC was recorded daily until hematological recovery. A detailed medical history was taken and a complete physical examination was performed before each course of treatment to document symptoms of disease and chemotherapy-related toxicities. Biochemical tests, CBC and ECG were performed every 3 weeks. Lesions assessable by computed tomography scans were evaluated after every 2 courses of treatment using the Response Evaluation Criteria in Solid Tumors (RECIST)1.1 [14].\n\nTreatment\nNab-paclitaxel (Abraxane®, Celgene) was given at a dose of 150 mg/m2 on days 1, 8 and 15 of each chemotherapy cycle (28-day cycles) until disease progression. This dose was derived from previous studies of metastatic breast cancer [15,16]. Treatment was administered until disease progression and dose-adjustment criteria were based on hematological parameters. The dosage of nab-paclitaxel was reduced by 25 mg/m2 in the subsequent cycle in case of febrile neutropenia or grade 4 neutropenia or thrombocytopenia lasting for more than 5 days. A one-week treatment delay and/or a 25 mg/m2 dose reduction of nab-paclitaxel was performed in patients with more than grade 2 non-hematological toxicity, with the exception of alopecia and nausea. Dose reductions were maintained for all subsequent treatment cycles and up to 2 dose level reductions were allowed. Treatment delays up to 14 days or the need for more than 2 dose level reductions were grounds for drug discontinuation. Toxicity was graded according to the NCI-Common Terminology Criteria for adverse events (NCTCAE: version 4.0). Prophylactic administration of recombinant human granulocyte colony-stimulating factor was not allowed.\n\nStatistical analysis\nThe study was an open-label, single-arm, multicenter phase II trial, conducted in 11 Greek centers. The primary endpoint of the study was the overall response rate (ORR) and the secondary endpoints were PFS, OS, and the toxicity profile. The study followed Fleming’s two-stage design for clinical phase II studies. The sample size calculation was based on the assumption that the expected ORR would be 20% (based on the data from the literature for second-line treatment in gastric and GEJ adenocarcinomas [6,10]) and the minimum acceptable response 7%; if at least two responses were observed among the first 26 enrolled patients during the first part of the study, then 13 additional patients had to be enrolled in the second part of the study, for a total of 39 patients [17]. The null hypothesis would be rejected, with 5% probability and 80% statistical power, if at least 5 responses were observed in 39 enrolled patients.\n\nAll patients who received at least one cycle of treatment were evaluable for analysis. OS and PFS were calculated from the date of randomization until the date of death and the date of documentation of disease progression, respectively. Qualitative variables were compared using the chi-square test. A P-value <0.05 was considered to indicate statistical significance. Continuous variables are summarized in frequency tables.\n\nResults\nPatient characteristics\nBetween January 2012 and April 2015, a total of 39 patients were enrolled in the study. Baseline patient characteristics are listed in Table 1. In brief, patients’ median age was 62 years (range 24-79), 29 (74.4%) were men and all had an ECOG PS of 0-1; histology was diffuse adenocarcinoma in 12 patients (30.8%), intestinal type adenocarcinoma in 16 patients (41%) and indeterminate type in 11 patients (28.2%). Four patients (10.2%) had received adjuvant treatment and 17 (43.6%) had initially undergone surgical resection. Thirty-three (84.6%) patients had received first-line chemotherapy with taxane-based regimens (DCF) while 6 patients were under treatment with a combination of fluoropyrimidines plus cisplatin. Nine (23.1%) patients had primary resistant disease (relapse < 3 months) to first-line chemotherapy, while 30 (76.9%) had refractory disease.\n\nTable 1 Demographic data\n\nCompliance with treatment\nΑ total of 123 chemotherapy cycles were administered with a median of 2 cycles per patient (range 1-8). Dose reduction was required in 28 cycles (23.6%), because of hematological (n=12 cycles) and non-hematological (n=16 cycles) toxicity. Dose reduction because of neurotoxicity was required in 4 cycles (3.2%). Thirty-nine cycles (31.7%) were delayed by a maximum of 5 days: for personal reasons unrelated to treatment or disease, in response to patients’ request or for reasons related to radiological assessment (n=16 cycles); hematological toxicity (n=9 cycles); or non-hematological toxicity (n=14 cycles). At the time of analysis, 31 patients (79.5%) discontinued treatment because of disease progression, three patients (7.7%) because of treatment-related adverse events; four patients (10.3%) refused further treatment; and one patient (2.6%) died for reasons unrelated to the disease or treatment. The mean dose intensity for nab-paclitaxel was 100 mg/m2/week, corresponding to 89% of the protocol-predicted dose.\n\nEfficacy\nΑ total of 38 patients were evaluable for response. One patient was not evaluable for response since he died suddenly for reasons unrelated to the disease (cardiac arrest). Partial response (PR) was documented in nine patients (23.1%; 95% confidence interval [CI] 10.1-37.2%); stable disease (SD) in 11 (28.6%); and disease progression in 18 (53.9%). Response rates were similar in patients with refractory disease and disease resistant to first-line chemotherapy (2 of 9, 22.2%, and 7 of 30, 23.3%, respectively). The disease control rate (PR+SD) was 51.3%. There was no correlation between the response rate and the patient’s PS or the stage of the disease. The median PFS (mPFS) was 3 months (range 0.3-13.6) (Fig. 1). At the time of analysis, 31 patients (79.5%) had died as a consequence of disease progression. The median OS (mOS) was 6.8 months (range 0.3-22.0) (Fig. 2). These efficacy results (ORR, mPFS and mOS) were not different in the group of patients (n=33) who had received first-line chemotherapy with docetaxel-based chemotherapy (DCF regimen).\n\nFigure 1 Kaplan-Meier curve for estimating progression-free survival\n\nFigure 2 Kaplan-Meier curve for estimating overall survival\n\nSafety\nAll patients who received at least one cycle of chemotherapy were evaluable for toxicity. Most of them reported only mild adverse events (grade 1-2). The most common grade 1-2 adverse events were neutropenia (66.7%), anemia (87.2%), and fatigue (41%). Grade 3-4 neutropenia occurred in 10.2% and 5.1% of the patients, respectively and grade 3 anemia in 2 patients (5.1%). The most common grade 3-4 non-hematological toxicities were vomiting (7.7%), neurotoxicity (5.1%), and pain (5.1%) (Table 2).\n\nTable 2 Adverse events related to study treatment\n\nDiscussion\nFor patients with gastric and GEJ adenocarcinomas, who retain a good PS, there are limited therapeutic options for second-line therapy. Several anti-tumor drugs have been tested in this setting; however, no “clear” winner has been identified and few trials have compared different agents. The response rates are low and the OS disappointing [17,18].\n\nThis study aimed to evaluate a new treatment option as second-line therapy for patients with advanced gastric and GEJ adenocarcinomas. This multicenter study met its primary endpoint, i.e. the ORR. Indeed, the administration of nab-paclitaxel resulted in an ORR of 23.1% and a disease control rate of 51.3%; moreover, the mPFS reached 3.0 months, and the mOS 6.8 months. These efficacy results compare favorably with those achieved in the arm with weekly paclitaxel single agent (ORR 16%, PFS 2.9 months, and OS 7.4 months) in the RAINBOW trial [12], or those with single-agent irinotecan (ORR 17.2%, PFS 2.2 months, and OS 5.8 months), or the FOLFIRI regimen (ORR 20%, PFS 3.0 months, and OS 6.7 months)[19], or single-agent ramucirumab (PFS 2.1 months, and OS 5.2 months) in the REGARD trial [20]. In contrast, the addition of ramucirumab to weekly paclitaxel achieved a significant improvement in PFS (4.4 months) and OS (9.2 months)[12]. We should underline that all but three patients had previously been treated with a taxane-based regimen DCF, whereas all patients were taxane-naïve in the RAINBOW trial [12]. In addition, the regimen had an expected and manageable toxicity profile, with already pre-described adverse events of single-agent nab-paclitaxel in other solid tumor studies [15,16]. Taking all the abovementioned data into perspective, we can conclude that nab-paclitaxel in combination with ramucirumab merits further evaluation in taxane-naïve and taxane-pretreated patients in randomized trials.\n\nIn the current study, nab-paclitaxel proved its efficacy, even in this taxane-based pretreated group of patients. Its efficacy may be explained by the ability of nab-paclitaxel to take advantage of the gp60 and caveolae-mediated albumin transport pathway to traverse the blood vessel endothelial lining into the tumor, wherein it may be referentially retained by tumoral SPARC [21,22]. Indeed, studies in nude mice bearing human tumor xenografts showed that mice could tolerate higher doses of nab-paclitaxel compared to Cremophor-paclitaxel, leading to more complete regressions and longer survival in the nab-paclitaxel-treated groups. These findings have been confirmed in clinical trials. Nowadays, apart from metastatic breast cancer, successful clinical trials have confirmed the activity of nab-paclitaxel in other tumor types, such as metastatic pancreatic adenocarcinoma and non-small-cell lung cancer of squamous origin [23-25]. Moreover, the absence of solvents, such as Cremophor, in conventional paclitaxel, makes it a much more patient-friendly taxane, since it is administered in a much shorter time without the need for premedication. Nevertheless, most of the patients relapsed early after their initial response, indicating a shared mechanism of resistance in all taxanes. The elucidation of this resistance mechanism may be the key for the rational design of treatment strategy in advanced or metastatic gastric cancer.\n\nToday, in the era of targeted therapies, only ramucirumab, an anti-VEGFR-2 monoclonal antibody, is currently approved as second-line treatment, as monotherapy or in combination with paclitaxel in advanced gastric cancer. In the monotherapy trial, the benefits were modest, with PFS and OS 2.1 months and 5.8 months, respectively, and ORR 8% [20]. Even in the combination trial, where the results were more encouraging (PFS and OS 4.4 and 9.6 months, respectively, ORR 28%), we should take into account that the population treated was taxane-naïve [12].\n\nRecently, an open-label, randomized, non-inferiority, multicenter Japanese trial has been reported, which compared solvent-based paclitaxel with nab-paclitaxel [26]. Patients were randomly assigned 1:1:1 to receive intravenous nab-paclitaxel on day 1 of each 3-week cycle, nab-paclitaxel on days 1, 8, and 15 of each 28-day cycle, or solvent-based paclitaxel on days 1, 8, and 15 of each 28-day cycle after progression to fluoropyrimidine-based first-line treatment. The study reported that weekly nab-paclitaxel was non-inferior to weekly solvent-based paclitaxel (hazard ratio 0.97; 95%CI 0.76-1.23; P=0.0085), with a mOS of 11.1 months (95%CI 9.9-13.0) for weekly nab-paclitaxel, and 10.9 months (95%CI 9.4-11.8) for weekly solvent-based paclitaxel. Although, the mOS was higher than that reported in the current study, this difference could be attributed to differences in patients’ ethnicity and disease characteristics, and more importantly to the fact that the vast majority of patients in our study had progressed after taxane-containing therapy in the first-line setting.\n\nOn the other hand, the results of the present study should be interpreted with caution (small sample size, possible selection bias in a phase II study) and can only serve as a hypothesis-generating trial. Nab-paclitaxel proved its efficacy in taxane-resistant/refractory tumors, with results comparable to those of single-agent weekly paclitaxel or biweekly irinotecan, as well as the FOLFIRI regimen. However, these results are inferior to the combination of weekly paclitaxel plus ramucirumab in taxane-naïve patients; thus, the evaluation of nab-paclitaxel plus ramucirumab in taxane-pretreated and taxane-naïve patients is the next logical step.\n\nIn conclusion, this phase II study demonstrated that nab-paclitaxel as second-line treatment in locally advanced inoperable or metastatic gastric and GEJ carcinoma is effective and merits further evaluation in subsequent clinical trials.\n\nSummary Box\nWhat is already known:\n\n\nSecond-line treatment of patients with advanced/metastatic gastric and gastro-esophageal adenocarcinomas is an unmet need\n\nWeekly paclitaxel in combination with ramucirumab is the preferable treatment of choice in this setting\n\nSingle-agent paclitaxel or irinotecan as well as the FOLFIRI regimen are considered as relevant choices\n\n\n\n\nWhat the new findings are:\n\n\nIn the current study nab-paclitaxel was proven effective in taxane-pretreated patients and had an acceptable toxicity profile\n\nThe efficacy of nab-paclitaxel in taxane-pretreated patients was comparable with those reported with single-agent paclitaxel or irinotecan, or FOLFIRI, but inferior to those obtained with the paclitaxel-ramucirumab combination in taxane-naïve patients\n\nRandomized trials are warranted for the evaluation of nab-paclitaxel plus ramucirumab in taxane-pretreated and taxane-naïve patients\n\n\n\n\nAcknowledgments\nWe would like to sincerely thank Dora Hatzidaki, Eva Maragoudaki, Ioannis Athanasakis, Marina Mavrogianni, Vassiliki Schoina, Aspasia Dimou, Spiros Georgiadis, Ageliki Kalisperi and Vasso Athanasaki for their contribution in this research.\n\nConflict of Interest: None\n\nIASO General Hospital, Athens; University General Hospital of Heraklion, Crete; 251 Air Force General Hospital, Athens; Medical School, University of Athens, Laikon General Hospital, Athens; Bioclinic of Thessaloniki; Henry Dunant Hospital, Athens; Hellenic Oncology Research Group, Athens, Greece\n==== Refs\nReferences\n1 Siegel RL Miller KD Jemal A Cancer statistics, 2015 CA Cancer J Clin 2015 65 5 29 25559415 \n2 Hundahl SA Phillips JL Menck HR The National Cancer Data Base Report on poor survival of U.S. gastric carcinoma patients treated with gastrectomy: Fifth Edition American Joint Committee on Cancer staging, proximal disease, and the “different disease” hypothesis Cancer 2000 88 921 932 10679663 \n3 Mavroudis D Kourousis C Androulakis N Frontline treatment of advanced gastric cancer with docetaxel and granulocyte colony-stimulating factor (G-CSF): a phase II trial Am J Clin Oncol 2000 23 341 344 10955859 \n4 Ajani JA Fodor MB Tjulandin SA Phase II multi-institutional randomized trial of docetaxel plus cisplatin with or without fluorouracil in patients with untreated, advanced gastric, or gastroesophageal adenocarcinoma J Clin Oncol 2005 23 5660 5667 16110025 \n5 Van Cutsem E Moiseyenko VM Tjulandin S Phase III study of docetaxel and cisplatin plus fluorouracil compared with cisplatin and fluorouracil as first-line therapy for advanced gastric cancer: a report of the V325 Study Group J Clin Oncol 2006 24 4991 4997 17075117 \n6 Al-Batran SE Homann N Pauligk C Effect of neoadjuvant chemotherapy followed by surgical resection on survival in patients with limited metastatic gastric or gastroesophageal junction cancer: The AIO-FLOT3 Trial JAMA Oncol 2017 3 1237 1244 28448662 \n7 Kodera Y Ito S Mochizuki Y Chubu Clinical Cancer Group A phase II study of weekly paclitaxel as second-line chemotherapy for advanced gastric Cancer (CCOG0302 study) Anticancer Res 2007 27 2667 2671 17695430 \n8 Lorenzen S Duyster J Lersch C Capecitabine plus docetaxel every 3 weeks in first- and second-line metastatic oesophageal cancer: final results of a phase II trial Br J Cancer 2005 92 2129 2133 15942631 \n9 Hartmann JT Pintoffl JP Al-Batran SE Mitomycin C plus infusional 5-fluorouracil in platinum-refractory gastric adenocarcinoma: an extended multicenter phase II study Onkologie 2007 30 235 240 17460417 \n10 Sym SJ Ryu MH Lee JL Salvage chemotherapy with biweekly irinotecan, plus 5-fluorouracil and leucovorin in patients with advanced gastric cancer previously treated with fluoropyrimidine, platinum, and taxane Am J Clin Oncol 2008 31 151 156 18391599 \n11 Chun JH Kim HK Lee JS Weekly irinotecan in patients with metastatic gastric cancer failing cisplatin-based chemotherapy Jpn J Clin Oncol 2004 34 8 13 15020657 \n12 Wilke H Muro K Van Cutsem E RAINBOW Study Group Ramucirumab plus paclitaxel versus placebo plus paclitaxel in patients with previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (RAINBOW): a double-blind, randomised phase 3 trial Lancet Oncol 2014 15 1224 1235 25240821 \n13 Gradishar WJ Tjulandin S Davidson N Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer J Clin Oncol 2005 23 7794 7803 16172456 \n14 Eisenhauer EA Therasse P Bogaerts J New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1) Eur J Cancer 2009 45 228 247 19097774 \n15 Aapro M Tjulandin S Bhar P Gradishar W Weekly nab-paclitaxel is safe and effective in ≥65 years old patients with metastatic breast cancer: a post-hoc analysis Breast 2011 20 468 474 21843943 \n16 Dent S Fraser J Graham N Campbell M Hopkins S Dranitsaris G Clinical outcomes of women with metastatic breast cancer treated with nab-paclitaxel: experience from a single academic cancer centre Curr Oncol 2013 20 24 29 23443761 \n17 Thallinger CM Raderer M Hejna M Esophageal cancer: a critical evaluation of systemic second-line therapy J Clin Oncol 2011 29 4709 4714 22067408 \n18 Wesolowski R Lee C Kim R Is there a role for second-line chemotherapy in advanced gastric cancer? Lancet Oncol 2009 10 903 912 19717092 \n19 Sym SJ Hong J Park J A randomized phase II study of biweekly irinotecan monotherapy or a combination of irinotecan plus 5-fluorouracil/leucovorin (mFOLFIRI) in patients with metastatic gastric adenocarcinoma refractory to or progressive after first-line chemotherapy Cancer Chemother Pharmacol 2013 71 481 488 23192279 \n20 Fuchs CS Tomasek J Yong CJ REGARD Trial Investigators Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD): an international, randomised, multicentre, placebo-controlled, phase 3 trial Lancet 2014 383 31 39 24094768 \n21 Zeng J Yin J Yuan D Assessing the clinical outcome of nab-paclitaxel in Chinese patients with advanced non-small-cell lung cancer Clin Respir J 2017 11 632 639 26404101 \n22 Zhang L Marrano P Kumar S Nab-paclitaxel is an active drug in preclinical model of pediatric solid tumors Clin Cancer Res 2013 19 5972 5983 23989978 \n23 Von Hoff DD Ervin T Arena FP Increased survival in pancreatic cancer with nab-paclitaxel plus gemcitabine N Engl J Med 2013 369 1691 1703 24131140 \n24 Von Hoff DD Ramanathan RK Borad MJ Gemcitabine plus nab-paclitaxel is an active regimen in patients with advanced pancreatic cancer: a phase I/II trial J Clin Oncol 2011 29 4548 4554 21969517 \n25 Socinski MA Okamoto I Hon JK Safety and efficacy analysis by histology of weekly nab-paclitaxel in combination with carboplatin as first-line therapy in patients with advanced non-small-cell lung cancer Ann Oncol 2013 24 2390 2396 23842283 \n26 Shitara K Takashima A Fujitani K Nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer (ABSOLUTE): an open-label, randomised, non-inferiority, phase 3 trial Lancet Gastroenterol Hepatol 2017 2 277 287 28404157\n\n",
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"keywords": "Nab-paclitaxel; chemotherapy regimen; gastric cancer; second-line treatment",
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"title": "Nab-paclitaxel as second-line treatment in advanced gastric cancer: a multicenter phase II study of the Hellenic Oncology Research Group.",
"title_normalized": "nab paclitaxel as second line treatment in advanced gastric cancer a multicenter phase ii study of the hellenic oncology research group"
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"abstract": "A 71-year-old male developed plasmacytoma on September 2015. He received radiotherapy, followed by posterior spinal fusion, at Th5 and L3 and was subsequently administered lenalidomide plus dexamethasone (Ld) from January 2016. After the 9th course of Ld, the patient complained of epigastric discomfort and papules on the face. FDG-PET showed duodenum 3rd potion and indicated nodular lesions with high glucose uptake on the lower lobe of the right lung and third portion of the duodenum. Biopsy of the skin, duodenum, and lung revealed Grocott's stain positive circular bodies, and the patient was subsequently diagnosed with disseminated cryptococcosis. Although disseminated cryptococcosis often causes encephalomeningitis, gastrointestinal involvement is rarely reported. The underlying conditions of disseminated cryptococcosis include AIDS, hematological malignancies, and steroid and immunosuppressant use. The sites of infections are the esophagus, stomach, small intestine, and colon. Disseminated cryptococcosis is diagnosed by abdominal pain, bloody stool, and gastrointestinal perforation. However, disseminated cryptococcosis may be asymptomatic; therefore, it is imperative that there is no delay in its diagnosis.",
"affiliations": "Department of internal medicine, Saiseikai Chuwa Hospital.;Department of internal medicine, Saiseikai Chuwa Hospital.;Department of Respiratory medicine and Hematology, Nara Medical University Hospital.;Department of Respiratory medicine and Hematology, Nara Medical University Hospital.;Department of Respiratory medicine and Hematology, Nara Medical University Hospital.;Department of Respiratory medicine and Hematology, Nara Medical University Hospital.",
"authors": "Okahashi|Nozomi|N|;Hoshino|Ei|E|;Kubo|Masayuki|M|;Hasegawa|Atsushi|A|;Tanaka|Haruyuki|H|;Amano|Itsuto|I|",
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"doi": "10.11406/rinketsu.60.1657",
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"issue": "60(12)",
"journal": "[Rinsho ketsueki] The Japanese journal of clinical hematology",
"keywords": "Disseminated cryptococcosis; Gastrointestinal cryptococcosis; Plasmacytoma",
"medline_ta": "Rinsho Ketsueki",
"mesh_terms": "D000368:Aged; D001706:Biopsy; D003453:Cryptococcosis; D006801:Humans; D007421:Intestine, Small; D008297:Male; D010954:Plasmacytoma; D049268:Positron-Emission Tomography",
"nlm_unique_id": "2984782R",
"other_id": null,
"pages": "1657-1662",
"pmc": null,
"pmid": "31902817",
"pubdate": "2019",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Development of disseminated cryptococcosis during chemotherapy for plasmacytoma.",
"title_normalized": "development of disseminated cryptococcosis during chemotherapy for plasmacytoma"
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"abstract": "Use of granulocyte colony-stimulating factor (G-CSF) has been associated with side effects including reports of acute glomerulonephritis (GN), almost all of which have been immune complex associated. There is one prior report of pauci-immune GN in a child, but was negative for ANCA (anti-neutrophilic cytoplasmic antibodies). We describe the first case of ANCA-positive pauci-immune GN exacerbated by the use of G-CSF for peripheral blood stem cell (PBSC) donation in a patient with no prior history of vasculitis. Given the use of G-CSF in PBSC donation and neutropenias associated with various conditions, it is important that both the nephrologist and the hematologist are aware of the renal risks associated with its use.",
"affiliations": "Division of Nephrology.;Division of Hematology Oncology, and.;Division of Hematology Oncology, and.;Division of Nephrology.;Division of Nephrology.;Division of Nephrology.;Division of Nephrology.;Department of Pathology, University of Maryland, Baltimore, MD, USA.;Division of Hematology Oncology, and.",
"authors": "Chandra|Preeti|P|;Dahiya|Saurabh|S|;Sanchez-Petitto|Gabriela|G|;Malik|Jawad|J|;Bolanos|Jonathan|J|;Haririan|Abdolreza|A|;Weir|Matthew|M|;Drachenberg|Cinthia|C|;Rapoport|Aaron|A|",
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"doi": "10.5414/CNCS110538",
"fulltext": "\n==== Front\nClin Nephrol Case Stud\nDustri\nClinical Nephrology. Case Studies\n2196-5293\nDustri-Verlag Dr. Karl Feistle\n\n10.5414/CNCS110538\nCase Report\nNephrology\nAcute glomerulonephritis in a hematopoietic blood stem cell donor\nChandra Preeti 1\nDahiya Saurabh 2\nSanchez-Petitto Gabriela 2\nMalik Jawad 1\nBolanos Jonathan 1\nHaririan Abdolreza 1\nWeir Matthew 1\nDrachenberg Cinthia 3\nRapoport Aaron 2\n1 Division of Nephrology,\n2 Division of Hematology Oncology, and\n3 Department of Pathology, University of Maryland, Baltimore, MD, USA\nCorrespondence to Preeti Chandra, MD Division of Nephrology, University of Maryland, 22 S Greene St., Baltimore, MD 21201, USA pchandra@som.umaryland.edu\n2021\n1 7 2021\n9 8186\n18 2 2021\n29 3 2021\n© Dustri-Verlag Dr. K. Feistle\n2021\nhttps://creativecommons.org/licenses/by/2.5/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.\nUse of granulocyte colony-stimulating factor (G-CSF) has been associated with side effects including reports of acute glomerulonephritis (GN), almost all of which have been immune complex associated. There is one prior report of pauci-immune GN in a child, but was negative for ANCA (anti-neutrophilic cytoplasmic antibodies). We describe the first case of ANCA-positive pauci-immune GN exacerbated by the use of G-CSF for peripheral blood stem cell (PBSC) donation in a patient with no prior history of vasculitis. Given the use of G-CSF in PBSC donation and neutropenias associated with various conditions, it is important that both the nephrologist and the hematologist are aware of the renal risks associated with its use.\n\nacute pauci-immune glomerulonephritis\nANCA-positive glomerulonephritis\nstem cell donor\ngranulocyte colony-stimulating factor\n==== Body\nIntroduction\n\nGranulocyte colony-stimulating factor (G-CSF) is a hematopoietic cytokine produced by monocytes, fibroblasts, endothelial cells, and in normal humans it leads to increased production of polymorphonuclear (PMN) leucocytes as well as dose-dependent reduction in their maturation time in the bone marrow, acts as a powerful activator of neutrophils, and enhances the respiratory burst in PMNs in response to various stimuli [1].\n\nWe describe a patient who developed acute glomerulonephritis after being given G-CSF for stem cell mobilization as part of stem cell donation to his father.\n\nCase presentation\n\nThe patient is a 30-year-old Caucasian male with no past medical history who was evaluated as a stem cell donor for his father. The father had T-cell prolymphocytic leukemia and was undergoing treatment with allogenic stem cell transplant. The patient was otherwise healthy. He worked as a personal trainer and denied any use of recreational drugs or over-the-counter medications including use of non-steroidal anti-inflammatory drugs. He worked out almost daily at the gym and ate a high-protein diet comprising 200 grams of dietary protein which was mostly meat based (2 g/kg body weight for his weight of 100 kg) and took ~ 5 g daily of creatine supplement. On initial assessment by the bone marrow transplant (BMT) team, the patient stated that he felt well and was asymptomatic. He had a creatinine of 1.86 mg/dL) and a urinalysis showed 2+ blood and 1+ protein, with 3 – 5 RBC/hpf. He was counseled to reduce the meat protein in his diet, stop the creatine supplement, and hold his exercise workouts. Repeat labs a week later showed a creatinine of 1.45 mg/dL. A simultaneous 24-hour urine collection done at this time showed a creatinine clearance of 101 mL/min for his body surface area of 2.35 m2. The creatinine clearance was 74 mL/min/1.73m2.\n\nGiven improvement in his creatinine with decrease of his protein intake and the window of opportunity to donate stem cells to his father, the BMT team decided to proceed with stem cell donation. He was started on 10 µg/kg/day dose of granulocyte-G-CSF (Granix) to be taken for a total of 5 days. Within a day of starting G-CSF, the patient developed bone pain, and over the subsequent days developed sore throat and some left upper abdominal discomfort, all anticipated side effects. He also noticed dark tea-colored urine after receiving 3 doses of G-CSF. He completed the duration of the G-CSF treatment and had repeat labs and urinalysis done on the day of apheresis and stem cell collection. Urinalysis showed 3+ blood, 1+ protein, more than 50 RBC/hpf, and serum creatinine was up to 2 mg/dL, though a repeat lab later in the afternoon showed creatinine of 1.8 mg/dL, serum total leucocyte count was 43,400/µL (69% neutrophils). The patient was asked to hydrate. Labs were repeated on the 2nd day after donation and showed creatinine of 2.3 mg/dL, urinalysis showed 3+ blood, 1+ protein, and > 50 RBC/hpf. He was admitted to the hospital, and nephrology was consulted. His vital signs were normal. His exam was unremarkable except some discomfort over the left upper quadrant. He had slightly tea-colored urine. Urine microscopy showed ~ 25 to 30 RBC/hpf ~ 25% acanthocytes, and there were no RBC casts. He had a baseline creatinine of 1.3 mg/dL ~ 2 years prior to presentation, but no other prior renal function tests, including urinalysis, were available. Platelets were decreased on admission, 83,000 cells/µL, from a normal baseline and dropped further to a nadir of 62,000 cells/µL the next day. This was attributed to the use of G-CSF and the apheresis procedure. His serum creatinine peaked at 2.45 mg/dL and then stabilized in the 2 – 2.2 mg/dL range. In subsequent days, he felt his urine color became pale yellow. A repeat urinalysis showed 11 – 25 RBC/hpf, and a spot urine showed 0.4 g per g of creatinine and albumin/creatinine ratio 0.2 g/g.\n\nWhen platelets improved to 85,000 cells/µL, he underwent a renal biopsy (Figure 1). This showed 13 glomeruli, of which none were globally sclerosed. Three glomeruli showed small segmental areas of tuft solidification and/or fibrinoid necrosis in association with epithelial crescents. The remaining tufts were open, capillary lumina appeared normocellular, with normal peripheral capillary basement membranes and no thrombotic changes. There was minimal interstitial fibrosis with no significant evidence of tubular atrophy (< 5% of the cortical areas sampled). The tubules showed acute tubular injury consisting of cytoplasmic swelling and vacuolization, apical blebbing, and occasional mitosis. There were clusters of tubules with red cell casts. Interlobular arteries showed mild wall thickening with no significant sclerosis. Congo red staining for amyloid was negative. Immunofluorescence on 2 – 3 glomeruli (1 with a crescent) was negative for IgG, IgM, IgA, C3, C1q, and κ and λ light chains. Electron microscopy showed 1 glomerulus with a minute area of parietal podocyte hyperplasia. Definite necrotizing and crescentic changes were not present. Overall, there was preserved glomerular architecture with mild accentuation of the mesangial areas. The peripheral capillary basement membranes were overall normal in thickness and texture. Podocyte foot processes were well formed. No immune-type electron-dense deposits were seen. No fibrils, tubuloreticular inclusions, or amyloid were present. The final diagnosis was focal necrotizing and crescentic glomerulonephritis, pauci-immune, no significant interstitial fibrosis and tubular atrophy.\n\nSerologies showed positive anti-nuclear antibody at a titer of 1 : 160 (reference range < 1 : 80), normal complement factors C3 and C4, and negative double-stranded DNA antibody. Additional tests that returned after the renal biopsy were a positive titer (1 : 160, reference range < 1 : 20) for anti-neutrophilic cytoplasmic antibodies (ANCA) in a peri-nuclear pattern on immunofluorescence (p-ANCA). Myeloperoxidase (MPO) antibody was detected, with a level of 74 AU/mL (reference range 0 – 19 AU/mL). Antibodies against proteinase 3 (PR3) and glomerular basement membrane were absent.\n\nHe was started on high-dose glucocorticoid after the biopsy and received pulse methyprednisolone 1 g daily for 2 consecutive days followed by high-dose prednisone at 80 mg daily, which was subsequently decreased to 60 mg daily. He was also given rituximab (1 g) and started on prophylaxis for Pneumocystis carinii infection. He subjectively felt better, the urine became clearer, and he was subsequently discharged. He received the second dose of rituximab 1 g 2 weeks after the first dose. We selected a 1-g rituximab dose for 2 doses (as opposed to 375 mg/m2 weekly doses for 4 doses) given the current COVID-19 pandemic. 0% lymphocytes in the blood were positive for CD19/20 after second rituximab dose. The prednisone dose has been slowly decreased outpatient.\n\nAt last evaluation ~ 10 weeks after the start of glucocorticoids and rituximab, his creatinine is ranging between 1.4 and 1.5 mg/dL, urinalysis shows microscopic hematuria, and the MPO titer is lower. Spot urine protein/creatinine ratio is 0.3 – 0.4 g/g, and a 24-hour collection shows urine protein of 1.5 g/day.\n\nDiscussion\n\nThe administration of recombinant human G-CSF (rhG-CSF) to normal healthy individuals stimulates proliferation of myeloid precursors, increases the neutrophil release from bone marrow, causes activation of neutrophils including increased respiratory burst, expression of surface CD11b/CD18 antigens, and increased elastase activity [2, 3]. G-CSF also results in increased number as well as activation of monocytes, increased markers of endothelial activation and coagulation [2, 3]. For stem cell donation, an optimal dose of rhG-CSF is one that ensures collection of an adequate number of CD34 + progenitor cells while minimizing donor’s exposure to the side effects of the cytokine. A peak increase in the circulating CD34+ progenitor cells usually occurs after 4 – 6 days of G-CSF therapy at a dose of 10 μg/kg/day. A wide range of dosages (3 – 20 µg/kg/day) have been used for healthy peripheral blood stem cell (PBSC) donation with dose-response effect and increased risk of side effects with doses higher than 10 µg/kg/day [4, 5, 6]. PBSC donation can be associated with side effects including bone pain, fatigue, flu-like symptoms, myalgias, insomnia, nausea, dizziness, anorexia, thrombocytopenia, hypocalcemia, and spleen enlargement. Serious adverse events are uncommon but reported and include cardiovascular events, acute lung injury, thromboembolic events, bleeding, splenic rupture, activation of autoimmunity, seizures, association with hematological malignancy, though the incidence of the latter is not higher than the expected incidence in the age- and sex-adjusted general population and the exact association remains unclear [6, 7, 8, 9].\n\nG-CSF has been associated with side effects including neutrophilic dermatosis and leucocytoclastic vasculitis [10]. In a case series of 18 patients with cutaneous vasculitis due to G-CSF [11], most were leucocytoclastic vasculitis which mostly occurred when absolute neutrophil count was above 800/µL. In this series, 3 patients were reported to have hematuria and proteinuria which resolved with the skin lesions; no renal biopsy was available. The use of G-CSF has been associated with reactivation of rheumatoid arthritis [12], as well as associated with flare or increased activity of the primary autoimmune disease prior to bone marrow transplant for such patients [13].\n\nG-CSF has been associated with development of acute glomerulonephritis as documented in case reports summarized in Supplemental Table 1. While some of them resolved with holding G-CSF, in other cases, immunosuppressants were given in addition. In most cases, holding G-CSF +/- immunosuppressive therapy improved the clinical picture but in some cases, patients had irreversible renal injury. Almost all of these cases of acute glomerulonephritis were immune complex associated. There is one report of pauci-immune glomerulonephritis occurring in a child but it was ANCA negative (reference 15 in Supplemental Table 1). There have been no prior reports of ANCA-positive pauci-immune glomerulonephritis associated with use of G-CSF in a patient with no known history of vasculitis or autoimmune disease.\n\nIn our case report, the patient developed acutely worsening renal function, hematuria, and proteinuria within days of receiving a standard-dose G-CSF. Renal biopsy was consistent with focal necrotizing crescentic glomerulonephritis with immunofluorescence showing a pauci-immune pattern. Subsequently, he tested positive for p-ANCA and anti-MPO antibodies consistent with microscopic polyangiitis. His baseline renal function was likely confounded to some degree by the high dietary intake of animal protein (~ 2 g/kg bodyweight) and to a small extent by the use of creatine supplements. This is evidenced by some improvement in his creatinine after he was asked to decrease the protein in his diet and hold creatine supplements. His baseline urinalysis showed small amount of microscopic hematuria, and baseline creatinine clearance was not normal which would indicate he likely had some baseline disease activity, which was undiagnosed. While there were no baseline levels of ANCA titers available prior to use of G-CSF, given his baseline urinalysis was abnormal, it is possible that he would have tested positive for the antibodies. However, he clearly had acute kidney injury and worsening hematuria consistent with an acute glomerulonephritis after use of G-CSF. Renal biopsy showed acute necrotizing lesions and acute tubular injury, there was minimal fibrosis consistent with the acute nature of the presentation. We cannot rule out a greater degree of fibrosis or chronicity that was missed on the renal biopsy.\n\nHellmich et al. [14] reported that recombinant human granulocyte colony-stimulating factor (rHuG-CSF) could be safely used in 6 patients with granulomatosis with polyangiitis (previously Wegener’s granulomatosis), all PR3 antibody positive, to treat severe neutropenia (absolute neutrophil count < 1,000/µL) after being treated with cyclophosphamide without causing disease flare. Of note, in this study, rHuG-CSF was used only to correct the neutropenia and the drug was stopped when the neutrophil count was above 1,000/µL, the mean duration of use was 3.8 ± 0.8 days, and the patients had been on cyclophosphamide prior to the neutropenia that could have prevented a disease flare.\n\nHowever, in a report of 2 patients with known ANCA-associated vasculitis, both positive for PR3 antibody, there was a clinical flare of the disease after receiving G-CSF [15]. The patients were given G-CSF in preparation for autologous stem cell collection as rescue treatment for their autoimmune diseases. The first patient received a dose of intravenous cyclophosphamide followed by 300 µg of filgrastim daily for 8 days when the patient developed a disease flare that required high-dose steroids. The second patient received a dose of intravenous cyclophosphamide followed by a reduced dose of G-CSF 300 µg for 4 days as well prednisone 50 mg daily prophylactically. The patient still had a disease flare and required start of oral cyclophosphamide. The total leucocyte count was 35,400/µL for the first patient and 10,700/µL for the second patient when they had a flare [15].\n\nFreeley et al. [16] noted that serum levels of G-CSF were significantly higher in patients with active ANCA vasculitis compared with age-matched healthy controls. In vitro priming of human neutrophils with G-CSF prior to administration of anti-MPO ANCA (but not anti-PR3 ANCA) resulted in greater respiratory burst consistent with greater neutrophil activation. They also noted that stimulation of neutrophils by G-CSF in murine model of anti-MPO crescentic glomerulonephritis resulted in greater histological severity of glomerulonephritis compared with controls. In vitro, G-CSF did not increase expression of MPO or PR3 on the neutrophil surface [16].\n\nHellmich et al. [17] describe that in in vitro studies of neutrophils from normal individuals, G-CSF did not significantly alter membrane PR3 expression on neutrophils that are either untreated or that are primed with tumor necrosis factor alpha (TNF-α). However, granulocyte monocyte colony-stimulating factor (GM-CSF) significantly increased PR3 expression on both intact and TNF-α-primed neutrophils. G-CSF or GM-CSF did not significantly alter MPO expression on the neutrophils [17].\n\nIn a mouse model of neutrophil-mediated heterologous-phase anti-glomerular basement membrane (GBM) glomerulonephritis, G-CSF knock-out mice were protected from anti-GBM glomerulonephritis compared with wild-type mice [18]. However, G-CSF knockout mice were not protected from T-cell/macrophage-mediated crescentic autologous-phase anti-GBM glomerulonephritis. This suggests that C-CSF has a role in neutrophil-mediated glomerular injury but not in experimental crescentic glomerulonephritis [18].\n\nANCA has been found in normal individuals, though in lower amounts compared to patients with vasculitis [19, 20], and thought to react to different epitopes compared with pathogenic ANCA [21]. Several lines of evidence suggest that ANCA antibodies are pathogenic in ANCA-associated vasculitis [22, 23, 24, 25]. Studies suggest that pathogenic ANCA react to the neutrophilic antigens (PR3, MPO) present on the surface of the neutrophils, resulting in production of reactive oxygen species as well as neutrophil extracellular traps (NETs), which contain chromatin material lined with proinflammatory proteins including MPO and PR3. NETs result in endothelial injury, activation of alternate complement pathway, and transfer of MPO and PR3 to the myeloid dendritic cells with resultant activation of autoreactive T and B cells and production of ANCA antibodies [22, 23, 24, 25].\n\nGiven the baseline abnormal urinalysis, it is plausible that our patient had underlying ANCA-associated disease that was undiagnosed. However, he clearly had an acute exacerbation of disease with use of G-CSF. Given the role of G-CSF in stimulating neutrophils and the role of neutrophils and ANCA antibodies in the pathogenesis of ANCA associated vasculitis (AAV), the possibility of developing or exacerbating an acute ANCA-associated pauci-immune glomerulonephritis with G-CSF should be considered. Consideration should be given for evaluating for undiagnosed AAV before administration of G-CSF and it should be added to the list of drugs that are associated with triggering AAV.\n\nFunding\n\nNo funding agency had a role in the preparation or review of this manuscript.\n\nConflict of interest\n\nNone of the authors declare a competing interest or conflict of interest in this manuscript.\n\nFigure 1 Renal biopsy. A: Segmental, necrotizing lesion with formation of an epithelial crescent (arrow). The adjacent glomerular arteriole shows evidence of vasculitis consisting of mural inflammation, karyorrhexis, and luminal obliteration (arrowheads). B: Segmental area of glomerular rarefaction with a small fibroepithelial crescent and adhesion to the Bowman’s capsule (arrow). Typical of a pauci-immune crescentic process, the remaining glomerular tufts are normocellular and have patent capillary lumina. C: Acute tubular injury with a tubular cell mitosis (arrowhead) and red cell casts were also noted (arrow). Bars: 20 µm.\n\nSupplemental material\n\nSupplemental material Supplementary Data - Table 1\n==== Refs\nReferences\n\n1 Anderlini P Przepiorka D Champlin R Körbling M Biologic and clinical effects of granulocyte colony-stimulating factor in normal individuals. Blood. 1996; 88 : 2819–2825. 8874177\n2 Anderlini P Champlin RE Biologic and molecular effects of granulocyte colony-stimulating factor in healthy individuals: recent findings and current challenges. Blood. 2008; 111 : 1767–1772. 18057230\n3 Falanga A Marchetti M Evangelista V Manarini S Oldani E Giovanelli S Galbusera M Cerletti C Barbui T Neutrophil activation and hemostatic changes in healthy donors receiving granulocyte colony-stimulating factor. Blood. 1999; 93 : 2506–2514. 10194429\n4 Anderlini P Körbling M Dale D Gratwohl A Schmitz N Stroncek D Howe C Leitman S Horowitz M Gluckman E Rowley S Przepiorka D Champlin R Allogeneic blood stem cell transplantation: considerations for donors. Blood. 1997; 90 : 903–908. 9242518\n5 Kröger N Zander AR Dose and schedule effect of G-GSF for stem cell mobilization in healthy donors for allogeneic transplantation. Leuk Lymphoma. 2002; 43 : 1391–1394. 12389618\n6 Hölig K G-CSF in healthy allogeneic stem cell donors. Transfus Med Hemother. 2013; 40 : 225–235. 24179471\n7 Tigue CC McKoy JM Evens AM Trifilio SM Tallman MS Bennett CL Granulocyte-colony stimulating factor administration to healthy individuals and persons with chronic neutropenia or cancer: an overview of safety considerations from the Research on Adverse Drug Events and Reports project. Bone Marrow Transplant. 2007; 40 : 185–192. 17563736\n8 Miller JP Perry EH Price TH Bolan CD Karanes C Boyd TM Chitphakdithai P King RJ Recovery and safety profiles of marrow and PBSC donors: experience of the National Marrow Donor Program. Biol Blood Marrow Transplant. 2008; 14 : 29–36. 18721778\n9 Halter J Kodera Y Ispizua AU Greinix HT Schmitz N Favre G Baldomero H Niederwieser D Apperley JF Gratwohl A Severe events in donors after allogeneic hematopoietic stem cell donation. Haematologica. 2009; 94 : 94–101. 19059940\n10 Spiekermann K Roesler J Emmendoerffer A Elsner J Welte K Functional features of neutrophils induced by G-CSF and GM-CSF treatment: differential effects and clinical implications. Leukemia. 1997; 11 : 466–478. 9096685\n11 Jain KK Cutaneous vasculitis associated with granulocyte colony-stimulating factor. J Am Acad Dermatol. 1994; 31 : 213–215. 7518847\n12 Vidarsson B Geirsson AJ Onundarson PT Reactivation of rheumatoid arthritis and development of leukocytoclastic vasculitis in a patient receiving granulocyte colony-stimulating factor for Felty’s syndrome. Am J Med. 1995; 98 : 589–591. 7539978\n13 Burt RK Fassas A Snowden J van Laar JM Kozak T Wulffraat NM Nash RA Dunbar CE Arnold R Prentice G Bingham S Marmont AM McSweeney PA Collection of hematopoietic stem cells from patients with autoimmune diseases. Bone Marrow Transplant. 2001; 28 : 1–12. 11498738\n14 Hellmich B Schnabel A Gross WL Granulocyte colony-stimulating factor treatment for cyclophosphamide-induced severe neutropenia in Wegener’s granulomatosis. Arthritis Rheum. 1999; 42 : 1752–1756. 10446877\n15 Iking-Konert C Ostendorf B Foede M Fischer-Betz R Jung G Haensch MG Schneider M Granulocyte colony-stimulating factor induces disease flare in patients with antineutrophil cytoplasmic antibody-associated vasculitis. J Rheumatol. 2004; 31 : 1655–1658. 15290749\n16 Freeley SJ Coughlan AM Popat RJ Dunn-Walters DK Robson MG Granulocyte colony stimulating factor exacerbates antineutrophil cytoplasmic antibody vasculitis. Ann Rheum Dis. 2013; 72 : 1053–1058. 23087180\n17 Hellmich B Csernok E Trabandt A Gross WL Ernst M Granulocyte-macrophage colony-stimulating factor (GM-CSF) but not granulocyte colony-stimulating factor (G-CSF) induces plasma membrane expression of proteinase 3 (PR3) on neutrophils in vitro. Clin Exp Immunol. 2000; 120 : 392–398. 10792393\n18 Kitching AR Ru Huang X Turner AL Tipping PG Dunn AR Holdsworth SR The requirement for granulocyte-macrophage colony-stimulating factor and granulocyte colony-stimulating factor in leukocyte-mediated immune glomerular injury. J Am Soc Nephrol. 2002; 13 : 350–358. 11805162\n19 Finnern R Bye JM Dolman KM Zhao MH Short A Marks JD Lockwood MC Ouwehand WH Molecular characteristics of anti-self antibody fragments against neutrophil cytoplasmic antigens from human V gene phage display libraries. Clin Exp Immunol. 1995; 102 : 566–574. 8536374\n20 Cui Z Zhao MH Segelmark M Hellmark T Natural autoantibodies to myeloperoxidase, proteinase 3, and the glomerular basement membrane are present in normal individuals. Kidney Int. 2010; 78 : 590–597. 20592714\n21 Roth AJ Ooi JD Hess JJ van Timmeren MM Berg EA Poulton CE McGregor J Burkart M Hogan SL Hu Y Winnik W Nachman PH Stegeman CA Niles J Heeringa P Kitching AR Holdsworth S Jennette JC Preston GA Falk RJ Epitope specificity determines pathogenicity and detectability in ANCA-associated vasculitis. J Clin Invest. 2013; 123 : 1773–1783. 23549081\n22 Kallenberg CGM Stegeman CA Abdulahad WH Heeringa P Pathogenesis of ANCA-associated vasculitis: new possibilities for intervention. Am J Kidney Dis. 2013; 62 : 1176–1187. 23810690\n23 Land J Rutgers A Kallenberg CGM Anti-neutrophil cytoplasmic autoantibody pathogenicity revisited: pathogenic versus non-pathogenic anti-neutrophil cytoplasmic autoantibody. Nephrol Dial Transplant. 2014; 29 : 739–745. 24398891\n24 Söderberg D Segelmark M Neutrophil extracellular traps in ANCA-associated vasculitis. Front Immunol. 2016; 7 :256. 27446086\n25 Lamprecht P Kerstein A Klapa S Schinke S Karsten CM Yu X Ehlers M Epplen JT Holl-Ulrich K Wiech T Kalies K Lange T Laudien M Laskay T Gemoll T Schumacher U Ullrich S Busch H Ibrahim S Fischer N Pathogenetic and clinical aspects of anti-neutrophil cytoplasmic autoantibody-associated vasculitides. Front Immunol. 2018; 9 : 680. 29686675\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2196-5293",
"issue": "9()",
"journal": "Clinical nephrology. Case studies",
"keywords": "ANCA-positive glomerulonephritis; acute pauci-immune glomerulonephritis; granulocyte colony-stimulating factor; stem cell donor",
"medline_ta": "Clin Nephrol Case Stud",
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"nlm_unique_id": "101638685",
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"pages": "81-86",
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"pmid": "34235045",
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"publication_types": "D016428:Journal Article",
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"title": "Acute glomerulonephritis in a hematopoietic blood stem cell donor.",
"title_normalized": "acute glomerulonephritis in a hematopoietic blood stem cell donor"
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"abstract": "A 30-year-old patient presented with hallucinations and profound shock. He was initially misdiagnosed as having severe sepsis; once ingestions were considered, he was diagnosed as potentially having arsenic toxicity.\n\n\n\nThe clinical story reveals many instructional lessons that could aid in the evaluation and management of future patients. This man presented with large amounts of blue crystals around his nose and lips from inhaling and eating boric acid (an ant poison) so he could, as he put it, kill the ants \"pouring into my mouth and nose and up into my brain.\" His profound pseudosepsis and sustained delirium were induced by co-ingestion of methamphetamine and a large quantity of boric acid. Delirium is a form of acute brain dysfunction that often is multifactorial in critical illness and, when seen in septic shock, is associated with prolonged mechanical ventilation, increased length of hospital stay, medical costs, higher mortality, and long-term cognitive impairment resembling dementia. Pseudosepsis is a noninfectious condition most commonly seen with ingestions such as salicylate (aspirin) toxicity.\n\n\n\nThis report emphasizes the need to recognize agents that contain boric acid as an etiology of unexplained delirium and profound shock.",
"affiliations": "From the Lipscomb University College of Pharmacy, the Department of Pharmaceutical Services, Vanderbilt University Medical Center, and the Division of Allergy/Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Veterans Affairs Tennessee Valley, Geriatric Research Education Clinical Center (GRECC), Nashville, Tennessee.;From the Lipscomb University College of Pharmacy, the Department of Pharmaceutical Services, Vanderbilt University Medical Center, and the Division of Allergy/Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Veterans Affairs Tennessee Valley, Geriatric Research Education Clinical Center (GRECC), Nashville, Tennessee.;From the Lipscomb University College of Pharmacy, the Department of Pharmaceutical Services, Vanderbilt University Medical Center, and the Division of Allergy/Pulmonary and Critical Care Medicine, Vanderbilt University School of Medicine, Veterans Affairs Tennessee Valley, Geriatric Research Education Clinical Center (GRECC), Nashville, Tennessee.",
"authors": "Johnson|Kayla|K|;Stollings|Joanna L|JL|;Ely|E Wesley|EW|",
"chemical_list": "D001888:Boric Acids; D000697:Central Nervous System Stimulants; D007306:Insecticides; D008694:Methamphetamine",
"country": "United States",
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"doi": "10.14423/SMJ.0000000000000599",
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"issn_linking": "0038-4348",
"issue": "110(2)",
"journal": "Southern medical journal",
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"medline_ta": "South Med J",
"mesh_terms": "D000328:Adult; D001888:Boric Acids; D000697:Central Nervous System Stimulants; D003693:Delirium; D003937:Diagnosis, Differential; D019468:Disease Management; D006212:Hallucinations; D006801:Humans; D007306:Insecticides; D008297:Male; D008694:Methamphetamine; D012772:Shock, Septic",
"nlm_unique_id": "0404522",
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"pages": "138-141",
"pmc": null,
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"pubdate": "2017-02",
"publication_types": "D002363:Case Reports; D016428:Journal Article; D013485:Research Support, Non-U.S. Gov't",
"references": "20473145;11679030;17456100;17102966;11797025;15082703;11511942;15640638;24846181;15071384;25176528;1388380;12799407;7249508;14672249;25984282;3370093;11445689",
"title": "Breaking Bad Delirium: Methamphetamine and Boric Acid Toxicity with Hallucinations and Pseudosepsis.",
"title_normalized": "breaking bad delirium methamphetamine and boric acid toxicity with hallucinations and pseudosepsis"
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"abstract": "Sodium glucose transporter 2 inhibitors (SGLT2i) inhibit the reabsorption of glucose in the renal tubules reducing glycemia and increasing glucosuria. The increased glucosuria causes a shift in normal flora and colonization of pathogenic microorganisms leading to an increase in mycotic genital infections. Recent Food and Drug Administration reported cases of diabetic ketoacidosis (DKA) after initiation of SGLT2i probes the question of safety with such agents. The mechanisms of ketoacidosis and the breakdown of lipids are often misunderstood, and blame is placed on lack of insulin or on medications used to treat diabetes. However, many patients living with diabetes do not experience DKA if the proper treatment and management of concomitant comorbidities are addressed. After a retrospective chart review of 250 patients, three patients were identified with DKA while on SGLT2i, but for three distinct contrasting reasons. Assessment of the pharmacodynamics of SGLT2i and the pathophysiology of DKA infers that emphasis for prevention of SGLT2i-associated DKA should be placed on appropriate diagnosis, infection, and electrolyte abnormalities.",
"affiliations": "The University of Mississippi School of Pharmacy, Jackson, MS, US.;The University of Mississippi School of Pharmacy, Jackson, MS, US.;The University of Mississippi School of Pharmacy, Jackson, MS, US.;Oxford Endocrinology Consultants, Oxford, MS, US.",
"authors": "Kelley|Jordan L|JL|;Strum|Matthew|M|;Riche|Daniel M|DM|;Chandler|Andrew M|AM|",
"chemical_list": null,
"country": "India",
"delete": false,
"doi": "10.4103/jpp.JPP_20_17",
"fulltext": "\n==== Front\nJ Pharmacol PharmacotherJ Pharmacol PharmacotherJPPJournal of Pharmacology & Pharmacotherapeutics0976-500X0976-5018Medknow Publications & Media Pvt Ltd India JPP-8-13710.4103/jpp.JPP_20_17Case SeriesSodium Glucose Transporter 2 Inhibitors and Diabetic Ketoacidosis in Three Patients with Diabetes: Underlying Causation Kelley Jordan L. 12Strum Matthew 13Riche Daniel M. 14Chandler Andrew M. 51 The University of Mississippi School of Pharmacy, Jackson, MS, US2 The University of Kentucky HealthCare, Lexington, KY, US3 Novo Nordisk, Plainsboro, NJ, US4 The University of Mississippi School of Medicine, Jackson, MS, US5 Oxford Endocrinology Consultants, Oxford, MS, USAddress for correspondence: Daniel M. Riche, University of Mississippi, School of Pharmacy, 2500 North State Street, Jackson, MS 39216. E-mail: driche@umc.eduJul-Sep 2017 8 3 137 139 06 2 2017 09 10 2017 10 7 2017 Copyright: © 2017 Journal of Pharmacology and Pharmacotherapeutics2017This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 License, which allows others to remix, tweak, and build upon the work non-commercially, as long as the author is credited and the new creations are licensed under the identical terms.Sodium glucose transporter 2 inhibitors (SGLT2i) inhibit the reabsorption of glucose in the renal tubules reducing glycemia and increasing glucosuria. The increased glucosuria causes a shift in normal flora and colonization of pathogenic microorganisms leading to an increase in mycotic genital infections. Recent Food and Drug Administration reported cases of diabetic ketoacidosis (DKA) after initiation of SGLT2i probes the question of safety with such agents. The mechanisms of ketoacidosis and the breakdown of lipids are often misunderstood, and blame is placed on lack of insulin or on medications used to treat diabetes. However, many patients living with diabetes do not experience DKA if the proper treatment and management of concomitant comorbidities are addressed. After a retrospective chart review of 250 patients, three patients were identified with DKA while on SGLT2i, but for three distinct contrasting reasons. Assessment of the pharmacodynamics of SGLT2i and the pathophysiology of DKA infers that emphasis for prevention of SGLT2i-associated DKA should be placed on appropriate diagnosis, infection, and electrolyte abnormalities.\n\nKeywords\nCase seriesdiabetesdiabetic ketoacidosiselectrolyte abnormalitieslatent autoimmune diabetes in adultssodium glucose transporter 2 inhibitors\n==== Body\nINTRODUCTION\nThe sodium glucose transporter 2 inhibitors (SGLT2i), such as canagliflozin, empagliflozin, and dapagliflozin, promote the renal excretion of glucose, and A1C is modified by the osmotic diuresis effect of the medication.[1] SGLT2i are commonly prescribed due to their ability to reduce weight and blood pressure, and lower the risk of hypoglycemia compared to sulfonylureas. Although SGLT2i use has become increasingly common (including advancing in therapy preference on the AACE/ACE algorithm), SGLT2i are not without limitation, particularly increased risk of infection.[234] A more recent finding is diabetic ketoacidosis (DKA). Around twenty atypical cases of acidosis were reported to the United States Food and Drug Administration (FDA) linking ketoacidosis with the SGLT2i class.[56] Underlying reasons for DKA with these SGLT2i has not been established. Therefore, the pharmacodynamics of SGLT2i combined with the pathophysiology of DKA was evaluated for causation.\n\nMETHODS\nA retrospective chart review was conducted on patients started on SGLT2i and later presented with DKA. There are 2200 patients at Oxford Endocrinology Consultants (OEC), and 250 of these patients were referred to a pharmacist through a collaborative practice management. Charts of pharmacist-managed patients were reviewed. Three patients were identified as diagnosed with type 2 diabetes mellitus (T2DM), started on a SGLT2i, and presented to an emergency department (ED) with DKA. Medications, previous illnesses, and A1C were collected, as well as administration, titration, and pharmacological parameters to distinguish commonalities among patients. An extensive literature search was used to identify possible causes for DKA in the three cases found at OEC.\n\nRESULTS\nPatient 1– appropriate diagnosis\nPatient 1 was a 55-year-old Caucasian female initially diagnosed with T2DM in 2005 with an A1C of 8.9%. She was referred to OEC after presenting to the ED with nausea and vomiting in January 2015. She was diagnosed with DKA and admitted to the intensive care unit (ICU). After obtaining a medication history at OEC, it was discovered that monotherapy with canagliflozin was initiated 2 months before the DKA episode. The Naranjo score for this adverse drug reaction (ADR) was possible. After resolution of DKA, insulin detemir and insulin lispro were started while canagliflozin was discontinued. In the following months, metformin, linagliptin, and empagliflozin were gradually initiated in addition to insulin. The patient was diagnosed with latent autoimmune diabetes in adults (LADA) based on a C-peptide of 0.4 ng/mL in April 2015. The patient's average self-monitoring blood glucose decreased from 205 mg/dL to 155 mg/dL in 5 months with a slight improvement in A1C to 8.6%. The patient has not had another episode of DKA.\n\nPatient 2– infection\nPatient 2 was a 47-year-old Caucasian female initially diagnosed with T2DM in 2005 and her most recent A1C was 9.2%. She presented to the ED with DKA (blood glucose = 459 mg/dL CO2= 5, and pH = 6.9) in February 2014. On presentation of DKA, the patient was receiving metformin ER, liraglutide, and canagliflozin. Canagliflozin and fluconazole were added 6 days before ED presentation. The Naranjo score for this ADR was possible. In the ED, the patient was diagnosed with an underlying septic pneumonia. The patient was discharged on multi-daily insulin monotherapy with an A1C = 8% 2 months after discharge. Sitagliptin and metformin were added before the patient was lost-to-follow-up.\n\nPatient 3– electrolyte abnormality\nPatient 3 was a 56-year-old African–American female diagnosed with T2DM for an unknown duration with an A1C = 8.2%. The patient was admitted to the ICU with DKA in June 2014 after being started on dapagliflozin 2 months ago. The Naranjo score for this ADR was possible. The patient was also treated with glipizide and insulin glargine before admission. In the ED, the patient was diagnosed with an underlying electrolyte abnormality due to Fanconi syndrome. After resolution of DKA and discontinuation of dapagliflozin, the patient was started on saxagliptin.\n\nDISCUSSION\nDKA occurs when the body does not have enough insulin to digest and utilize glucose, and the adipose tissue is catabolized to make energy instead, resulting in ketone formation.[7] SGLT functions by sodium following glucose and water following sodium through osmosis [Figure 1]. When SGLT2 is inhibited, the fluid and electrolytes are shifted and excreted in urine causing decreased blood volume hyperkalemia, and dehydration.[89] The addition of other medications that cause hyperkalemia (e.g., ACE inhibitors) may have an additive effect.[10] Dehydration and hyperkalemia are both predisposing factors for metabolic acidosis due to significant increase in anion gap with sodium loss.[7]\n\nFigure 1 Mechanisms of diabetic ketoacidosis resulting from glucose transporter 2 inhibitors\n\nLADA is a genetic intermediate between type 1 diabetes mellitus (T1DM) and T2DM that is a slow progressing immune-mediated T1DM. DKA occurs more often in T1DM compared to T2DM due to insulin deficiency versus decreased insulin sensitivity. The diagnosis of the type of diabetes age of onset (e.g., >30 years), a low C-peptide (e.g., <0.51 ng/mL), insulin independence for < 6 months after diagnosis, and/or the presence of circulating islet antibodies.[11] LADA is often misdiagnosed as T2DM due to advanced age at onset, and often LADA patients are not initiated on insulin secondary to T2DM algorithmic recommendations for initial oral therapy.[12] Patient 1 was not diagnosed with LADA before initiation of SGLT2i. The lack of exogenous insulin therapy contributed greatly to the onset of DKA in patient 1. Exposure to SGLT2i may have synergistically contributed to DKA in this patient. Interestingly, a different SGLT2i was initiated after insulin therapy without further DKA episodes.\n\nIncreased glucosuria causes a shift in normal flora and colonization of pathogenic microorganisms leading to an increase in mycotic genital infections, particularly candidiasis yeast and urinary tract infections.[9] Patients tend to lose glycemic control during infections leading to DKA.[913] Patient 2 is the quintessential example of infection leading to DKA. However, the addition of an SGLT2i cannot be overlooked in its contribution to infection for this patient.\n\nFanconi syndrome is a disorder of the proximal renal tubules (where sodium glucose transporters are located) that results in excretion of excessive electrolytes and protein into the urine.[14] Electrolyte abnormality due to Faconi syndrome is possibly triggered by the SGLT2i use which can lead to dehydration and ketoacidosis. Patient 3 had undiagnosed Faconi syndrome and consequently exhibited symptoms of DKA following SGLT2i use.\n\nCONCLUSION\nDKA is a potential risk of taking the SGLT2i, and there appear to be three forewarnings that could aid in the assessment of DKA risk with SGLT2i.[234] Early and appropriate diagnosis of LADA may decrease the risk of hospitalization from DKA in patients started on SGLT2i without insulin therapy. SGLT2i use was safe in LADA when added to insulin therapy in this case series. The osmotic effects of these medications include: (1) increasing glucosuria, (2) causing electrolyte imbalances due to dehydration, (3) changing the normal flora, and (4) causing infection. Proper hydration, including taking SGLT2i with a glass of water, could reduce DKA incidence with SGLT2i.[10] Overly vigilant monitoring of infection, especially on SGLT2i initiation, may be warranted. It is important to rule out Faconi syndrome and other diseases that induce electrolyte abnormalities before SGLT2i initiation. Furthermore, preexisting electrolyte abnormalities must be corrected before initiation of SGLT2i.\n\nFinancial support and sponsorship\nNil.\n\nConflicts of interest\nThere are no conflicts of interest.\n==== Refs\nREFERENCES\n1 Chao EC SGLT-2 inhibitors: A new mechanism for glycemic control Clin Diabetes 2014 32 4 11 26246672 \n2 INVOKANA ® [Prescribing Information] 2015 Titusville, NJ Janssen Pharmaceuticals, Inc \n3 FARXIGA [Package Insert] 2014 Wilmington, DE AstraZeneca Pharmaceuticals LP \n4 JARDIANCE ® [Package Insert] 2015 Ridgefield, CT Boehringer Ingelheim \n5 Handelsman Y Mechanick JI Blonde L Grunberger G Bloomgarden ZT Bray GA American association of clinical endocrinologists medical guidelines for clinical practice for developing a diabetes mellitus comprehensive care plan Endocr Pract 2011 17 Suppl 2 1 53 \n6 Fda.gov. FDA Drug Safety Communication: FDA Warns that SGLT2 Inhibitors for Diabetes May Result in a Serious Condition of Too Much Acid in the Blood 2015 Last accessed on 2015 Oct 27 Available from: http://www.fda.gov/Drugs/DrugSafety/ucm446845.htm \n7 Seifter JL Goldman L Schafer SI Acid-base disorders Goldman's Cecil Medicine 2011 24th ed Philadelphia, PA Elsevier Saunders Ch. 120 \n8 Urology-textbook.com. Kidney: Physiology of the Tubular Reabsorption 2015 Last accessed on 2015 Oct 27 Available from: http://www.urology-textbook.com/kidney-tubular-reabsorption.html \n9 Halimi S Vergès B Adverse effects and safety of SGLT-2 inhibitors Diabetes Metab 2014 40 S28 34 25554069 \n10 American Pharmacists Association SGLT2 Inhibitors for Type 2 Diabetes: Clinical Considerations 2015 Last accessed on 2015 Nov 12 Available from: https://www.pharmacist.com/sglt2-inhibitors-type-2-diabetes-clinical-considerations \n11 Stenström G Gottsäter A Bakhtadze E Berger B Sundkvist G Latent autoimmune diabetes in adults: Definition, prevalence, beta-cell function, and treatment Diabetes 2005 54 Suppl 2 S68 72 16306343 \n12 American Diabetes Association. Standards of medical care in diabetes - 2014 Diabetes Care 2014 37 Suppl 1 S14 80 24357209 \n13 Bender DA A Dictionary of Food and Nutrition 2014 Last accessed on 2015 Oct 27 4th ed Oxford, United Kingdom Oxford University Press Available from: http://www.oxfordreference.com/view/10.1093/acref/9780191752391.001.0001/acref-9780191752391 \n14 Hall AM Bass P Unwin RJ Drug-induced renal Fanconi syndrome QJM 2014 107 261 9 24368854\n\n",
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"issue": "8(3)",
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"keywords": "Case series; diabetes; diabetic ketoacidosis; electrolyte abnormalities; latent autoimmune diabetes in adults; sodium glucose transporter 2 inhibitors",
"medline_ta": "J Pharmacol Pharmacother",
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"title": "Sodium Glucose Transporter 2 Inhibitors and Diabetic Ketoacidosis in Three Patients with Diabetes: Underlying Causation.",
"title_normalized": "sodium glucose transporter 2 inhibitors and diabetic ketoacidosis in three patients with diabetes underlying causation"
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... |
{
"abstract": "The global incidence and mortality rates of lung cancer are the highest of any cancer. Smallcell lung cancer (SCLC) is an undifferentiated carcinoma which accounts for 15-20% of all lung cancers. Compared with the other major lung cancer type, non-small cell lung cancer, SCLC exhibits worse biological behavior, has a higher degree of malignancy, and develops more rapidly. The majority of SCLC present with extensive-stage disease, and the prognosis for these patients remains poor. Recently, immunotherapy has been demonstrated clinical activity in extensive-stage SCLC (ES-SCLC); however, the efficacy and safety of immunotherapy in ES-SCLC needs further confirmation. Durvalumab, a selective, high-affinity human IgG1 monoclonal antibody that blocks PD-L1 binding to PD-1 and CD80, showed durable clinical activity and a manageable safety profile in patients with pretreated ES-SCLC as a first-line treatment. Here, we report the case of an ES-SCLC patient who achieved complete remission (CR) of local lesions after receiving durvalumab monotherapy as a third-line treatment, experiencing no obvious immune-related side effects, such as rash, diarrhea, fatigue, myelosuppression, or thyroid dysfunction. No immune-related pulmonary or hepatorenal toxicities occurred. The case suggests that immunotherapy can be selected for third-line or multi-line treatment of ES-SCLC, and anti-PD-L1 antibody may be the better choice for patients who have poor performance status (PS) scores.",
"affiliations": "Department of Rare and Head and Neck Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China; Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China.;Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China; Department of Head and Neck Surgery, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.;Department of Oncology, Jinhua Guangfu Cancer Hospital, Jinhua, China.;Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China; Department of Integrated Chinese Traditional Medicine and Western Medicine, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China.;Department of Rare and Head and Neck Oncology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou, China; Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China. susang409@hotmail.com.",
"authors": "Zhou|Qinfei|Q|;Zhao|Jiazheng|J|;Wang|Jie|J|;Bao|Guanai|G|;Gong|Li-Yan|LY|",
"chemical_list": "D000911:Antibodies, Monoclonal; C000613593:durvalumab",
"country": "China",
"delete": false,
"doi": "10.21037/apm-20-1244",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "2224-5820",
"issue": "9(4)",
"journal": "Annals of palliative medicine",
"keywords": "Small-cell lung cancer (SCLC); case report; durvalumab; immunotherapy; third-line treatment",
"medline_ta": "Ann Palliat Med",
"mesh_terms": "D000911:Antibodies, Monoclonal; D002289:Carcinoma, Non-Small-Cell Lung; D006801:Humans; D008175:Lung Neoplasms; D055752:Small Cell Lung Carcinoma",
"nlm_unique_id": "101585484",
"other_id": null,
"pages": "2386-2392",
"pmc": null,
"pmid": "32692233",
"pubdate": "2020-07",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Durvalumab monotherapy as a third-line treatment for extensive-stage small-cell lung cancer: a case report.",
"title_normalized": "durvalumab monotherapy as a third line treatment for extensive stage small cell lung cancer a case report"
} | [
{
"companynumb": "CN-ACCORD-227786",
"fulfillexpeditecriteria": "1",
"occurcountry": "CN",
"patient": {
"drug": [
{
"actiondrug": "4",
"activesubstance": {
"activesubstancename": "DURVALUMAB"
},
"drugadditional": null,
"drug... |
{
"abstract": "Chronic Mucocutaneous Candidiasis (CMC) is the chronic, recurrent, noninvasive Candida infections of the skin, mucous membranes, and nails. A 26-month-old girl was admitted with the complaints of recurrent oral Candidiasis, diarrhea, and respiratory infections. Candida albicans grew in oral mucosa swab. CMV and EBV DNA titers were elevated. She had hypergammaglobulinemia; IgE level, percentages of lymphocyte subgroups, and in vitro T-cell proliferation responses were normal. She had parenchymal nodules within the lungs and a calcific nodule in the liver. Chronic-recurrent infections with different pathogens leading to significant morbidity suggested combined immunodeficiency, CMC, or Mendelian susceptibility to mycobacterial diseases. Genetic analysis revealed a predefined heterozygous gain-of-function mutation (GOF) (c.1154 C>T, p.Thr385Met) in the gene coding STAT1 molecule. Hematopoietic stem cell transplantation (HSCT) was planned because of severe recurring infections. Patients with STAT1 GOF mutations may exhibit diverse phenotypes including infectious and noninfectious findings. HSCT should be considered as an early treatment option before permanent organ damage leading to morbidity and mortality develops. This case is presented to prompt clinicians to consider STAT1 GOF mutations in the differential diagnosis of patients with chronic Candidiasis and recurrent infections with multiple organisms, since these mutations are responsible for nearly half of CMC cases reported.",
"affiliations": "Ege University Medical Faculty, Department of Pediatric Immunology, Izmir, Turkey.;Ege University Medical Faculty, Department of Pediatric Immunology, Izmir, Turkey.;Ege University Medical Faculty, Department of Pediatric Immunology, Izmir, Turkey.;Ege University Medical Faculty, Department of Pediatric Genetics, Izmir, Turkey.;Ege University Medical Faculty, Department of Pediatric Immunology, Izmir, Turkey.;Laboratory of Human Genetics of Infectious Diseases, INSERM, Paris, France.;Ege University Medical Faculty, Department of Pediatrics, Izmir, Turkey.;Ege University Medical Faculty, Department of Pediatric Immunology, Izmir, Turkey.;Laboratory of Human Genetics of Infectious Diseases, INSERM, Paris, France.;Laboratory of Human Genetics of Infectious Diseases, INSERM, Paris, France.;Ege University Medical Faculty, Department of Pediatric Immunology, Izmir, Turkey.",
"authors": "Eren Akarcan|Sanem|S|0000-0002-2170-765X;Ulusoy Severcan|Ezgi|E|;Edeer Karaca|Neslihan|N|0000-0002-2202-7082;Isik|Esra|E|;Aksu|Guzide|G|;Migaud|Mélanie|M|;Evin Gurkan|Ferda|F|;Azarsiz|Elif|E|0000-0002-2887-7029;Puel|Anne|A|;Casanova|Jean-Laurent|JL|;Kutukculer|Necil|N|0000-0002-9196-3819",
"chemical_list": null,
"country": "Egypt",
"delete": false,
"doi": "10.1155/2017/2846928",
"fulltext": "\n==== Front\nCase Reports ImmunolCase Reports ImmunolCRIICase Reports in Immunology2090-66092090-6617Hindawi 10.1155/2017/2846928Case ReportGain-of-Function Mutations in STAT1: A Recently Defined Cause for Chronic Mucocutaneous Candidiasis Disease Mimicking Combined Immunodeficiencies http://orcid.org/0000-0002-2170-765XEren Akarcan Sanem saneren@yahoo.com\n1\nUlusoy Severcan Ezgi \n1\nhttp://orcid.org/0000-0002-2202-7082Edeer Karaca Neslihan \n1\nIsik Esra \n2\nAksu Guzide \n1\nMigaud Mélanie \n3\nEvin Gurkan Ferda \n4\nhttp://orcid.org/0000-0002-2887-7029Azarsiz Elif \n1\nPuel Anne \n3\n\n5\nCasanova Jean-Laurent \n3\n\n5\nhttp://orcid.org/0000-0002-9196-3819Kutukculer Necil \n1\n\n1Ege University Medical Faculty, Department of Pediatric Immunology, Izmir, Turkey\n2Ege University Medical Faculty, Department of Pediatric Genetics, Izmir, Turkey\n3Laboratory of Human Genetics of Infectious Diseases, INSERM, Paris, France\n4Ege University Medical Faculty, Department of Pediatrics, Izmir, Turkey\n5St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY, USAAcademic Editor: Christian Drouet\n\n2017 13 11 2017 2017 284692821 6 2017 3 10 2017 10 10 2017 Copyright © 2017 Sanem Eren Akarcan et al.2017This 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.Chronic Mucocutaneous Candidiasis (CMC) is the chronic, recurrent, noninvasive Candida infections of the skin, mucous membranes, and nails. A 26-month-old girl was admitted with the complaints of recurrent oral Candidiasis, diarrhea, and respiratory infections. Candida albicans grew in oral mucosa swab. CMV and EBV DNA titers were elevated. She had hypergammaglobulinemia; IgE level, percentages of lymphocyte subgroups, and in vitro T-cell proliferation responses were normal. She had parenchymal nodules within the lungs and a calcific nodule in the liver. Chronic-recurrent infections with different pathogens leading to significant morbidity suggested combined immunodeficiency, CMC, or Mendelian susceptibility to mycobacterial diseases. Genetic analysis revealed a predefined heterozygous gain-of-function mutation (GOF) (c.1154 C>T, p.Thr385Met) in the gene coding STAT1 molecule. Hematopoietic stem cell transplantation (HSCT) was planned because of severe recurring infections. Patients with STAT1 GOF mutations may exhibit diverse phenotypes including infectious and noninfectious findings. HSCT should be considered as an early treatment option before permanent organ damage leading to morbidity and mortality develops. This case is presented to prompt clinicians to consider STAT1 GOF mutations in the differential diagnosis of patients with chronic Candidiasis and recurrent infections with multiple organisms, since these mutations are responsible for nearly half of CMC cases reported.\n==== Body\n1. Introduction\nChronic Mucocutaneous Candidiasis (CMC) is a general name used for the chronic or recurrent, noninvasive Candida infections of the skin, mucous membranes, and nails. Primary immune deficiencies (PID) should be considered after exclusion of secondary reasons affecting the immune system such as prolonged immunosuppressive drug use (glucocorticoids), infections (HIV), or metabolic defects (diabetes mellitus) [1].\n\nCMC is frequently a component of combined immunodeficiencies (with decreased T-cell number or function) in which susceptibility to various infectious agents and noninfectious signs such as autoimmunity is expected. CMC may be the single or coexisting infectious condition in some other PID syndromes such as autosomal recessive (AR) autoimmune polyendocrinopathy syndrome type I (AR AIRE mutations), autosomal dominant (AD) hyper IgE syndrome (AD STAT3 mutations), AR caspase recruitment domain-containing protein 9 (CARD9) deficiency with invasive fungal diseases, AR IL12 receptor-beta1, and IL12-p40 deficiency causing susceptibility to mycobacterial diseases. There is also one more group of patients having CMC as the most prominent feature and defined as CMC disease (CMCD) [1–3].\n\nDespite the narrow definition, most chronic mucocutaneous Candidiasis disease (CMCD) patients were reported to have further susceptibilities to noncandidal fungal and nonfungal infections and develop noninfectious findings such as autoimmunity, aneurysms, and cancer [1, 2].\n\nHerein, we present a CMC patient with granulomas in the lungs and the liver, persistent oral Candidiasis, eosinophilic esophagitis, bronchiectasis, and recurrent diarrhea suggesting a combined immunodeficiency. The cause of the disease was found to be gain-of-function (GOF) mutation in transducer and activator of transcription 1 (STAT1) which was recently reported to lead to CMCD; the literature about STAT1 GOF mutations was also reviewed.\n\n2. Case Report\nA 26-month-old girl was admitted to inpatient clinics with the complaints of recurrent oral Candidiasis, lower respiratory tract infections, and diarrhea. Candidiasis recurred whenever antifungal treatment was interrupted since the newborn period. She had bronchiolitis, pneumonia, and otitis media recurring 4-5 times a year, and these infections had started in the first month of life. She had a severe varicella infection when she was 5 months old. She had mild mental and motor developmental delay. She was the second child of third-degree consanguineous healthy parents. Her elder six-month-old brother died due to pneumonia. No further information on the nature of his infection could be obtained, and it was learned that no evaluation was carried out for him.\n\nShe had failure to thrive (height and weight under the third percentile), oral Candidiasis, and bronchitis at admission. Complete blood count and biochemistry were normal. C-reactive protein was 1.7 mg/dL (normal: <0.3 mg/dL), and erythrocyte sedimentation rate was 10 mm/hour (normal: <20 mm/hour). Chest X-ray revealed bilateral microcalcifications and chronic lung disease findings. There were bilateral multiple parenchymal nodules, the biggest one being 5 mm, in high-resolution CT (Figure 1). An 8 mm calcific nodular lesion of the liver was reported and interpreted as a granuloma in the abdominal US.\n\n\nCandida albicans was isolated from oral mucosa swab. Blood Aspergillus antigen was negative. Rhinovirus antigen was detected in a nasal swab. CMV and EBV DNA (1966 IU/ml and 7600 IU/ml, resp., by PCR) were present in blood and successfully treated with ganciclovir, significantly lowering the titers. However, these tended to rise again with pneumonia or gastroenteritis attacks or upon temporary withdrawal of the drug, suggesting chronicity. As oral fluconazole was not effective for Candidiasis, parenteral caspofungin was initiated with good response. E. coli grew in urine culture which was responsive to proper antibacterial medication. Tuberculin skin test was negative; interferon-gamma release assay (IGRA) was positive.\n\nMucopurulent secretions and mucous plaques on airways with normal anatomical structure were observed by bronchoscopy. Bronchoalveolar lavage fluid had benign cytology, and there was no evidence of bacteria, fungi, parasites, or mycobacteria. Repeated IGRA was found to be negative, and isoniazid (INH) prophylaxis was preferred instead of multidrug tuberculosis treatment. It was discontinued due to increased liver enzymes after the second month.\n\nInvestigations for persistent diarrhea showed negative results for viruses, parasites, and bacteria. Recurrent vomiting was also a problem in the patient. Upper gastrointestinal barium scan and pH monitorization did not show gastrointestinal reflux. The endoscopic evaluation revealed inflammatory findings in esophagus and bulbus with a loose lower esophageal sphincter. There were no candidal plaques, probably because she was under antifungal treatment at the time of examination. Pathological studies showed eosinophilic esophagitis and fibrosis.\n\nVaccine responses to Hepatitis B, Rubella, and Mumps were positive. Autoantibodies (antinuclear antibody, anti-gliadin antibodies, anti-thyroid peroxidase, and anti-thyroglobulin antibodies) and direct Coombs tests were negative, and thyroid hormone levels were normal.\n\nFirst line immunological workup revealed hypergammaglobulinemia with normal complement and IgE levels. Percentages and numbers of lymphocyte subgroups were normal compared to age-related healthy controls [4–6] (Table 1). The quantitative determination of oxidative burst, the foxp3 expression on CD4+CD25+ T cells, and in vitro T-cell proliferation response to mitogens were normal.\n\nShe had chronic recurring infections with various pathogens including fungi, viruses, and bacteria. She had hypergammaglobulinemia, persistent oral Candidiasis, persistent granulomas, and nodules in the liver and the lungs. She was unresponsive to oral treatment and required parenteral treatments with frequent, over one-week hospitalizations warranting extensive workout for PID. Type and course of the infections with substantial organ damage suggested the presence of a severe combined immune deficiency, Mendelian susceptibility to mycobacterial diseases (MSMD), or CMC as preliminary diagnoses.\n\nRegular intravenous immunoglobulin (IVIG) replacement was commenced when she was three years old, as a supportive measure to frequent hospitalizations for pneumonia and diarrhea attacks. Routine prophylactic antibacterial and antifungal therapies besides ganciclovir were continued. Despite these measures, she developed bronchiectasis at the age of four (Figure 2).\n\nMolecular genetic analyses of IL12R/IFN gamma and Th17-IL17 pathways were planned and the former was found to be negative. The investigation of the Th17/IL17 pathway revealed a heterozygous gain-of-function, de novo mutation in STAT1 gene, which was described recently (c.1154C>T, p.Thr385Met, T385M). Parents were wild-type for the gene (Figure 3). HSCT was planned because of ongoing infections despite adequate supportive measures. There was no matched related donor. Thus, an unrelated donor search was initiated.\n\n3. Discussion\nEarly-onset infections with diverse microorganisms, accompanying CMC, warrant search for combined immunodeficiency. Our case had normal lymphocyte subgroup distribution and normal in vitro T-cell proliferation response to mitogens. The granulomas in the lungs and the liver, hypergammaglobulinemia, and positive IGRA compatible with a mycobacterial infection and persistent candidal infection directed us to investigate IL-12/IFN gamma and Th17-IL17 pathways. However, a positive mycobacterial evidence could not be confirmed; she neither developed new lesions nor disseminated disease after cessation of INH which ruled out the possibility of MSMD. Conversely, the granulomas and nodules disappeared in follow-up with continuous parenteral antifungal treatment.\n\nImpaired IL-17 immunity is the underlying cause of CMC. T helper 17 (Th17) cells and their effector cytokines IL-17 (IL-17A, IL-17F) and IL-22 have critical functions for candidal host defense via epithelial cells [3, 7, 8]. IL-17A and IL-17F bind to interleukin-17 receptor A (IL-17RA) and IL-17RC, respectively, in various tissues [8]. In this IL-17 signaling pathway, homozygous IL17RA, IL17RC, ACT 1, and heterozygous IL17F mutations were found to be causative in some CMCD patients [1, 2, 9]. Many patients in this group could not be identified genetically until GOF heterozygous missense mutations in the STAT1 molecule were defined in this decade [10, 11]. After that, GOF STAT1 mutations were found to be responsible for more than half of CMCD patients [1, 2].\n\nSTAT molecules are signal transducers for regulation of transcription in various cell types. After stimulation with cytokines (e.g., IFN-γ), STAT1 molecules are phosphorylated, dimerized, and translocated into the nucleus for gene expression and then dephosphorylated and released to the cytoplasm [12]. Proinflammatory cytokines, such as IL-6 and IL-21, activate STAT3, subsequently inducing transcription of IL-17 and IL-22 in T cells, transforming them into Th17 cells. Some interferons and cytokines (IFN-α/β, IFN-γ, IFN-λ and IL-27) activate STAT1, inhibiting transcription of IL-6 and IL-21 [12, 13]. In GOF STAT1 mutations, dephosphorylation is defective causing prolonged phosphorylation and gain-of-function for STAT1-dependent cytokines inhibiting STAT3-mediated Th17 cell differentiation [1, 2, 10, 13].\n\nTo date, more than thirty GOF STAT1 mutations were identified. Early reported mutations were all in the coiled-coil domain (CCD) of STAT1 gene [1, 2, 10, 11]. Firstly discovered mutation in DNA binding domain (DBD) was a T385M mutation (as in our case) in two unrelated patients from Japan. The investigators showed STAT1 hyperphosphorylation (due to impaired dephosphorylation) in response to IFN-γ, IFN-α, and IL-27 stimulation and defective Th17 cell differentiation as in CCD mutations. Both patients suffered from recurrent oral Candidiasis and lower and upper respiratory tract infections that led to bronchiectasis in childhood period as in our case. Autoimmune diseases developed in the late childhood period in both of them; our patient did not have any autoimmune manifestation for the moment [14]. Enhanced IFN-α/β response may contribute to autoimmunity which is a late and variable finding [2, 10].\n\nIn an article evaluating nine patients with STAT1 GOF mutations, including one patient carrying a T385M mutation, functional studies confirmed gain of phosphorylation and impaired Th17 response to Candida. Most obvious findings in this patient were early esophageal Candidiasis causing strictures and recurrent HSV infections [15]. Although macroscopic esophageal candidal involvement was not reported in our case, biopsy evaluation as eosinophilic esophagitis and fibrosis might be a hint in that direction.\n\nPhenotypic presentation in STAT1 GOF mutations may be heterogeneous and may not be directly related to the specific mutation. Diverse clinical features of the recently reported patients support this observation [1, 2].\n\nUzel et al. demonstrated STAT1 GOF mutations in five patients with IPEX-like features (autoimmunity and enteropathy) and accompanying CMC phenotype. Two patients with the same mutation (T385M) had different clinical presentation: one had CMC and enteropathy as the prominent features starting in infancy with recurrent respiratory infections, bronchiectasis, recurrent viral infections, cerebral aneurysms, and autoimmunity (Type 1 diabetes mellitus). The other patient had very mild CMC and recurrent upper respiratory infections presenting in early childhood. Short stature was a common feature and most likely related to enteropathy suggesting the IPEX-like disease. Four of the five patients showed eosinophilic/lymphocytic enteritis [16]. Our case had recurrent diarrhea without chronicity. Her failure to thrive may be due to mild enteropathy or malnutrition secondary to frequent infections.\n\nPatients with STAT1 GOF mutations have various infections with bacteria, viruses, and mycobacteria. Infrequent invasive fungal infections are also seen [1, 2]. Five patients, each with different STAT1 GOF mutations (including T385M), were reported to have disseminated infections with intracellular dimorphic fungi such as Coccidioides immitis and Histoplasma capsulatum [17]. Loss of function mutations (complete/partial recessive or dominant) in STAT1 gene cause increased susceptibility to viral, bacterial, and mycobacterial infections varying in severity, and the underlying mechanism is impaired IFN-α/β, IFN-γ responses to these intracellular microorganisms [2, 12]. Conversely, IFN-γ and IFN-α induced STAT1 phosphorylation is enhanced in GOF STAT1 mutations [14–16]. The impaired response to IFN restimulation due to prolonged phosphorylation which leads to a loss of function presents a possible explanation for increased susceptibility to viral, mycobacterial, and dimorphic fungal infections [17].\n\nOur case presented with a combined immunodeficiency (CID) phenotype resembling several cases reported before [18, 19]. Two patients (one with T385M mutation) presented in early infancy with Candidiasis, CMV infection, and chronic lung findings. One of them also developed a mycobacterial infection. Despite CID findings, both patients had normal lymphocyte subgroup distribution except reversed CD4/CD8 ratio. One of them had low and the other normal proliferation response to mitogens [19]. Some STAT1 GOF mutated patients developed T and B cell lymphopenia, hypogammaglobulinemia, and loss of memory B cells as with age. This progressive loss of immunologic functions may be another possible reason for newly acquired infections in time [16]. On the other hand, most patients (% 70–80) had normal lymphocyte ratios, immunoglobulin levels, and T-cell functions despite the high rate of infections [2]. Our case already had CMV and EBV viremia at admission while she had normal lymphocyte distribution and function. Namely, both cellular defects and abnormal regulation of IFN-α/β, IFN-γ responses are likely mechanisms underlying noncandidal infection susceptibility in STAT1 GOF mutations.\n\nManagement of patients with STAT1 GOF mutations should target prevention and treatment of infections. Prophylactic antimicrobials and IVIG are routinely used for this purpose [2, 16]. Since these mutations are just recently defined, HSCT is reported in a small number of patients and accepted as a radical treatment modality spared for patients with severe morbidity [2, 18–20]. Most patients are followed with various diagnoses as CID, IPEX-like syndrome and even undergo HSCT before identification of the molecular defect. Unfortunately, more than half of the reported patients died after transplantation due to multiple complications, most probably related to the late decision or poor selection of patients for HSCT [2, 18–20].\n\n4. Conclusion\nCareful consideration to the possibility of STAT1 GOF mutations should be given at the time of CMC diagnosis since they are reported to be causative in more than half of CMC patients. These patients may exhibit quite different phenotypes. New infections, autoimmune diseases, even malignancies, and aneurysms may emerge gradually with age. The fact that CMC is heterogeneous, progressive, and unpredictable in its course should alert physicians to recognize early stem cell transplantation decision as a feasible treatment option to avoid severe morbidity and mortality.\n\nConflicts of Interest\nThe authors declare that there are no conflicts of interest regarding the publication of this paper.\n\nFigure 1 (a) Chest X-ray: bilateral infiltrations, microcalcifications in chest and abdomen. (b) and (c) Thorax CT: multiple, parenchymal nodules in both lungs, the biggest one 5 mm in diameter. (d) Thorax CT, the slices passing liver: a calcific nodule (At 26 months old).\n\nFigure 2 (a) Chest X-ray: bilateral infiltrations, bronchial thickenings, and air trapping. (b) Thorax CT: bronchiectasis in the left upper lobe and lower lobe, peribronchial thickenings, mucous plaques, and air trapping in both lungs (At four years of age).\n\nFigure 3 Identification of de novo autosomal dominant STAT1 mutation in the patient.\n\nTable 1 Serum immunoglobulin, complement levels, lymphocyte subgroups as ratios, and absolute cell numbers with age-related reference values [4–6].\n\n \tPatient\tReference values (mean ± SD)\tMin–max\t\nIgG (mg/dL)\t1320\t822.3 ± 208.4\t430–1290\t\nIgA (mg/dL)\t98.9\t53.5 ± 26.8\t23–130\t\nIgM (mg/dL)\t149\t92.5 ± 33.9\t36–199\t\nIgE (IU/mL)\t0.9\t<100\t2–199\t\nC3 (mg/dL)\t171\t120 ± 45\t81–171\t\nC4 (mg/dL)\t28.3\t22 ± 13\t9–36\t\nCD3+ T cells (%)\n(cells/mm3)\t71\n2620\t70.0 ± 7.18\n3220 ± 1180\t48.2–81.4\n506–7267\t\nCD19+ B cells (%)\n(cells/mm3)\t23\n849\t16.5 ± 5.70\n739 ± 329\t6.7–30.4\n242–1459\t\nCD3+CD4+ Th cells (%)\n(cells/mm3)\t40\n1476\t40.3 ± 7.27\n1314 ± 542\t23.2–59.5\n118–3245\t\nCD3+CD8+ Tc cells (%)\n(cells/mm3)\t28\n1033\t24.2 ± 5.48\n803 ± 417\t15.2–39\n108–2367\t\nCD3−CD1656+ NK cells (%)\n(cells/mm3)\t5\n185\t11.2 ± 4.85\n509 ± 295\t3.4–26.4\n143–1599\t\nCD3+HLA-DR+ active T cells (%)\n(cells/mm3)\t18\n664\t7.84 ± 3.7\n375 ± 235\t2.1–16.2\n22–954\n==== Refs\n1 Depner M. 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Inborn errors of human STAT1: allelic heterogeneity governs the diversity of immunological and infectious phenotypes Current Opinion in Immunology 2012 24 4 364 378 10.1016/j.coi.2012.04.011 2-s2.0-84865308028 22651901 \n13 Pichard D. C. Freeman A. F. Cowen E. W. Primary immunodeficiency update: Part II. Syndromes associated with mucocutaneous candidiasis and noninfectious cutaneous manifestations Journal of the American Academy of Dermatology 2015 73 3 367 381 2-s2.0-84939430185 10.1016/j.jaad.2015.01.055 26282795 \n14 Takezaki S. Yamada M. Kato M. Chronic mucocutaneous candidiasis caused by a gain-of-function mutation in the STAT1 DNA-binding domain The Journal of Immunology 2012 189 3 1521 1526 2-s2.0-84864126962 10.4049/jimmunol.1200926 22730530 \n15 Soltész B. Tóth B. Shabashova N. New and recurrent gain-of-function STAT1 mutations in patients with chronic mucocutaneous candidiasis from Eastern and Central Europe Journal of Medical Genetics 2013 50 9 567 578 10.1136/jmedgenet-2013-101570 2-s2.0-84883157575 23709754 \n16 Uzel G. Sampaio E. P. Lawrence M. G. Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like syndrome The Journal of Allergy and Clinical Immunology 2013 131 6 1611 1623 10.1016/j.jaci.2012.11.054 2-s2.0-84878556463 23534974 \n17 Sampaio E. P. Hsu A. P. Pechacek J. Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis The Journal of Allergy and Clinical Immunology 2013 131 6 1624 1634 10.1016/j.jaci.2013.01.052 2-s2.0-84878568160 23541320 \n18 Aldave J. C. Cachay E. Núñez L. A 1-year-old girl with a gain-of-function STAT1 mutation treated with hematopoietic stem cell transplantation Journal of Clinical Immunology 2013 33 8 1273 1275 2-s2.0-84889053021 10.1007/s10875-013-9947-5 24105462 \n19 Baris S. Alroqi F. Kiykim A. Severe Early-Onset Combined Immunodeficiency due to Heterozygous Gain-of-Function Mutations in STAT1 Journal of Clinical Immunology 2016 36 7 641 648 2-s2.0-84977138681 10.1007/s10875-016-0312-3 27379765 \n20 Kilic S. S. Puel A. Casanova J.-L. Orf Infection in a Patient with Stat1 Gain-of-Function Journal of Clinical Immunology 2015 35 1 80 83 2-s2.0-84943588600 10.1007/s10875-014-0111-7 25367169\n\n",
"fulltext_license": "CC BY",
"issn_linking": "2090-6617",
"issue": "2017()",
"journal": "Case reports in immunology",
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"title": "Gain-of-Function Mutations in STAT1: A Recently Defined Cause for Chronic Mucocutaneous Candidiasis Disease Mimicking Combined Immunodeficiencies.",
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"abstract": "Lung cancer is the leading cause of cancer-related death worldwide. Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. It is characterized by rapid tumor growth and early metastasis to multiple organs. Response to initial chemotherapy is generally good; however, the majority of patients develop recurrence and the prognosis of such patients is reportedly 2-4 months. Evolution of the treatment for SCLC has stagnated, and cisplatin + etoposide has been the standard chemotherapy for decades. Meanwhile, the combination of cisplatin + irinotecan has demonstrated equivalent efficacy to cisplatin + etoposide. Recently, maintenance chemotherapy has been extensively investigated in non-small-cell lung cancer (NSCLC), and is currently recommended as a standard treatment in clinical guidelines. On the contrary, a maintenance strategy has not been established for SCLC. Here, we describe an SCLC patient who received maintenance chemotherapy with irinotecan for more than 2 years after induction chemotherapy with cisplatin + irinotecan, and survived long term with no recurrence.",
"affiliations": "Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.;Division of Respiratory Medicine, Osakafu Saiseikai Noe Hospital, Osaka, Japan.;Division of Respiratory Medicine, Osakafu Saiseikai Noe Hospital, Osaka, Japan.;Division of Respiratory Medicine, Osakafu Saiseikai Noe Hospital, Osaka, Japan.;Division of Respiratory Medicine, Osakafu Saiseikai Noe Hospital, Osaka, Japan.;Division of Respiratory Medicine, Osakafu Saiseikai Noe Hospital, Osaka, Japan.;Division of Respiratory Medicine, Osakafu Saiseikai Noe Hospital, Osaka, Japan.;Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan.",
"authors": "Yagi|Yoshitaka|Y|;Kim|Young Hak|YH|;Tajima|Noriyuki|N|;Baba|Kiichiro|K|;Aihara|Kensaku|K|;Soo|Hong Hyun|HH|;Yamaoka|Shinpachi|S|;Mishima|Michiaki|M|",
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"fulltext": "\n==== Front\nCase Rep OncolCase Rep OncolCROCase Reports in Oncology1662-6575S. Karger AG Allschwilerstrasse 10, P.O. Box · Postfach · Case postale, CH–4009, Basel, Switzerland · Schweiz · Suisse, Phone: +41 61 306 11 11, Fax: +41 61 306 12 34, karger@karger.ch 10.1159/000356826cro-0006-0569Published online: November, 2013Long Survival of a Small-Cell Lung Cancer Patient Who Received Maintenance Chemotherapy with Irinotecan Yagi Yoshitaka aKim Young Hak b*Tajima Noriyuki bBaba Kiichiro bAihara Kensaku bSoo Hong Hyun bYamaoka Shinpachi bMishima Michiaki aaDepartment of Respiratory Medicine, Kyoto University Graduate School of Medicine, Kyoto, JapanbDivision of Respiratory Medicine, Osakafu Saiseikai Noe Hospital, Osaka, Japan*Young Hak Kim, MD, PhD, Department of Respiratory Medicine, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawaharacho, Sakyo-ku, Kyoto 606-8507 (Japan), E-Mail ekim@kuhp.kyoto-u.ac.jpSep-Dec 2013 14 11 2013 14 11 2013 6 3 569 573 Copyright © 2013 by S. Karger AG, Basel2013This is an Open Access article licensed under the terms of the Creative Commons Attribution-NonCommercial 3.0 Unported license (CC BY-NC) (www.karger.com/OA-license), applicable to the online version of the article only. Users may download, print and share this work on the Internet for noncommercial purposes only, provided the original work is properly cited, and a link to the original work on http://www.karger.com and the terms of this license are included in any shared versions.Lung cancer is the leading cause of cancer-related death worldwide. Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers. It is characterized by rapid tumor growth and early metastasis to multiple organs. Response to initial chemotherapy is generally good; however, the majority of patients develop recurrence and the prognosis of such patients is reportedly 2–4 months. Evolution of the treatment for SCLC has stagnated, and cisplatin + etoposide has been the standard chemotherapy for decades. Meanwhile, the combination of cisplatin + irinotecan has demonstrated equivalent efficacy to cisplatin + etoposide. Recently, maintenance chemotherapy has been extensively investigated in non-small-cell lung cancer (NSCLC), and is currently recommended as a standard treatment in clinical guidelines. On the contrary, a maintenance strategy has not been established for SCLC. Here, we describe an SCLC patient who received maintenance chemotherapy with irinotecan for more than 2 years after induction chemotherapy with cisplatin + irinotecan, and survived long term with no recurrence.\n\nKey Words\nSmall-cell lung cancerIrinotecanMaintenanceLong survivorExtensive disease\n==== Body\nIntroduction\nLung cancer is the leading cause of cancer-related death worldwide [1]. Small-cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers [2], and it is characterized by rapid tumor growth and early metastasis to multiple organs. Response to initial chemotherapy is generally good; however, the majority of patients develop recurrence and the prognosis of such patients remains poor [3]. Recently, a strategy of maintenance chemotherapy has been established for non-small-cell lung cancer (NSCLC) and is currently recommended as a standard treatment in clinical guidelines [4, 5]; however, cumulative data have indicated that this maintenance strategy is not effective for SCLC.\n\nCase Report\nA 58-year-old Japanese man was referred to our hospital due to a dry cough continuing for over 3 weeks. He was a former smoker with a 45 pack-year history. Chest X-ray showed left pleural effusion and consolidation in the left hilum. Computed tomography (CT) of the chest revealed left pleural effusion and a large tumor of about 120 mm invading the aorta and main pulmonary artery directly (fig. 1). He was diagnosed with SCLC based on pleural effusion cytology. The serum concentration of neuron-specific enolase had increased to 24.8 ng/ml, and pro-gastrin-releasing peptide had also increased to 987.5 pg/ml. Abdominal CT, whole-body bone scintigraphy and brain magnetic resonance imaging did not reveal any distant metastasis. Therefore, the clinical stage of his disease was determined as T4N2M1a, stage IV. Four cycles of chemotherapy, consisting of cisplatin and irinotecan, were performed and a partial response was achieved (fig. 2). Neuron-specific enolase and pro-gastrin-releasing peptide levels decreased to the normal range. Toxicity was quite mild and the patient had a strong wish to continue chemotherapy. Therefore, we started maintenance chemotherapy with irinotecan after the initial treatment. The patient underwent 24 cycles of maintenance treatment with irinotecan without marked toxicity. Subsequently, 2 years and 6 months after the initial diagnosis, 18F-fluorodeoxyglucose positron emission tomography showed no positive sign of disease; the main tumor, lymph nodes, and pleural effusion had completely disappeared and the response was defined as a complete response (fig. 3). Based on these results, we decided to withdraw chemotherapy. Currently (3 years since the initial diagnosis), disease relapse has not been documented and the patient is still alive without any complaints.\n\nDiscussion\nRecent meta-analyses have shown that thoracic radiotherapy with concurrent chemotherapy resulted in a 5-year survival rate of 20–30% in patients with limited disease; however, long-term survivors with extensive disease are extremely rare [6]. Consequently, the majority of SCLC patients inevitably develop recurrence. Currently, topotecan is the only drug approved by the US Food and Drug Administration for relapsed SCLC, and is considered the standard second-line chemotherapy in many countries [7]. More recently, amrubicin has also shown promising antitumor activity in this setting [8, 9]; however, the prognosis of such patients remains dismal. Although maintenance chemotherapy has been extensively investigated for NSCLC and is currently recommended as a standard treatment in clinical guidelines [4, 5], the strategy has not been established for SCLC. However, previous studies tested only old agents, and newer agents such as irinotecan and amrubicin have not been investigated in the maintenance setting. Considering that the maintenance strategy succeeded in NSCLC using newer agents, such as pemetrexed and erlotinib, which are more effective and less toxic than older agents, newer agents for SCLC, such as irinotecan, topotecan, and amrubicin, should also be investigated in the maintenance setting for SCLC. To our knowledge, only one study has investigated the efficacy of irinotecan as maintenance chemotherapy in SCLC [10]. Although the results of the study were negative, our successful case indicates that maintenance strategy may merit further investigation for patients with SCLC.\n\nDisclosure Statement\nNo author has a financial relationship with a commercial entity that has an interest in the topic of this paper.\n\nFig. 1 A large tumor located in the mediastinum with accompanying left pleural effusion is shown. The tumor is about 120 mm in diameter and invades the main pulmonary artery and aorta. a Chest X-ray. b Enhanced CT.\n\nFig. 2 Enhanced CT showing a markedly reduced tumor and pleural effusion after four cycles of induction chemotherapy.\n\nFig. 3 18F-fluorodeoxyglucose positron emission tomography showing complete response after 24 cycles of maintenance chemotherapy with irinotecan.\n==== Refs\nReferences\n1 Jemal A Bray F Center MM Ferlay J Ward E Forman D Global cancer statistics CA Cancer J Clin 2011 61 69 90 21296855 \n2 Field JK Duffy SW Lung cancer screening: the way forward Br J Cancer 2008 99 557 562 18665179 \n3 Lally BE Urbanic JJ Blackstock AW Miller AA Perry MC Small cell lung cancer: have we made any progress over the last 25 years? Oncologist 2007 12 1096 1104 17914079 \n4 Azzoli CG Temin S Aliff T Baker S Jr Brahmer J Johnson DH Laskin JL Masters G Milton D Nordquist L Pao W Pfister DG Piantadosi S Schiller JH Smith R Smith TJ Strawn JR Trent D Giaccone G American Society of Clinical Oncology 2011 Focused Update of 2009 American Society of Clinical Oncology Clinical Practice Guideline Update on Chemotherapy for Stage IV Non-Small-Cell Lung Cancer J Clin Oncol 2011 29 3825 3831 21900105 \n5 Peters S Adjei AA Gridelli C Reck M Kerr K Felip E ESMO Guidelines Working Group Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2012 23 suppl 7 vii56 vii64 22997455 \n6 Sørensen M Pijls-Johannesma M Felip E ESMO Guidelines Working Group Small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann Oncol 2010 21 suppl v120 v125 20555060 \n7 von Pawel J Schiller JH Shepherd FA Fields SZ Kleisbauer JP Chrysson NG Stewart DJ Clark PI Palmer MC Depierre A Carmichael J Krebs JB Ross G Lane SR Gralla R Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer J Clin Oncol 1999 17 658 667 10080612 \n8 Inoue A Sugawara S Yamazaki K Maemondo M Suzuki T Gomi K Takanashi S Inoue C Inage M Yokouchi H Watanabe H Tsukamoto T Saijo Y Ishimoto O Hommura F Nukiwa T Randomized phase II trial comparing amrubicin with topotecan in patients with previously treated small-cell lung cancer: North Japan Lung Cancer Study Group Trial 0402 J Clin Oncol 2008 26 5401 5406 18854562 \n9 Jotte R Conkling P Reynolds C Galsky MD Klein L Fitzgibbons JF McNally R Renschler MF Oliver JW Randomized phase II trial of single-agent amrubicin or topotecan as second-line treatment in patients with small-cell lung cancer sensitive to first-line platinum-based chemotherapy J Clin Oncol 2011 29 287 293 21135284 \n10 Han JY Kim HT Lim KY Yoon SJ Lee DH Lee JS Randomized phase II study of maintenance irinotecan therapy versus observation following induction chemotherapy with irinotecan and cisplatin in extensive disease small cell lung cancer J Thorac Oncol 2008 3 1039 1045 18758308\n\n",
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"issue": "6(3)",
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"keywords": "Extensive disease; Irinotecan; Long survivor; Maintenance; Small-cell lung cancer",
"medline_ta": "Case Rep Oncol",
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"title": "Long survival of a small-cell lung cancer patient who received maintenance chemotherapy with irinotecan.",
"title_normalized": "long survival of a small cell lung cancer patient who received maintenance chemotherapy with irinotecan"
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"abstract": "We report a case of mantle cell lymphoma mimicking Castleman disease. A 76-year-old man presented with generalized lymphadenopathy, splenomegaly, anemia, polyclonal gammopathy, and pulmonary infiltrations. Lymph node biopsy revealed histological features of hyaline vascular Castleman disease. Treatment with prednisolone induced lymphocytosis with immunophenotypic and genetic features of mantle cell lymphoma. A detailed immunohistochemical study of the lymph node demonstrated a mantle cell lymphoma-mantle zone growth pattern. Glucocorticoid-induced distribution lymphocytosis has not been reported in mantle cell lymphoma. Careful observation of circulating lymphocytes during steroid treatment may enable diagnosis of the underlying occult lymphoma in a subset of patients exhibiting clinical manifestations of Castleman disease.",
"affiliations": "Department of Hematology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.;Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.;Department of Laboratory Medicine, Kochi Medical School Hospital, Nankoku, Kochi, Japan.;Department of Hematology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.;Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.;Department of Hematology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan.",
"authors": "Togitani|Kazuto|K|;Iguchi|Mitsuko|M|;Asagiri|Tadashi|T|;Ogasawara|Fumiya|F|;Murakami|Ichiro|I|;Kojima|Kensuke|K|",
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"doi": "10.3960/jslrt.21024",
"fulltext": "\n==== Front\nJ Clin Exp Hematop\nJ Clin Exp Hematop\njslrt\nJournal of Clinical and Experimental Hematopathology : JCEH\n1346-4280\n1880-9952\nJSLRT\n\n34707036\n21024\n10.3960/jslrt.21024\nCase Report\nGlucocorticoid-induced redistribution lymphocytosis in mantle cell lymphoma with hyaline vascular Castleman disease-like features\nTogitani Kazuto 1\nIguchi Mitsuko 2\nAsagiri Tadashi 3\nOgasawara Fumiya 1\nMurakami Ichiro 2\nKojima Kensuke 1\n1)Department of Hematology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan, 2)Department of Pathology, Kochi Medical School, Kochi University, Nankoku, Kochi, Japan, 3)Department of Laboratory Medicine, Kochi Medical School Hospital, Nankoku, Kochi, Japan\nCorresponding author: Kazuto Togitani, M.D., Department of Hematology, Kochi Medical School, Kochi University, Nankoku, Kochi 783–8505, Japan. E-mail: togitani@kochi-u.ac.jp\n26 10 2021\n3 2022\n62 1 4651\n15 6 2021\n20 8 2021\n07 9 2021\n© 2021 by The Japanese Society for Lymphoreticular Tissue Research\n2021\nThe Japanese Society for Lymphoreticular Tissue Research\nhttps://creativecommons.org/licenses/by-nc-sa/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution ShareAlike (CC BY-NC-SA) 4.0 License.\nWe report a case of mantle cell lymphoma mimicking Castleman disease. A 76-year-old man presented with generalized lymphadenopathy, splenomegaly, anemia, polyclonal gammopathy, and pulmonary infiltrations. Lymph node biopsy revealed histological features of hyaline vascular Castleman disease. Treatment with prednisolone induced lymphocytosis with immunophenotypic and genetic features of mantle cell lymphoma. A detailed immunohistochemical study of the lymph node demonstrated a mantle cell lymphoma-mantle zone growth pattern. Glucocorticoid-induced distribution lymphocytosis has not been reported in mantle cell lymphoma. Careful observation of circulating lymphocytes during steroid treatment may enable diagnosis of the underlying occult lymphoma in a subset of patients exhibiting clinical manifestations of Castleman disease.\n\nKeywords:\n\nmantle cell lymphoma\nhyaline vascular Castleman disease\nredistribution lymphocytosis\nglucocorticoid\n==== Body\npmcINTRODUCTION\n\nMantle cell lymphoma (MCL) is a distinct type of B-cell lymphoma genetically characterized by balanced t(11;14) (q13; q32) translocation involving the CCND1 gene at 11q13 and immunoglobulin heavy chain (IGH) gene at 14q32.1 MCL is histologically subclassified into diffuse, nodular, and mantle zone growth patterns.2 The diffuse pattern is the most frequent (~ 80%), followed by the nodular growth pattern (~ 18%), and much less frequently, the mantle zone growth pattern (MZGP) (< 2%).3 In MCL-MZGP, lymph node architecture is preserved, as seen in in situ mantle cell neoplasia (ISMCN), a condition formerly known as in situ MCL.4 Patients with ISMCN do not require treatment in the absence of coexisting overt MCL, and as the clinical impact of the diagnosis is unclear, close follow-up is recommended. As routine staining for cyclin D1 is not usually applied to reactive-appearing lymph nodes, MCL-MZGP and ISMCN represent a diagnostic challenge.5 Castleman disease (CD), also known as angiofollicular lymph node hyperplasia, is a heterogeneous group of lymphoproliferative disorders.6 Multicentric CD is characterized by generalized lymphadenopathy, hepatosplenomegaly, cytopenia, and organ dysfunction in association with increased levels of interleukin (IL)-6 and other pro-inflammatory cytokines.7 Onion skin pattern mantle zone hyperplasia is a histological feature of hyaline vascular CD, which is reminiscent of MCL-MZGP.5 Redistribution lymphocytosis, a condition in which rapid lymph node shrinkage occurs with an increased number of peripheral blood lymphocytes, is now widely recognized as an on-target effect of the Bruton tyrosine kinase inhibitor ibrutinib in MCL and chronic lymphocytic leukemia. Before its recognition, redistribution lymphocytosis was sporadically reported in patients with CLL receiving glucocorticoids as a single agent.8\n\nWe report a case of MCL-MZGP in which glucocorticoid-induced redistribution lymphocytosis helped establish a diagnosis of MCL in a patient presenting with hyaline vascular CD-like features. Glucocorticoid-induced redistribution of lymphocytosis has not been previously reported in MCL. Our case suggests that careful observation of circulating lymphocytes during steroid treatment enables the diagnosis of the underlying occult lymphoma in a subset of patients exhibiting clinical manifestations of CD.\n\nCASE REPORT\n\nA 76-year-old man with diabetes mellitus was referred to our hospital because of generalized lymphadenopathy and abnormal findings on chest imaging. He reported mild non-productive cough, but was otherwise asymptomatic. Chest radiography revealed bilateral infiltrative opacities (Fig. 1a). Computed tomography (CT) demonstrated airspace consolidation with air bronchogram in the right upper lung lobe, systemic lymphadenopathy, and splenomegaly (Fig. 1b-d). His hemoglobin level was 11.5 g/dL, white blood cell count was 3200/µL with 10% segmented neutrophils, 4% eosinophils, 1% basophils, 26% monocytes, and 59% lymphocytes, and platelet count was 18.7×104 /µL. The serum lactate dehydrogenase level was within the normal range (112 U/L, normal: 124–222 IU/L). Increased serum levels of creatinine (3.45 mg/dL, normal: 0.65–1.07 mg/dL), C-reactive protein (6.08 mg/dL, normal: <0.14 mg/dL), and IL-6 (49.1 pg/mL, normal: ≤ 4.0 pg/mL), and polyclonal hypergammaglobulinemia (IgG, 4623 mg/dL, normal: 861–1747 mg/dL; IgA, 787 mg/dL, normal: 93–393 mg/dL; IgM, 214 mg/dL, normal: 33–183 mg/dL) were observed. Immunofixation electrophoresis did not detect monoclonal proteins in serum or urine. The serum levels of lung cancer markers, including pro-gastrin-releasing peptide, cytokeratin 19 fragment, and carcinoembryonic antigen, were all within the normal range. The serum level of soluble IL-2 receptor increased to 5398 U/mL (normal: 157–475 U/mL). Both human immunodeficiency virus antibody and anti-nuclear antibody tests were negative. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) revealed a modest uptake in the neck, mediastinal, paraaortic, pelvic, and inguinal lymph nodes and spleen, with high maximum standardized uptake (SUVmax) values of 3–5 and higher uptake in lung consolidations of 7.3–7.6 (Fig. 1e). The patient declined bronchoscopy with transbronchial biopsy. Biopsy of the right inguinal lymph node revealed an increased number of follicles with inconspicuous germinal centers and slightly expanded mantle zones (Fig. 2a). Hyalinized blood vessels penetrating into germinal centers were observed (Fig. 2b). Immunohistochemistry did not detect latent nuclear antigen-1 of human herpesvirus 8 or immunoglobulin light chain restriction.\n\nFig. 1 (a) Chest X-ray showing bilateral air space consolidation opacities (arrows). (b-d) Initial computed tomography showing right lung consolidations, systemic lymphadenopathy, and splenomegaly. (e) 18F-fluorodeoxyglucose positron emission tomogram showing a modest uptake in neck, mediastinal, paraaortic, pelvic, and inguinal lymph nodes and spleen, with high maximum standardized uptake values of 3–5 and higher uptake in lung consolidations of 7.3–7.6. (f-h) Computed tomography one month after the introduction of prednisolone and during lymphocytosis showing shrinkage of the lung lesions and enlarged lymph nodes and spleen.\n\nFig. 2 (a-b) Biopsy of the right inguinal lymph node showing an increased number of follicles with inconspicuous germinal centers and slightly expanded mantle zones (a), and hyalinized blood vessels penetrating into germinal centers (b). (c) Peripheral blood smear during prednisolone treatment showing medium-sized lymphoid cells with clumped chromatin and nuclear clefts (May-Giemsa staining, ×1000). (d-e) Immunohistochemical study showing cyclin D1- (d) and SOX11-expressing (e) mantle zone cells.\n\nHe was tentatively diagnosed with hyaline vascular CD and received daily oral prednisolone at 1 mg/kg. One week later, an abrupt increase in circulating lymphocytes, reaching 7100/µL, was observed (Fig. 2c, Fig. 3). Rapid shrinkage of the lung lesions (92% reduction in sum of the product of the perpendicular diameters (SPD)), enlarged lymph nodes (38% reduction in SPD), and spleen (55% reduction in splenic volume) was observed on CT (Fig. 1f-h). Flow cytometric (FCM) analysis revealed that the lymphocytes were positive for CD5, CD19, CD20, CD22, CD79a, and cytoplasmic kappa light chain, and negative for CD23 and CD200. Interphase fluorescence in situ hybridization analysis revealed a CCND1-IGH gene fusion signal characteristic of t(11;14) in 66% of peripheral blood mononuclear cells. A detailed immunohistochemical study of the lymph node specimen revealed that mantle zone cells exclusively expressed cyclin D1 (Fig. 2d) and SOX11 (Fig. 2e). Identical monoclonal IGH gene rearrangements in peripheral blood and lymph node cells were found in polymerase chain reaction (PCR)-amplified fragments using IGH gene consensus primer sets (FR1, FR2, and FR3-JH) (Fig. 4).9 A diagnosis of MCL-MZGP with glucocorticoid-induced redistribution lymphocytosis was made. The patient received VR-CAP (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisolone) chemoimmunotherapy,10 which resulted in complete remission.\n\nFig. 3 Changes in white blood cells (WBC) and abnormal lymphocytes during prednisolone treatment and chemotherapy (bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisolone: VR-CAP).\n\nFig. 4 Detection of monoclonal immunoglobulin heavy chain gene rearrangement in peripheral blood cells during lymphocytosis, and the affected lymph node specimen using the FR1-JH, FR2-JH, and FR3-JH consensus primer sets (arrows). The expected polymerase chain reaction product sizes for FR1-JH, FR2-JH, and FR3-JH in normal control are 310-360 base pairs (bp), 250-295 bp, and 100-170 bp, respectively.\n\nDISCUSSION\n\nWe reported a case of mantle cell lymphoma initially diagnosed as CD. CD is characterized by systemic inflammatory symptoms, polyclonal lymphoproliferation, hypergammaglobulinemia, cytopenia, and multiple organ system dysfunction. Although a high IL-6 level is indicative of CD, it is not CD-specific and has been described in a wide range of inflammatory and malignant disorders. As CD is an exclusion diagnosis, histopathology of affected lymph nodes is essential to establish the diagnosis.7 In a recent histopathological validation study of CD diagnosed at a single institute over a period of 20 years, 2 of 273 (0.7%) lymph node specimens from CD patients exhibited histological features of non-Hodgkin’s lymphoma (NHL).11 In that study, SUVmax values of affected lymph nodes in FDG-PET helped differentiate lymphoma lesions from those of CD. The median SUVmax value was as low as 4.5 and higher SUVmax values were associated with lymphoma. SUVmax values ranged from 3 to 5 in our case, emphasizing the difficulty in determining the underlying lymphoma.\n\nThere have been seven reported cases of MCL presenting with CD-like features, including ours (Table 1).12-15 Histological subtypes were available in six cases: MZGP (n=5) or ISMCN (n=1). There were no cases of diffuse or nodular MCL subtypes. As normal lymph node architecture is preserved in MZGP and ISMCN, immunohistochemical staining of cyclin D1 and immunoglobulin light chains may improve the diagnostic accuracy for MCL with CD-like features. Considering the localized proliferation of lymphoma cells exclusively in the mantle zone in MZGP and ISMCN, flow cytometric analysis of whole lymph node cells may have limited efficacy. In our case, the kappa/lambda light chain ratio in cells from the affected lymph node was 4.2, probably due to background normal B-cells (Table 1). The normal kappa/lambda ratio was described in a previously reported case (case 1).\n\nTable 1 Summary of mantle cell lymphoma with Castleman disease-like features.\n\nCase no.\tAge/Sex\tCD histology\tMCL histology\tSOX11\tImmunoglobulin light chains\tTreatment\tFollow-up (months)\tReference\t\n1\t51/M\tPC\tMZGP\t+\tκ chain: 14.2%, λ chain: 19.4%\tH-CVAD/MA\tNA\tIgawa T, 201712\t\n2\t81/M\tPC\tMZGP\t+\tκ chain: 75.7%, λ chain: 3.5%\tR-THP-COP+BR\tAlive (8)\tIgawa T, 201712\t\n3\t74/M\tPC\tMZGP\t+\tκ chain: 81.5%, λ chain: 13.1%\tNA\tNA\tIgawa T, 201712\t\n4\t81/M\tNA\tNA\tNA\tNA\tRX\tDOD (21)\tYatabe Y, 200113\t\n5\t31/F\tHV\tISMCN\tNA\tNA\tNone\tAlive (8)\tDobrea C, 201114\t\n6\t70/M\tHV\tMZGP\tNA\tκ light chain+\tNone\tNA\tSiddiqi IN, 201115\t\n7\t76/M\tHV\tMZGP\t+\tκ chain: 68.8%, λ chain: 16.5%\tPSL, VR-CAP\tAlive (8)\tPresent Case\t\nAbbreviations: BR, bendamustine plus rituximab; CD, Castleman’s disease; DOD, died of disease; F, female; H-CVAD/HD-MTX+AraC, hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone combined with high-dose methotrexate and cytarabine; HV, hyaline vascular; ISMCN, in situ mantle cell neoplasma; M, male; MZGP, mantle zone growth pattern; NA, not available; ND, not determined; PC, plasma cells; R-THPCOP, rituximab, pirarubicin (tetrahydropyranyl adriamycin [THP]), cyclophosphamide, vincristine, and predonisolone; RX, radiation.\n\nIn our case, prednisolone treatment triggered MCL cell release from the node lesions into the circulation. Circulating MCL cells were not morphologically detected before treatment. We hypothesize that glucocorticoid-induced redistribution lymphocytosis occurs through the inactivation of important MCL homing mediators, including adhesion molecules and chemokine receptors,8,16-20 thereby interfering with lymphoma-stroma interaction in the tumor microenvironment. In either case, CD-related increases in IL-6 and other pro-inflammatory cytokines may sensitize MCL to glucocorticoid-induced redistribution. Of note, activated NF-kB signaling, which is observed in MCL cells, has been reported to be actively involved in IL-6 overproduction in CD.21\n\nACKNOWLEDGMENTS\n\nWe thank Drs. Takuro Igawa and Tadashi Yoshino from the Department of Pathology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Science for the pathological review and professional comments.\n\nCOMPLIANCE WITH ETHICAL STANDARDS\n\nWritten informed consent was received from the patient for publication.\n\nCONFLICT OF INTEREST\n\nKensuke Kojima received scientific grants from Daiichi-Sankyo, Kyowa-Kirin, Ono Pharmaceutical, and honoraria from Janssen.\n==== Refs\nREFERENCES\n\n1 Maddocks K. Update on mantle cell lymphoma. Blood. 2018; 132 : 1647-1656.30154113\n2 Swerdlow SH, Campo E, Harris NL, et al., eds. WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues. Lyon, IARC Press. 2016.\n3 Tiemann M, Schrader C, Klapper W, et al. Histopathology, cell proliferation indices and clinical outcome in 304 patients with mantle cell lymphoma (MCL): a clinicopathological study from the European MCL Network. Br J Haematol. 2005; 131 : 29-38.16173960\n4 Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016; 127 : 2375-2390.26980727\n5 Yuan J, Li S, Liu X, et al. Mantle cell lymphoma with mantle zone growth pattern. Am J Clin Pathol. 2019; 152 : 132-145.31140550\n6 Fajgenbaum DC, Uldrick TS, Bagg A, et al. International, evidence-based consensus diagnostic criteria for HHV-8–negative/idiopathic multicentric Castleman disease. Blood. 2017; 129 : 1646-1657.28087540\n7 Dispenzieri A, Fajgenbaum DC. Overview of Castleman disease. Blood. 2020; 135 : 1353-1364.32106302\n8 Burger JA, Montserrat E. Coming full circle: 70 years of chronic lymphocytic leukemia cell redistribution, from glucocorticoids to inhibitors of B-cell receptor signaling. Blood. 2013; 121 : 1501-1509.23264597\n9 van Dongen JJM, Langerak AW, Brüggemann M, et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936. Leukemia. 2003; 17 : 2257-2317.14671650\n10 Robak T, Jin J, Pylypenko H, et al. Frontline bortezomib, rituximab, cyclophosphamide, doxorubicin, and prednisone (VR-CAP) versus rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) in transplantation-ineligible patients with newly diagnosed mantle cell lymphoma: final overall survival results of a randomised, open-label, phase 3 study. Lancet Oncol. 2018; 19 : 1449-1458.30348538\n11 Oksenhendler E, Boutboul D, Fajgenbaum D, et al. The full spectrum of Castleman disease: 273 patients studied over 20 years. Br J Haematol. 2018; 180 : 206-216.29143319\n12 Igawa T, Omote R, Sato H, et al. A possible new morphological variant of mantle cell lymphoma with plasma-cell type Castleman disease-like features. Pathol Res Pract. 2017; 213 : 1378-1383.28974340\n13 Yatabe Y, Suzuki R, Matsuno Y, et al. Morphological spectrum of cyclin D1-positive mantle cell lymphoma: study of 168 cases. Pathol Int. 2001; 51 : 747-761.11881727\n14 Dobrea C, Mihai M, Dănăilă E, et al. “In situ” mantle cell lymphoma associated with hyaline-vascular Castleman disease. Rom J Morphol Embryol. 2011; 52 : 1147-1151.22119840\n15 Siddiqi IN, Brynes RK, Wang E. B-cell lymphoma with hyaline vascular Castleman disease-like features: a clinicopathologic study. Am J Clin Pathol. 2011; 135 : 901-914.21571963\n16 Wu W, Wang W, Franzen CA, et al. Inhibition of B-cell receptor signaling disrupts cell adhesion in mantle cell lymphoma via RAC2. Blood Adv. 2021; 5 : 185-197.33570628\n17 Rudelius M, Rosenfeldt MT, Leich E, et al. Inhibition of focal adhesion kinase overcomes resistance of mantle cell lymphoma to ibrutinib in the bone marrow microenvironment. Haematologica. 2018; 103 : 116-125.29079592\n18 Kurtova AV, Tamayo AT, Ford RJ, Burger JA. Mantle cell lymphoma cells express high levels of CXCR4, CXCR5, and VLA-4 (CD49d): importance for interactions with the stromal microenvironment and specific targeting. Blood. 2009; 113 : 4604-4613.19228923\n19 Smoak KA, Cidlowski JA. Mechanisms of glucocorticoid receptor signaling during inflammation. Mech Ageing Dev. 2004; 125 : 697-706.15541765\n20 Bouazzaoui A, Spacenko E, Mueller G, et al. Steroid treatment alters adhesion molecule and chemokine expression in experimental acute graft-vs.-host disease of the intestinal tract. Exp Hematol. 2011; 39 : 238-249.21108989\n21 Fajgenbaum DC. Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease. Blood. 2018; 132 : 2323-2330.30487129\n\n",
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"abstract": "Patients with adenomatous polyposis, usually defined as patients with >10 adenomatous polyps in the colorectum, are at increased risk for colorectal cancer (CRC). Since surgical and endoscopic treatment do not completely eliminate the potential for future polyps or extraintestinal neoplasms, there is an unmet medical need to identify pharmacological agents to delay major surgical interventions. We present two cases of patients with adenomatous polyposis who developed chronic myelogenous leukaemia and were treated with imatinib as part of their chemotherapy. A sustained regression of the colonic polyps documented in both cases was observed after the initiation of the tyrosine kinase inhibitor. Despite the presence of potential confounders, we hypothesise the potential role of imatinib as a chemopreventive agent in patients with familial adenomatous polyposis.",
"affiliations": "Internal Medicine Department, Fundación Valle de Lili, ICESI University, Cali, Colombia.;Department of Gastroenterology, Hospital Clínic de Barcelona, Centro de Investigación Biomédica de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Department of Gastroenterology, Hospital Clínic de Barcelona, Centro de Investigación Biomédica de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Department of Gastroenterology, Hospital Clínic de Barcelona, Centro de Investigación Biomédica de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain.;Department of Gastroenterology, Hospital Clínic de Barcelona, Centro de Investigación Biomédica de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain FPRUNES@clinic.cat.",
"authors": "Tobon|Angelica|A|0000-0002-3341-9962;Olivas|Pol|P|;Ocaña|Teresa|T|;Pellisé|María|M|;Balaguer|Francesc|F|",
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"fulltext": "\n==== Front\nBMJ Open Gastroenterol\nBMJ Open Gastroenterol\nbmjgast\nbmjgast\nBMJ Open Gastroenterology\n2054-4774\nBMJ Publishing Group BMA House, Tavistock Square, London, WC1H 9JR\n\n33376108\nbmjgast-2020-000555\n10.1136/bmjgast-2020-000555\nColorectal Cancer\n1506\nImatinib: a new chemopreventive option in adenomatous polyposis?\nhttp://orcid.org/0000-0002-3341-9962\nTobon Angelica 1\nOlivas Pol 2\nOcaña Teresa 2\nPellisé María 2\nBalaguer Francesc 2\n1 Internal Medicine Department, Fundación Valle de Lili, ICESI University, Cali, Colombia\n2 Department of Gastroenterology, Hospital Clínic de Barcelona, Centro de Investigación Biomédica de Enfermedades Hepáticas y Digestivas (CIBEREHD), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain\nCorrespondence to Dr Francesc Balaguer; FPRUNES@clinic.cat\n2020\n29 12 2020\n7 1 e00055514 10 2020\n04 12 2020\n06 12 2020\n© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.\n2020\nhttp://creativecommons.org/licenses/by-nc/4.0/ This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.\n\nPatients with adenomatous polyposis, usually defined as patients with >10 adenomatous polyps in the colorectum, are at increased risk for colorectal cancer (CRC). Since surgical and endoscopic treatment do not completely eliminate the potential for future polyps or extraintestinal neoplasms, there is an unmet medical need to identify pharmacological agents to delay major surgical interventions. We present two cases of patients with adenomatous polyposis who developed chronic myelogenous leukaemia and were treated with imatinib as part of their chemotherapy. A sustained regression of the colonic polyps documented in both cases was observed after the initiation of the tyrosine kinase inhibitor. Despite the presence of potential confounders, we hypothesise the potential role of imatinib as a chemopreventive agent in patients with familial adenomatous polyposis.\n\nfamilial adenomatous polyposis\ncolorectal cancer\nchemoprevention\ncancer prevention\nspecial-featureunlocked\n==== Body\nIntroduction\n\nPatients with adenomatous polyposis, usually defined as patients with >10 adenomatous polyps in the colorectum, are at increased risk for colorectal cancer (CRC). Familial adenomatous polyposis (FAP) is an autosomal dominant inherited disorder caused by mutations in the APC or MUTYH genes and characterised by the progressive development of multiple adenomas throughout the colon and rectum.1 2 In a meaningful proportion of patients, adenomatous polyposis is not associated to a germline mutation. In FAP, regular colonoscopy surveillance is recommended until colectomy is planned. However, there are many potential complications associated with surgery, and it does not prevent from lower gastrointestinal surveillance in patient with retained rectum of ileal pouch. Accordingly, in this group of patients, it is essential to develop strategies for the prevention of both adenoma and CRC development. Chemoprevention refers to a pharmacological intervention to stop or reverse the process of carcinogenesis. As chemoprevention is intended to be taken for long periods, it must meet certain requirements such as low or no toxicity, ease of administration and cost-effectiveness.3 Whereas multiple pharmacological agents (ie, sulindac, COX-2 inhibitors) have been tested for this purpose, chemoprevention is not yet currently the standard of care in FAP.4 5\n\nHere, we describe two clinical cases of patients with adenomatous polyposis in whom imatinib, a tyrosine kinase inhibitor, was administered as part of their treatment for a haematological entity (chronic myelogenous leukaemia, CML). Despite the presence of potential confounders, we believe the present observations deserve more investigation about the potential role of imatinib as a chemopreventive agent.\n\nCase 1\n\nThe first case is a 69-year-old man with a history of heart transplant in 2001 due to an ischaemic cardiomyopathy (current treatment cyclosporine 75 mg/day, azathioprine 50 mg/day and acetylsalicylic acid (ASA) 100 mg/day), radical cystectomy due to urothelial tumour managed with Bricker-type urethro-ileostomy in 2009, chronic kidney disease on haemodialysis since 2015 and diagnosis of Philadelphia-positive (BCR-ABL fusion transcript) CML in 2011. Patient was treated with imatinib 300 mg/day from 2011 to 2015, discontinued due to chronic kidney disease, starting dasatinib (a highly potent inhibitor of BCR-ABL) 50 mg/day in 2015. The patient participated in the CRC population screening programme in 2016, and presented a positive faecal immunochemical test. He underwent screening colonoscopy on July 2016 with poor preparation finding 50 polyps throughout the colon that were classified as Paris 0-Is and 0-IIa (sizes 6–12 mm) (figure 1A). The examination could reach only the hepatic flexure. Due to the incompleteness of the procedure and poor prep, only four polyps were resected in the rectum, with the pathology report showing tubular-villous adenomas with low-grade dysplasia. The patient had a family history of CRC (two maternal granduncles at age of 76 years, a granduncle and a maternal cousin over 60 years). A germline genetic analysis was performed which was negative for MUTYH and APC mutations. Due to comorbidities, in agreement with the patient, neither treatment nor surveillance was indicated. Regarding CML treatment, in 2017 dasatinib was suspended due to associated pulmonary complication (pleural effusion and pulmonary fibrosis), and imatinib was restarted in the beginning of 2018, initially at 400 mg/day with gradual reduction to 200 mg as a result of associated infectious complications. At the end of 2018, he presented abdominal pain and change in bowel habit with diarrhoea. Drug and infectious aetiology were ruled out and a colonoscopy study was repeated, this time reaching the cecum with adequate preparation. Diverticula were identified at sigmoid colon and a single 5 mm sessile polyp in the rectum was identified managed with cold snare polypectomy (figure 1B, C). The pathology report showed a tubular adenoma with low-grade dysplasia.\n\nFigure 1 Case 1. (A) Colonoscopy before the administration of imatinib, a 10 mm sessile polyp is shown. (B) and (C) Descending colon explored with LCI (linked colour imaging; FUJIFILM) after the administration of imatinib for 1 year.\n\nCase 2\n\nA 33-year-old man with an APC pathogenic germline variant started surveillance in our centre in 2014. Colonoscopy showed 100 adenomas <10 mm throughout that colon, with rectal sparing (figure 2A). The patient participated in the randomised clinical trial CPP-FAP-310 (NCT01483144) aimed at determining if the combination of eflornithine plus sulindac was superior to sulindac or eflornithine as single agents in delaying time to any FAP-related event.6 He initiated the trial medication (eflornithine alone) in October 2014. Surveillance colonoscopy in November 2015 evidenced 10–12 polyps of 1–3 mm in the ascending colon, with no polyps in the rest of the study. The trial was extended until January 2017, when eflornithine was suspended due to diagnosis of Philadelphia-positive (BCR-ABL) CML. The patient began treatment with imatinib at a dose of 400 mg/day, with adequate tolerance and clinical response to treatment. Surveillance colonoscopy in September 2017 showed no evidence of lesions in the colon. Later in September 2020, an endoscopic control was performed and only around 10 polyps <3 mm in the recto-sigmoid were observed (figure 2B).\n\nFigure 2 Case 2. (A) Colonoscopy with chromoendoscopy with indigo carmine showing several sessile polyps 1–3 mm in size in the descending colon. (B) Transverse colon after the administration of imatinib for 30 months without polyps.\n\nDiscussion\n\nImatinib is a derivative of 2-phenylaminopyrimidine, a potent inhibitor directed against protein tyrosine kinases, including BCR-ABL, c-kit and the platelet-derived growth factor receptor (PDGF-R).7 In CML, the drug appears to work primarily by occupying the ATP binding site of the BCR-ABL oncoprotein and, therefore, prevents phosphorylation of the substrate and interrupts contact with the effector protein, resulting in the nullification of the enzymatic function of the BCR-ABL oncoprotein.8 Although its mechanism of action is not directly involved in preventing the development of cancer precursor lesions in the colon, we describe two cases in which regression of the polyps is observed after administration.\n\nThe precise potential mechanism of imatinib in the colorectal carcinogenesis remains poorly understood. To date, it is known that EphB tyrosine kinase receptors regulate the positioning and promote the proliferation of intestinal stem and progenitor cells.9 10 In tumour growth, these receptors play dual roles, acting as tumour promoters during adenoma development but as tumour suppressors in the progression to invasive CRC.11 12 Experimental evidence suggests that inhibiton of EphB signalling pathway by imatinib in the cell could explain the suppression of development of intestinal tumours. The relationship of this pathway to the inhibition of transduction signals from PDGF-R or c-Kit remain unclear. In the case reported by Itsukuma et al,13 the authors described that the immunohistochemical analysis of adenomas did not show expression of c-Kit and the anti-PDGFR alpha (PDGFRA) antibodies did not provide conclusive information on the expression of PDGFRA. There are experimental studies10 14 in which EphB tyrosine kinase receptors were shown to promote the proliferation of intestinal stem and progenitor cells. They also determined the inhibitory effect of imatinib on this receptor in a model with Knockout mice with an APC mutation.10 Treatment with imatinib inhibited the tumour-promoting effects of EphB signalling in Knockout mice, without attenuating EphB-mediated tumour suppression, demonstrating a role for EphB signalling in the initiation of intestinal tumours. The imatinib treatment regimen extended the lifespan of ApcMin/+ mice and reduced cell proliferation in cultured sections of adenomas from patients with familial adenomatous polyposis.\n\nWe report two cases of adenomatous polyposis and CML both treated with imatinib. The coexistence of these two entities is very rare, being found only in case reports such as the one published in 2007 by Itsukuma et al,13 in which a 38-year-old man with an FAP complicated by CML was treated with imatinib achieving haematological and cytogenetic remission in 6 months. Numerous polyps, 2–3 mm in diameter, observed in the rectum prior to the administration of imatinib, regressed in size, but not in number, after 1 year of treatment with imatinib. In our cases, there was a total regression of the polyps concerning those visualised in the initial endoscopic studies with a similar therapeutic approach.\n\nAlthough we cannot infer causality in neither of our cases, we believe our observation deserves further studies. Regarding case 1, although the patient began treatment with tyrosine kinase inhibitors in 2011, this medication had to be continuously adjusted, changed and restarted in 2018 due to its multiple comorbidities, among which chronic kidney disease that entered the final stage. Once the patient was on imatinib treatment, it was surprisingly noticed that the polyps almost disappeared compared with the previous examination.\n\nIn case 2, a patient with a germline mutation in the APC gene,1 there is a clear confounding factor which is having received eflornithine, an active chemopreventive agent for 27 months prior to the initiation of imatinib. Eflornithine (also known as DMFO) is an irreversible inhibitor of ornithine decarboxylase. This enzyme is normally negatively regulated by APC and overexpressed in tumour tissues. In our case, in the setting of the study, we already observed a clinical response 12 months after being on this medication. However, despite suspending eflornithine, he showed a sustained response with the disappearance of the polyps 3 years after, while he continued on imatinib.\n\nIn summary, we describe two cases that highlight the potential effect of imatinib as a chemopreventive agent in colorectal carcinogenesis. Imatinib is usually well-tolerated but long-term administration carries serious side effects, including cardiotoxicity.15 However, short-term or intermittent treatment would reduce the side effects substantially, and could potentially reduce polyp burden in severe duodenal or rectum/pouch cases. Although still speculative, if this hypothesis is confirmed, imatinib could be properly evaluated as a chemopreventive drug in the setting of FAP patients.\n\nWe thank the High-Risk Colorectal Cancer Clinic and the Endoscopy Unit of Hospital clinic for providing the facilities and for their hard work in this study.\n\nContributors: FB was responsible for the study concept and design. AT, TO and PO were responsible for the acquisition of data, analysis and interpretation. AT, PO and FB drafted the manuscript. MP, FB and AT contributed to final revision of the manuscript. FB was responsible for the study supervision.\n\nFunding: The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.\n\nCompeting interests: None declared.\n\nPatient consent for publication: Obtained.\n\nData availability statement: All data relevant to the study are included in the article or uploaded as supplementary information and aditional data is available upon request.\n==== Refs\nReferences\n\n1 Sabela C , Maria LA , Leticia M , et al Hereditary colorectal cancer syndromes10.2217/CRC.13.80. 2014 future medicine LTD. Colorect. Cancer 2014;3 :1–20.\n2 Galiatsatos P , Foulkes WD Familial adenomatous polyposis. Am J Gastroenterol 2006;101 :385–98. 10.1111/j.1572-0241.2006.00375.x 16454848\n3 Umezawa S , Higurashi T , Komiya Y , et al Chemoprevention of colorectal cancer: past, present, and future. Cancer Sci 2019;110 :3018–26. 10.1111/cas.14149 31361372\n4 Mangas-Sanjuan C Vigilancia tras resección de pólipos de colon Y de cáncer colorrectal. Actualización 2018. Gastroenterol Hepatol 2018.\n5 Cubiella J et al Guía de práctica clínica. Diagnóstico Y prevención del cáncer colorrectal Actualización 2018. Gastroenterología y Hepatología 2018;41 :585–96.30245076\n6 Burke CA , Dekker E , Lynch P , et al Eflornithine plus sulindac for prevention of progression in familial adenomatous polyposis. N Engl J Med 2020;383 :1028–39. 10.1056/NEJMoa1916063 32905675\n7 Heinrich MC , Griffith DJ , Druker BJ , et al Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a selective tyrosine kinase inhibitor. Blood 2000;96 :925–32. 10.1182/blood.V96.3.925 10910906\n8 Mughal TI , Schrieber A Principal long-term adverse effects of imatinib in patients with chronic myeloid leukemia in chronic phase. Biologics 2010;4 :315–23. 10.2147/BTT.S5775 21209726\n9 Kundu P , Genander M , Straat K An EphB-Abl signaling pathway is associated with intestinal tumor initiation and growth. Sci Transl Med 2015;281 :ra44.\n10 Batlle E , Henderson JT , Beghtel H , et al Beta-Catenin and TCF mediate cell positioning in the intestinal epithelium by controlling the expression of EphB/ephrinB. Cell 2002;111 :251–63. 10.1016/S0092-8674(02)01015-2 12408869\n11 Genander M , Halford MM , Xu N-J , et al Dissociation of EphB2 signaling pathways mediating progenitor cell proliferation and tumor suppression. Cell 2009;139 :679–92. 10.1016/j.cell.2009.08.048 19914164\n12 Genander M , Frisén J Eph receptors tangled up in two: independent control of cell positioning and proliferation. Cell Cycle 2010;9 :1865–6. 10.4161/cc.9.10.11677 20436281\n13 Itsukuma T , Ishikawa H , Misawa M , et al Familial adenomatous polyposis complicated by chronic myelogenous leukemia: response to imatinib mesylate. J Gastroenterol 2007;42 :402–5. 10.1007/s00535-007-2009-0 17530366\n14 Batlle E , Bacani J , Begthel H , et al EphB receptor activity suppresses colorectal cancer progression. Nature 2005;435 :1126–30. 10.1038/nature03626 15973414\n15 Kalmanti L , Saussele S , Lauseker M , et al Safety and efficacy of imatinib in CML over a period of 10 years: data from the randomized CML-study IV. Leukemia 2015;29 :1123–32. 10.1038/leu.2015.36 25676422\n\n",
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"abstract": "A 26-year-old parturient with Eisenmenger's syndrome and complete atrioventricular block was presented for emergency Cesarean section due to preterm labor. Ventricular tachycardia (VT), which progressed to ventricular fibrillation (VF), started immediately after the incision. Cardiopulmonary resuscitation with electric shocks was given by anesthesiologists while the obstetrician delivered the baby between the shocks. A cardiac surgeon was ready for extracorporeal membrane oxygenation institution in case of emergency but spontaneous circulation of the patient returned after the 3rd shock and the delivery of the baby. The newborn's Apgar score was 4 at 1 minute and 8 at 5 minutes. An implantable cardioverter-defibrillator was inserted before the discharge because the patient had recurrent episodes of VT and VF postoperatively.",
"affiliations": "Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.;Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.",
"authors": "Kim|Gaab Soo|GS|;Yang|Mikyung|M|;Chang|Choo Hoon|CH|;Lee|Eun Kyung|EK|;Choi|Jeong Yeon|JY|",
"chemical_list": null,
"country": "Korea (South)",
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"doi": "10.4097/kjae.2015.68.6.617",
"fulltext": "\n==== Front\nKorean J AnesthesiolKorean J AnesthesiolKJAEKorean Journal of Anesthesiology2005-64192005-7563The Korean Society of Anesthesiologists 10.4097/kjae.2015.68.6.617Case ReportManagement of cardiac arrest in a parturient with Eisenmenger's syndrome and complete atrioventricular block during Cesarean section: a case report Kim Gaab Soo Yang Mikyung Chang Choo Hoon Lee Eun Kyung Choi Jeong Yeon Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.Corresponding author: Mikyung Yang, M.D. Department of Anesthesiology and Pain Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 50, Irwondong, Gangnam-gu, Seoul 06351, Korea. Tel: 82-2-3410-2462, Fax: 82-2-3410-6626, anesyang@skku.edu12 2015 25 11 2015 68 6 617 621 14 2 2014 25 4 2014 28 4 2014 Copyright © the Korean Society of Anesthesiologists, 20152015This 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.A 26-year-old parturient with Eisenmenger's syndrome and complete atrioventricular block was presented for emergency Cesarean section due to preterm labor. Ventricular tachycardia (VT), which progressed to ventricular fibrillation (VF), started immediately after the incision. Cardiopulmonary resuscitation with electric shocks was given by anesthesiologists while the obstetrician delivered the baby between the shocks. A cardiac surgeon was ready for extracorporeal membrane oxygenation institution in case of emergency but spontaneous circulation of the patient returned after the 3rd shock and the delivery of the baby. The newborn's Apgar score was 4 at 1 minute and 8 at 5 minutes. An implantable cardioverter-defibrillator was inserted before the discharge because the patient had recurrent episodes of VT and VF postoperatively.\n\nAtrioventricular blockCardiopulmonary resuscitationCesarean sectionEisenmenger complex\n==== Body\nEisenmenger's syndrome is an obstructive pulmonary vascular disease, which results from pre-existing cardiac defects with large left-to-right shunt. This increases pulmonary artery pressures and when this approaches to systemic levels, the direction of blood flow becomes bi-directional or right-to-left. Patients with Eisenmenger's syndrome are advised to avoid the pregnancy due to high maternal and fetal mortality [1]. There are several case reports on anesthetic management of patients with Eisenmenger's syndrome during Cesarean section [234]. However, the patient in this case was combined with complete atrioventricular block (AVB), which resulted in cardiac arrest before the delivery of the baby. Therefore, this is the first case to report a successful management of cardiac arrest in a parturient with Eisenmenger's syndrome combined with complete AVB.\n\nCase Report\nA 26-year-old woman (41 kg/155 cm) with known Eisenmenger's syndrome due to patent ductus arteriosus (PDA) and ventricular septal defect (VSD) was referred to our hospital at 7th week of gestation for further management of the pregnancy. Transthoracic echocardiography showed a large VSD of 3.9 cm diameter and a PDA of 0.6-0.7 cm diameter resulting in a left-to-right dominant bidirectional shunt flow. The left ventricle (LV) was severely enlarged and systolic function was normal with ejection fraction of 62%. The right ventricle (RV) and pulmonary artery (PA) were also dilated and severe pulmonary hypertension was present with RV systolic pressure of 128 mmHg and left atrium enlargement (LAE). An immediate therapeutic abortion was highly recommended because of high risk pregnancy, but the patient refused and showed a strong desire for the maintenance of the pregnancy. Sildenafil 20 mg three times a day was prescribed and an elective induction of delivery was planned at 34-35th week of gestation after regular follow up. During follow up, echocardiographic findings were aggravated [slightly increased mitral regurgitation (MR), tricuspid regurgitation (TR), left atrial volume index amount < 106 ml/m2 → 179 ml/m2 >], and the cardiac enzyme were increased (NTproBNP 493.4 pg/ml → 860.0 pg/ml < reference range; 0-153 pg/ml >). She was admitted to our hospital and began to receive a continuous intravenous (IV) infusion (3 ng/kg/min) of treprostinil, a vasodilator, to reduce pulmonary hypertension. The preterm uterine contraction started two days after admission (33+1 week of gestation), and the obstetrician tried to control the preterm labor with atosiban, a tocolytics. But the attempt failed and an emergency Cesarean section was decided. Preoperative chest antero-posterior view showed cardiomegaly with pulmonary hypertension, and 3rd degree AVB, left ventricular hypertrophy, LAE, and intraventricular conduction delay were observed on electrocardiography. Preoperative arterial blood gas analysis (ABGA) findings were pH 7.48, PaCO2 24.7 mmHg, PaO2 74 mmHg, and HCO3- 18 mmol/L. Preoperative hemoglobin (Hb) was 12.6 g/dl and hematocrit was 36.4%. Oxygen saturation (SpO2) was maintained with 94-95% at O2 1 L via nasal cannula. The blood pressure was 140-160/50-70 mmHg at ward, and heart rates were 30-50 beats per minute (bpm). The patient gave her permission about the possibility of extracorporeal membrane oxygenation (ECMO) support in case of cardiac arrest.\n\nOn arrival at the operating room, the patient was on a continuous infusion of IV treprostinil 25 ng/kg/min via peripherally inserted central catheter. Due to the complete AVB, the heart rates were 30-40 bpm. An external patch (adult/child multifunction defibrillation electrode pads, Philips, Andover, USA) was attached for intraoperative pacing or defibrillation. The patient was positioned at 15° left tilt position using a right buttock wedge and an arterial line was cannulated in an awake state. Obstetrician, cardiac surgeon, perfusionist, and neonatologist stood by for emergency situation. Anesthesia was induced with etomidate 10 mg and rocuronium 50 mg, and mask ventilation was performed with nitric oxide (NO) 20 ppm added in oxygen and sevoflurane (2 vol%). Norepinephrine 0.02 µg/kg/min, isoproterenol 0.02 µg/kg/min, and milrinone 0.5 µg/kg/min were infused continuously from the start of induction. After intubation, blood pressure was 140/40 mmHg, HR was 35 bpm, SpO2 was 100%. Post-induction ABGA findings (FIO2 0.67, ETCO2 25 mmHg) were pH 7.34, PaCO2 25 mmHg, PaO2 209 mmHg, and HCO3- 13.2 mmol/L. Anesthesia was maintained with sevoflurane and a continuous remifentanil infusion.\n\nImmediately after incision, VT developed suddenly and synchronized direct current (DC) cardioversion shock (200 J) was given with a temporary interruption of operation. After shock, her rhythm changed into VF and defibrillation shock (200 J) was given again, but was not effective. IV Epinephrine 100 µg was given and chest compression was started by an anesthesiologist. Obstetrician re-started the operation and cardiac surgeon prepared for the insertion of ECMO cannula under the rhythm of VF. Two minutes after, defibrillation shock (200 J) was given again and the baby was delivered shortly after the shock. Return of spontaneous circulation (ROSC) was obtained and blood pressure was normalized after the shock and baby-out. Ten minutes after induction, a female baby with 1.7 kg weight was delivered with Apgar scores of 4 at 1 minute and 8 at 5 minutes. Even though the baby's initial crying was weak and the skin color was pale, her crying and skin color rapidly improved after mask bagging with O2 5 L without intubation. The cord pH was 7.32 and the newborn was transferred to the neonatal intensive care unit (ICU) for further management. Oxytocin was not administered after the delivery of the baby and the placenta in order to prevent aggravation of RV failure and pulmonary hypertension. A rectal suppository of misoprostol 200 µg 4 EA was used for uterine contraction instead. NaHCO3 40 mEq was slowly infused after ROSC. At the end of operation, ABGA findings (FIO2 0.37, ETCO2 30) were pH 7.32, PaCO2 31 mmHg, PaO2 83.5 mmHg, and HCO3- 15.6 mmol/L and Hb was 10.5 g/dl. The total anesthesia time was 78 minutes and the operation time was 35 minutes. Total input/output was described as below: crystalloid 1,100 ml, hydroxyethyl starch 500 ml, urine output 200 ml, estimated blood loss 500 ml. The patient was then transferred to the coronary care unit and received mechanical ventilation with NO 20 ppm inhalation and a continuous infusion of remifentanil 0.02 µg/kg/min and with treprostinil 8 ng/kg/min.\n\nOn postoperative day (POD) 1, NO was stopped and the patient was extubated but showed hemoptysis for several times. As prophylactic antibiotics, cefuroxime 0.75 g was IV given three times a day for 4 days. On POD 3, the patient received red blood cell transfusion due to anemia (Hb 8.2 g/dl) and a continuous infusion with furosemide to maintain negative fluid balance with a target body weight of 39-40 kg to decrease pulmonary edema and improve dyspnea. On POD 7, her chest computed tomography (CT) showed diffuse alveolar hemorrhage (Fig. 1). The patient complained about insomnia and depressive mood, and so she was transferred to the sub-ICU after psychological consultation. Immediately after moving to the sub-ICU bed, her eyeballs were deviated and she became pulseless, and CPR was started. During 2 cycles of CPR, 500 ml normal saline was rapidly dripped and 2 mg epinephrine was given. Then the electrocardiogram monitoring revealed VF. Defibrillation shock was given and ROSC was obtained after another 1 cycle of CPR, and she was transferred to the ICU again. On POD 8, the patient showed Torsades de Points type VT (Fig. 2), pulseless VT, and eyeball deviation, and an electric shock was given. K+ and Mg++ were replaced for the maintenance of high normal ranges to prevent fatal arrhythmia, but repetitive VT with basal rhythm of complete AVB occurred, and so the patient received DC shocks more than 30 times. A transient pacemaker was inserted and maintained over-pacing of the heart rate at 100 bpm. On POD 9, the transient pacemaker rate was reduced to 60 bpm and then was removed at POD 12. On POD 12, lung sonography showed post-CPR lung contusion or alveolar hemorrhagic consolidation. In spite of aggressive treatment, her dyspnea has not improved (WHO functional class IV), so IV treprostinil was increased up to 18 ng/kg/min and oral 62.5 mg bosentan, an endothelin receptor antagonist, twice a day was added. On POD 18, she was transferred to the general ward, and an implantable cardioverter-defibrillator (ICD) was inserted on POD 19. The patient showed persistent anemia despite negative stool occult blood test and intermittent transfusion, and was presumed to have anemia of chronic disease with severe iron deficiency (Hb 7.4 g/dl). Chest CT showed resolving diffuse alveolar hemorrhage and combined pneumonia on POD 25. On POD 26, IV treatment with treprostinil was changed into subcutaneous form with 20 ng and warfarin was started with a target aPTT of 45-70 sec. Heparin therapy was initiated on POD 8 and stopped on POD 35. On POD 32, ferric hydroxide sucrose 400 mg was IV given to replace iron and the patient's Hb level was 8.4 g/dl with a target of 14-15 g/dl just before discharge. The patient was discharged with home O2, subcutaneous treprostinil 22 ng, and warfarin 4 mg on POD 37.\n\nDiscussion\nOur patient had been coming to our hospital for regular check-up and management since the early pregnancy. Therefore, her emergency Cesarean section could be performed under the supervision of a multidisciplinary experienced team including an obstetrician, anesthesiologists, a cardiac surgeon, a perfusionist, and a neonatologist. The patient had a complete AVB, but a transient pacemaker was not preoperatively inserted because of the risk of systemic embolization through VSD and PDA. General anesthesia was selected for this case because the chance of cardiac failure or arrest and the need for pacing, electric shock, or ECMO support were high due to underlying complete heart block. Advantages of regional anesthesia were reducing the risk of venous embolism and providing postoperative analgesia. Disadvantages of regional anesthesia were the possibility of increasing the amount of right-to-left shunt by sympathetic block and decrease in systemic vascular resistance (SVR) and less controllability in case of arrest. Disadvantages of general anesthesia were the possibility of acute rising of pulmonary vascular resistance (PVR) during intubation and reduced venous return because of positive pressure ventilation [3].\n\nFor the anesthetic management of patients with Eisenmenger's syndrome, it is important to minimize the increment of PVR and decrement of SVR, to avoid hypovolemia, and to preserve cardiac contractility in order to avoid hypoxemia and right heart failure. To achieve this goal, we prepared NO inhalation and a continuous infusion of milrinone to reduce PVR, norepinephrine to maintain SVR, and hydroxyethyl starch infusion to compensate volume loss.\n\nPatients with Eisenmenger's syndrome present with high PVR associated with pulmonary hypertension at or near the systemic values with a reversed or bidirectional shunt. In our case, the patient had a bidirectional shunt with a left-to-right shunt dominant state. Therefore, she did not show profound hypoxemia as described in other reports [2345]. An excessive decrease in PVR compared to SVR causes temporary high oxygen saturation in case of bidirectional shunt, but can eventually result in decreased systemic perfusion leading to systemic hypotension and acidosis. Therefore, it is very important to control the relative ratio of right-to-left or left-to-right shunt. During induction, a high FIO2 of 1.0 was used to prevent an acute rise of PVR. After baby was out and after confirmation of adequate oxygenation, FIO2 was decreased to 0.6. However, the diastolic pressure was maintained at 40 mmHg, which might imply an inadequate left side stroke volume due to an increased left-to-right shunt. Since SpO2 was well maintained at FIO2 0.6, we reduced FIO2 further to 0.4 to counterbalance the amount of left-to-right shunt by slightly increasing PVR.\n\nA PA catheter was not inserted in this case because the risk of arrhythmia, pulmonary artery rupture or provoking pulmonary hypertensive crisis might be greater than the benefit of the evaluation of hemodynamic status and the severity of shunt flow. Moreover, its proper placement may have not been easy [2, 5] and its information may not reflect the actual hemodynamic status because of the large VSD. Patients with Eisenmenger's syndrome due to ASD or PDA will benefit from PA catheter monitoring because it can monitor pressure gradients between right and left circulations. However, in patients with Eisenmenger's syndrome due to VSD, it is impossible to monitor the intraventricular pressure gradients between right and left ventricles. Systemic arterial saturations are related to the amount of right-to-left shunt. SpO2 will decrease if the right-to-left shunt increases because of an increased PVR or decreased SVR. Use of pulse oximetry could be a safer and better method of determining the degree of right-to-left shunt flow in these patients [6].\n\nIn this case, the complete AVB might have been the triggering factor for the arrhythmia. Previously, a cardiac arrest from Torsades de Points was reported in a patient with complete heart block (the \"R-on-T\" phenomenon) [7]. The complete heart block was associated with an atrioventricular septal defect and could precipitate Torsades de Points and arrest through QT prolongation. Women appear to be more susceptible than men [8]. To prevent sudden death, pacemaker insertion and ICD implantation were advocated [9]. The patient in this case had a large VSD and a complete AVB preoperatively, developed VT/VF intraoperatively, sustained repetitive Torsades de Points type VT and VF postoperatively, and was treated with a transient pacemaker insertion followed by an ICD implantation. Therefore, it is reasonable to presume the complete AVB as the cause of arrhythmia in this case.\n\nIsoproterenol was continuously infused because of complete AVB, but it was stopped after VT and VF. However, isoproterenol can be used for the treatment of idiopathic recurrent VF if the induction mechanism of VF is associated with enhanced vagal tone rather than with enhanced sympathetic activity. Mittadodla et al. [10] reported a VF storm could be effectively treated by increasing heart rate with isoproterenol or overdrive pacing in a pregnant woman not responding to traditional antiarrhythmic therapy.\n\nCongestive heart failure followed by pregnancy is the most common cause of death in patients with Eisenmenger's syndrome. In many reports, cardiac failures occurred shortly after the delivery of the fetus and blood loss [234], which caused hypovolemia, decrease in SVR, increase in PVR, and severe hypoxemia: were usually treated with volume replacement, vasopressor, and NO inhalation. However, this patient developed sudden VT immediately after the incision and then progressed to VF and returned to ROSC after delivery. Even though the total arrest time was 2 minutes, if it had lasted longer it could have been fatal to both the mother and the baby. Several studies reported that the ROSC did not occur until the uterus was emptied by a perimortem Cesarean section [11] and suggested perimortem Cesarean section might be regarded as one treatment option when all other resuscitation methods fail. However, perimortem Cesarean section is rarely done within 5 minutes to optimize maternal salvage from cardiac arrest [1213]. In our case, the patient received perimortem Cesarean section and resuscitation simultaneously. Cesarean section was interrupted three times because of the electric shocks. Transthoracic impedance was not significantly altered during pregnancy [13]. Therefore, usual defibrillation dosages can be applied to a parturient. Chest compressions in a left lateral tilt from the horizontal are feasible but less forceful compared to the supine position and manual leftward displacement of the gravid uterus was preferred to lateral tilt during maternal resuscitation [14].\n\nWas the electric shock given to the mother harmful to the baby? After the review of 44 case reports of electrical cardioversion during pregnancy, Tromp et al. [15] concluded that it was a highly effective procedure and assumed it as safe for both, the mother and the baby. However, there were two cases of fetal distress directly after the cardioversion, necessitating an immediate Cesarean section at 37th and 28th week of gestational age. Even though both neonates of the above cases were born healthy, facilities for fetal monitoring and emergency Cesarean section should be available when an electrical cardioversion is planned. The intensity and the pathway of the current are important in case of electric shock. Therefore, it is necessary to place the patch properly away from the uterus.\n\nWas the ROSC obtained from the CPR or the delivery? Several studies report that the delivery itself can terminate the VF. Therefore, delivery should not be delayed in case of cardiac arrest in patients with Eisenmenger's syndrome because it can guarantee the safety of the fetus and the mother simultaneously. To wait for a moment for defibrillation can be permitted. On the other side, it could be insisted that the ROSC was the result of effective defibrillation and proper CPR because this patient suffered repetitive VT/VF postoperatively and successfully recovered after electric shock each time.\n\nPatients with Eisenmenger's syndrome should be closely monitored in the ICU after delivery because they are vulnerable to heart failure, arrhythmia, and severe hypoxemia in this period. Our patient also suffered from fatal arrhythmias, diffuse alveolar hemorrhage, anemia, and congestive heart failure.\n\nIn conclusion, the anesthetic management of a parturient with Eisenmenger's syndrome should be focused on controlling the relative ratio of the bidirectional shunt by avoiding the increase in PVR and decrease in SVR. In patients with complete AVB, preoperative insertion of a transient pacemaker is recommended because they have a high risk of developing cardiac arrest from Torsades de Points type VT. When a parturient suffers sudden cardiac arrest during Cesarean section, a high quality CPR and perimortem Cesarean section should be simultaneously performed without delay for the safety of the mother and the baby.\n\nFig. 1 There are extensive centrilobular consolidation and ground-glass opacity on both lungs which imply diffuse alveolar hemorrhage.\nFig. 2 Electrocardiogram strip shows Torsades de Pointes type ventricular tachycardia and its termination with a cardioversion shock.\n==== Refs\n1 Drenthen W Pieper PG Roos-Hesselink JW van Lottum WA Voors AA Mulder BJ Outcome of pregnancy in women with congenital heart disease J Am Coll Cardiol 2007 49 2303 2311 17572244 \n2 Lee SY Ko JS Jung JW Lee SM Kang IS Park SW Perioperative management of a parturient with Eisenmenger's syndrome undergoing Cesarean section Anesth Pain Med 2007 2 246 251 \n3 Lee BJ Anesthesia for Cesarean section in a parturient patient with Eisenmenger's syndrome Anesth Pain Med 2006 1 116 119 \n4 Hwang BM Sim JY Cho SK Lee DM Epidural Anesthesia for Cesarean section in parturient with Eisenmenger's syndrome Korean J Anesthesiol 2000 38 563 566 \n5 Chung KH Kim SH Chun DH Lee JY Park SC Park CH Anesthetic management for emergent craniotomy in a patient with Eisenmenger's syndrome Korean J Anesthesiol 2009 57 666 669 \n6 Devitt JH Noble WH Byrick RJ A Swan-Ganz catheter related complication in a patient with Eisenmenger's syndrome Anesthesiology 1982 57 335 337 7125276 \n7 Nguyen AP Sarmast SA Kowal RC Schussler JM Cardiac arrest due to torsades de pointes in a patient with complete heart block: the \"R-on-T\" phenomenon Proc (Bayl Univ Med Cent) 2010 23 361 362 20944757 \n8 Nijjer S White S Gatzoulis MA Torsades de Pointes in atrioventricular septal defect Int J Cardiol 2009 134 e51 e52 18353464 \n9 Wilmin S De Bels D Knecht S Gottignies P Gazagnes MD Devriendt J Torsade de pointes in Kearns-Sayre syndrome Pract Neurol 2012 12 199 201 22661355 \n10 Mittadodla PS Salen PN Traub DM Isoproterenol as an adjunct for treatment of idiopathic ventricular fibrillation storm in a pregnant woman Am J Emerg Med 2012 30 251.e3 251.e5 21075581 \n11 Katz V Balderston K DeFreest M Perimortem cesarean delivery: were our assumptions correct? Am J Obstet Gynecol 2005 192 1916 1920 15970850 \n12 Dijkman A Huisman CM Smit M Schutte JM Zwart JJ van Roosmalen JJ Cardiac arrest in pregnancy: increasing use of perimortem caesarean section due to emergency skills training? BJOG 2010 117 282 287 20078586 \n13 Jeejeebhoy FM Zelop CM Windrim R Carvalho JC Dorian P Morrison LJ Management of cardiac arrest in pregnancy: a systematic review Resuscitation 2011 82 801 809 21549495 \n14 Kundra P Khanna S Habeebullah S Ravishankar M Manual displacement of the uterus during Cesarean section Anaesthesia 2007 62 460 465 17448057 \n15 Tromp CH Nanne AC Pernet PJ Tukkie R Bolte AC Electrical cardioversion during pregnancy : safe or not? Neth Heart J 2011 19 134 136 21475392\n\n",
"fulltext_license": "CC BY-NC",
"issn_linking": "2005-6419",
"issue": "68(6)",
"journal": "Korean journal of anesthesiology",
"keywords": "Atrioventricular block; Cardiopulmonary resuscitation; Cesarean section; Eisenmenger complex",
"medline_ta": "Korean J Anesthesiol",
"mesh_terms": null,
"nlm_unique_id": "101502451",
"other_id": null,
"pages": "617-21",
"pmc": null,
"pmid": "26634088",
"pubdate": "2015-12",
"publication_types": "D016428:Journal Article",
"references": "15970850;17448057;7125276;21075581;17572244;21549495;22661355;20078586;20944757;21475392;18353464",
"title": "Management of cardiac arrest in a parturient with Eisenmenger's syndrome and complete atrioventricular block during Cesarean section: a case report.",
"title_normalized": "management of cardiac arrest in a parturient with eisenmenger s syndrome and complete atrioventricular block during cesarean section a case report"
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"abstract": "Spinal epidural hematoma (SEH) is rare but causes neurological disorders. Rapid diagnosis and treatment maximize neurological recovery. We present the case of SEH after lung cancer surgery under epidural and general anesthesia. A 64-year-old man underwent right upper lobectomy. Pulmonary embolism occurred on postoperative day 2. Anticoagulant therapy with fondaparinux and warfarin was started 2 hours after epidural catheter removal and he gradually recovered. On postoperative day 13, the level of prothrombin time-international normalized ratio reached 1.47 and fondaparinux administration was stopped. The next day, he developed back pain and paraplegia, and magnetic resonance imaging revealed a mass between Th4 and Th7 compressing the spinal cord. Emergency decompression laminectomy and hematoma evacuation were performed. After 2.5 months of rehabilitation, he regained almost all motor function and sensation. Late after epidural anesthesia, attention should be paid to possible SEH even though appropriate anticoagulant therapy had been initiated after epidural catheter removal.",
"affiliations": "Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi, Japan.",
"authors": "Kobayashi|Yoshihisa|Y|;Nakada|Junya|J|;Kuroda|Hiroaki|H|;Sakakura|Noriaki|N|;Usami|Noriyasu|N|;Sakao|Yukinori|Y|",
"chemical_list": "D000925:Anticoagulants",
"country": "Japan",
"delete": false,
"doi": "10.5761/atcs.cr.13-00177",
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"issn_linking": "1341-1098",
"issue": "20 Suppl()",
"journal": "Annals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia",
"keywords": null,
"medline_ta": "Ann Thorac Cardiovasc Surg",
"mesh_terms": "D000767:Anesthesia, Epidural; D000925:Anticoagulants; D046748:Hematoma, Epidural, Spinal; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D008875:Middle Aged; D010264:Paraplegia; D011013:Pneumonectomy; D011183:Postoperative Complications; D011517:Prothrombin Time; D011655:Pulmonary Embolism",
"nlm_unique_id": "9703158",
"other_id": null,
"pages": "493-6",
"pmc": null,
"pmid": "24492175",
"pubdate": "2014",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
"references": null,
"title": "Spinal epidural hematoma during anticoagulant therapy for pulmonary embolism: postoperative complications in a patient with lung cancer.",
"title_normalized": "spinal epidural hematoma during anticoagulant therapy for pulmonary embolism postoperative complications in a patient with lung cancer"
} | [
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"companynumb": "JP-MYLANLABS-2015M1039498",
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"abstract": "SIOD is rare disorder related to SMARCAL1 or SMARCAL2 gene mutation, including (among other comorbidities) T-cell immunodeficiency, nephrotic syndrome, and renal failure. Up to 22% of primary patients may develop various autoimmune disorders. We report the case of 11-year-old male with SIOD, who presented ITP at 2 years after renal transplantation with decrease in platelet count (from normal) to 56 000/μL and then (gradually) to 2000/μL. There was no effect of iv. methylprednisolone/dexamethasone. As the presence of antibodies against GPIIb/IIIa, GPIb, and GPIaIIa platelet glycoproteins was confirmed, patient was given 50 g of IVIG and then was put on plasmapheresis; however, both showed poor direct effect. As we were afraid to give rituximab (due to expected overimmunosuppression), we prescribed the oral TPO-receptor agonist (eltrombopag). Patient responded after 17 days of therapy, to the final dose of 50 mg/d (approx. 2 mg/kg). The antiplatelet antibodies disappeared after four plasmapheresis. Overall, the therapy was continued for 7 weeks and was stopped at platelet count of 433 000/μL. Platelet count remained stable in 8-month follow-up. Combination of plasmapheresis and TPO-receptor agonist was effective in post-renal transplant acute ITP in patient with SIOD.",
"affiliations": "Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.;Department of Nephrology, Kidney Transplantation and Hypertension, The Children's Memorial Health Institute, Warsaw, Poland.",
"authors": "Grenda|Ryszard|R|;Jarmużek|Wioletta|W|;Latoszyńska|Joanna|J|;Prokurat|Sylwester|S|;Rubik|Jacek|J|",
"chemical_list": "D001565:Benzoates; D006834:Hydrazines; D011720:Pyrazoles; D013926:Thrombopoietin; C412482:SMARCAL1 protein, human; D004265:DNA Helicases; C520809:eltrombopag",
"country": "Denmark",
"delete": false,
"doi": "10.1111/petr.12828",
"fulltext": null,
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"issn_linking": "1397-3142",
"issue": "20(8)",
"journal": "Pediatric transplantation",
"keywords": "Schimke immuno-osseous dysplasia; acute immune thrombocytopenia; plasmapheresis; renal transplantation; thrombopoietin-receptor agonist",
"medline_ta": "Pediatr Transplant",
"mesh_terms": "D001161:Arteriosclerosis; D001565:Benzoates; D002648:Child; D004265:DNA Helicases; D006801:Humans; D006834:Hydrazines; D007153:Immunologic Deficiency Syndromes; D016030:Kidney Transplantation; D008297:Male; D009154:Mutation; D009404:Nephrotic Syndrome; D010009:Osteochondrodysplasias; D010956:Plasmapheresis; D010976:Platelet Count; D000081207:Primary Immunodeficiency Diseases; D011655:Pulmonary Embolism; D016553:Purpura, Thrombocytopenic, Idiopathic; D011720:Pyrazoles; D013926:Thrombopoietin; D013997:Time Factors",
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"title": "Eltrombopag (thrombopoietin-receptor agonist) and plasmapheresis as rescue therapy of acute post-renal transplant immune thrombocytopenia in a child with Schimke immuno-osseous dysplasia-case report.",
"title_normalized": "eltrombopag thrombopoietin receptor agonist and plasmapheresis as rescue therapy of acute post renal transplant immune thrombocytopenia in a child with schimke immuno osseous dysplasia case report"
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"abstract": "Bivalirudin is a direct thrombin inhibitor approved for use in adult patients with heparin-induced thrombocytopenia (HIT) undergoing percutaneous coronary intervention. Recently, its use in the pediatric population has increased due to its anti-thrombin-independent mechanism of action. As heparin products produce great inter- and intraindividual variability in pediatric patients, often due to decreased anti-thrombin concentrations in the first year of life, some practitioners have turned to direct thrombin inhibitors, such as bivalirudin, for more predictable pharmacokinetics and effects on bound and circulating thrombin. We report our experience using bivalirudin in a 2-month-old female with recurrent systemic thrombi despite continuous unfractionated heparin infusion. Due to the patient's inability to maintain therapeutic activated partial thromboplastin time (aPTT) values during heparin infusion, bivalirudin was initiated at 0.1 mg/kg/h and increased due to subtherapeutic aPTTs to a maximum of 0.58 mg/kg/h. Therapeutic aPTTs were achieved at the increased dose; however, the patient's worsening renal impairment with resultant drug accumulation and overwhelming sepsis on day 5 of therapy led to discontinuation of the infusion and the initiation of comfort measures.",
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"title": "Bivalirudin use in an infant with persistent clotting on unfractionated heparin.",
"title_normalized": "bivalirudin use in an infant with persistent clotting on unfractionated heparin"
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"abstract": "Background: Non-functional neuroendocrine tumors of the pancreas (NF-pNETs) are a varied group of extremely rare malignancies. The majority of patients already have liver metastases at the diagnosis moment, thus, treatment options are restricted, and the survival rate is reserved. Case report: We presented the case of 59-year-old patient, diagnosed with non-functional well-differentiated pancreatic neuroendocrine tumor grade II (NET G2) with the presence of chromogranin A, synaptophysin and somatostatin receptor 2, together with liver and bone metastases. Patient underwent a surgical excision of the pancreatic tumor, started long-acting somatostatin analogues (octreotide), interferon therapy for liver metastases and local radiotherapy for bone metastases. After one year, the patient developed diabetes, needing insulin therapy. At approximately three years after the diagnosis, the patient was still living, had a good quality of life, and was free of local recurrence of the tumor or other metastases. Conclusion: Our case report presented a rare case of metastatic non-functional well-differentiated pancreatic neuroendocrine tumor, involving a multidisciplinary therapeutic approach in order to obtain a good long-term survival.",
"affiliations": "\"C. I. Parhon\" National Institute of Endocrinology, Bucharest, Romania ; Department of Physiology I, \"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.;Department of Physiology I, \"Carol Davila\" University of Medicine and Pharmacy, Bucharest, Romania.;\"Sf. Ioan\" Emergency Hospital, Bucharest, Romania.;\"Floreasca\" Clinical Emergency Hospital, Bucharest, Romania.;\"C. I. Parhon\" National Institute of Endocrinology, Bucharest, Romania.",
"authors": "Mirică|A|A|;Bădărău|I A|IA|;Mirică|R|R|;Păun|S|S|;Păun|D L|DL|",
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"fulltext": "\n==== Front\nJ Med LifeJ Med LifeJMedLifeJournal of Medicine and Life1844-122X1844-3117Carol Davila University Press Romania 27928440JMedLife-09-369Original ArticlesA rare case of metastasized non-functional pancreatic \nneuroendocrine tumor with a good long-term survival\n Mirică A ***Bădărău IA **Mirică R ***Păun S ****Păun DL ** ”C. I. Parhon” National Institute of Endocrinology, Bucharest, Romania\n** Department of Physiology I, “Carol Davila” University of Medicine and Pharmacy, Bucharest, Romania\n*** ”Sf. Ioan” Emergency Hospital, Bucharest, Romania\n**** ”Floreasca” Clinical Emergency Hospital, Bucharest, Romania\nCorrespondence to: Sorin Păun, MD, PhD,\n”Floreasca” Clinical Emergency Hospital, Bucharest,\n8 CaleaFloreasca Street, Code 014461, Bucharest, Romania,\nPhone: +4021 599 23 00, E-mail: drspaun@yahoo.com\nOct-Dec 2016 9 4 369 372 24 6 2016 17 9 2016 ©Carol Davila University Press\n2016This is \nan open-access article distributed under the terms of the Creative \nCommons Attribution License, which permits unrestricted use,\ndistribution, and reproduction in any medium, provided the original work \nis properly cited.Background: Non-functional neuroendocrine tumors of the pancreas (NF-pNETs) are a varied group of extremely rare malignancies. The majority of patients already have liver metastases at the diagnosis moment, thus, treatment options are restricted, and the survival rate is reserved.\n\nCase report: We presented the case of 59-year-old patient, diagnosed with non-functional well-differentiated pancreatic neuroendocrine tumor grade II (NET G2) with the presence of chromogranin A, synaptophysin and somatostatin receptor 2, together with liver and bone metastases. Patient underwent a surgical excision of the pancreatic tumor, started long-acting somatostatin analogues (octreotide), interferon therapy for liver metastases and local radiotherapy for bone metastases. After one year, the patient developed diabetes, needing insulin therapy. At approximately three years after the diagnosis, the patient was still living, had a good quality of life, and was free of local recurrence of the tumor or other metastases.\n\nConclusion: Our case report presented a rare case of metastatic non-functional well-differentiated pancreatic neuroendocrine tumor, involving a multidisciplinary therapeutic approach in order to obtain a good long-term survival.\n\npancreatic non-functional well-differentiated neuroendocrine tumorsurvival ratetype 2 diabetes\n==== Body\nIntroduction\nPancreatic neuroendocrine tumors (p-NETs) are a captivating and diverse group of rare neoplasms, which arise from pancreatic islet cells. In this article, we presented the case of a female patient with non-functional pancreatic neuroendocrine tumor with multiple liver and bone metastases, whose therapy included a multidisciplinary team of medical specialties: surgery, endocrinology, oncology, radiology, and gastroenterology. After treatment, the metastases were monitored, with no local recurrence of primary tumor. One year after the excision of the pancreatic head and tail, the patient developed diabetes, needing insulin therapy.\n\nCase report\nIn 2013, a 59-year-old white Caucasian non-smoking woman presented to the surgery department describing symptoms of diffuse abdominal pain, weight loss (18 kilograms/1 year) and unselective anorexia with the insidious onset of symptoms in the previous 6 months. The patient reported a personal history of chronic hepatitis C treated with pegylated interferon and ribavirin 16 years before and no particular familial history.Laboratory tests were within normal ranges, except for an elevated alkaline phosphatase of 158 u/l (normal range <104 U/L), a moderate hepatic cytolysis with a small elevation of transaminases, alanine transaminase (ALT) of 36 U/L (normal range 5-21 U/L) and aspartate transaminase (AST) of 37 U/L (normal range 5-30 U/L ) and increased carcinoembryonic antigen of 9.75 ng/mL (normal range for non-smokers < 3 ng/ mL). Pelvic and abdominal computer tomography (CT) with contrast substance revealed hepatomegaly with multiple hypodense formations, the largest with a diameter of 3 cm and a pancreatic tumor of 4/ 3.8 cm diameter, with distal development, involving hilum splenic (Fig. 1 a,b).\n\nA surgical laparoscopic intervention, which revealed numerous whitish tumor formations of 5-30 mm at both liver lobes, without peritoneal carcinomatosis, was performed. A conversion to median celiotomy was decided, finding a 4/4 cm pancreatic tumor located in the distal part of the pancreas, involving peripancreatic tissues and the vessels of splenic hilum. Then, a distal pancreatectomy and splenectomy was performed. Postoperative CT scan performed at 2 weeks after surgery revealed the presence of a pseudocystic collection in the pancreatic stump, of 3.8/ 3.4 cm, which was effectively drained through the locally installed drain. Histopathological and immunohistochemical results diagnosed well-differentiated pancreatic neuroendocrine tumor grade II (NETG2) with liver metastases and no spleen invasion, with the presence of diffuse positive chromogranin A and synaptophysin. The cellular marker for proliferation Ki67 was 15 to 20% and the tumor cells also expressed somatostatin receptor 2 (SSR2) (Fig. 2 a,b,c). \n\nFig. 1 Computed tomography location and aspects of pancreatic tumor a,b\n\nFig. 2 Immunohistochemistry aspects of neuroendocrine pancreatic tumor\n\na. Diffuse positive marker Ki67 15-20% in tumor cells, \n\nb. b. Diffuse positive synaptophysin in tumor cells, 4X optical microscopy, c. Diffuse positive chromogranin A in tumor cells\n\nThe patient was subsequently sent to the endocrinology service, where extensive further medical tests were conducted. Hormonal investigations indicated an elevated serum chromogranin A of 468 ng/ mL (normal range 20-125 ng/mL) and serum neuron specific enolase of 56 ng/mL (normal range 0-12 ng/mL) with normal values of plasmatic serotonin and urinary 5-hydroxyindoleacetic acid. Furthermore, endocrine investigations including pituitary, thyroid, parathyroid, and adrenal hormones were normal and even though genetic testing was not possible, MEN1 syndrome was excluded. Moreover, a bone scintigraphy with technetium 99 was performed and it revealed multiple bone metastases in the vertebral body L3, L4, coccygeal region, posterior rib 10 and 6, left iliac wing, right clavicle and left femoral diaphysis. Based on these results, after a multidisciplinary cooperation between the oncologist, endocrinologist and radiotherapist, the patient started treatment with long-acting somatostatin analogues (octreotide) 30 mg at 4 weeks, interferon alfa 2B – 3 million units three times a week for 6 months and a single local external radiation therapy (dose of 8 Gy) for the relieve of lumbar pains. After completing treatment with interferon, the patient began systemic chemotherapy with 5-fluorouracil. The patient was monitored at short intervals, with no local recurrence of the pancreatic tumor or other metastases and the optimal control of symptoms was obtained. The follow-up examination, one year later, revealed elevated glycemic values, diagnosed as a type 2 diabetes and the patient was started on therapy with long-acting insulin.\n\nDiscussions\nP-NETshave a low incidence of less than 1 per 100,000 persons, representing 1.3-2% of all types of pancreatic tumors.They are classified as functional p-NETs, associated with a particular clinical syndrome such as Cushing syndrome and non-functional p-NETs, frequently asymptomatic, associated with no particular medical sign. Non-functional p-NETs frequently secrete chromogranin A, neuron-specific enolase, human chorionic gonadotrophin subunits, pancreatic polypeptide or other peptides, but they do not manifest with particular clinical symptoms and thus they are referred as non-functional tumors. At the same time, approximately 10–30% of pNETs are functional and the most common functional p-NETs are gastrinomas and insulinomas, with the rare functional p-NETS represented by vasoactive intestinal peptide tumor (VIPomas) and somatostatinomas [1,2]. Most p-NETs are sporadic, but in 10% of cases they can occur in association with the hereditary syndromes such as MEN-1 syndrome, Von Hippel Lindau syndrome, tuberous sclerosis and neurofibromatosis type 1 [3,4]. \n\nNon-functional p-NETS frequently present with distant metastasis, especially to the liver and bones, as in our patient’s case, due to their asymptomatic nature. Although the majority of p-NETs occur in the head of the pancreas, in our patient’s case, the tumor affected the body and the tail of the pancreas [5,6]. \n\nThe diagnostic strategy includes localization of the tumor (abdominal CT or MRI, somatostatin receptor scintigraphy) and laboratory tests, in order to confirm the functional or non-functional status. Therapeutic management includes surgery as first choice therapy in resectable tumors, somatostatin analogue or specific molecular targeted therapy,systemic chemotherapy and liver-directed therapies (radiofrequency ablation, hepatic artery embolization) in patients with a metastatic disease [7,8]. In our patient’s case, the first choice of treatment was the surgical excision of the pancreatic tumor, followed by treatment with somatostatin analogues and medical therapy for liver metastases, noting that the patient had diffuse bilobed involvement with associated bone metastases. In addition, systemic chemotherapy and a single dose of radiation therapy have been recommended. Furthermore, in our case, the occurrence of diabetes might have been either due tothe partial excision of the pancreas or due to the treatment with somatostatin analogues, which are known to reduce theinsulin levels secreted by the pancreatic cells. \n\nPatients with p-NETS with metastatic disease have a worse prognosis, with a median survival rate of 22 months [9,10]. Our patient is still living, having a good quality of life of approximately 34 months since the diagnosis moment.\n==== Refs\n1 Fraenkel M Kim MK Faggiano A Epidemiology of gastroenteropancreatic neuroendocrine tumours Best Pract Res ClinGastroenterol 2012 26 691 703 \n2 Lawrence B Gustafsson BI Chan A Svejda B Kidd M Modlin IM The epidemiology of gastroenteropancreatic neuroendocrine tumors EndocrinolMetabClin North Am 2011 40 1 18 doi: 10.1016/j.ecl.2010.12.005 \n3 Jensen RT Berna MJ Bingham DB Norton JA Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management, and controversies Cancer 2008 113 1807 1843 doi: 10.1002/cncr.23648 18798544 \n4 Hallet J Law CH Cukier M Saskin R Liu N Singh S Exploring the rising incidence of neuroendocrine tumors: a population-based analysis of epidemiology, metastatic presentation, and outcomes Cancer 2015 121 589 597 25312765 \n5 Kuo JH Lee JA Chabot JA Nonfunctional pancreatic neuroendocrine tumors SurgClin North Am 2014 94 689 708 doi: 10.1016/j.suc.2014.02.010 \n6 Halfdanarson TR Rabe KG Rubin J Petersen GM Pancreatic neuroendocrine tumors (PNETs): Incidence, prognosis and recent trend toward improved survival Ann Oncol 2008 19 1727 1733 18515795 \n7 Vinik A Advances in diagnosis and treatment of pancreatic neuroendocrine tumors EndocrPract 2014 20 1222 1230 \n8 Falconi M Bartsch DK Eriksson B Klöppel G Lopes JM O’Connor JM ENETS Consensus Guidelines for the management of patients with digestive neuroendocrine neoplasms of the digestive system: well-differentiated pancreatic non-functioning tumors Neuroendocrinology 2012 95 120 134 22261872 \n9 Krampitz GW Norton JA Pancreatic neuroendocrine tumors CurrProbl Surg 2013 50 509 545 doi: 10.1067/j.cpsurg.2013.08.001 \n10 National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program http://seer.cancer.gov/\n\n",
"fulltext_license": "CC BY",
"issn_linking": "1844-122X",
"issue": "9(4)",
"journal": "Journal of medicine and life",
"keywords": "pancreatic non-functional well-differentiated neuroendocrine tumor; survival rate; type 2 diabetes",
"medline_ta": "J Med Life",
"mesh_terms": "D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D008875:Middle Aged; D015282:Octreotide; D010190:Pancreatic Neoplasms; D011788:Quality of Life; D011994:Recombinant Proteins; D016019:Survival Analysis; D013997:Time Factors; D014057:Tomography, X-Ray Computed",
"nlm_unique_id": "101477617",
"other_id": null,
"pages": "369-372",
"pmc": null,
"pmid": "27928440",
"pubdate": "2016",
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"references": "25312765;22261872;24857584;24206780;18515795;21349409;18798544;25297671;23582913",
"title": "A rare case of metastasized non-functional pancreatic neuroendocrine tumor with a good long-term survival.",
"title_normalized": "a rare case of metastasized non functional pancreatic neuroendocrine tumor with a good long term survival"
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"abstract": "BACKGROUND\nThe incidence of AIDS-defining cancers (ADCs) has decreased markedly in the era of highly active antiretroviral therapy (HAART). The occurrence of two ADCs is rare in people living with HIV or AIDS (PWHA) who are severely immunosuppressed or have incomplete virologic suppression.\n\n\nMETHODS\nWe report a case of dual primary ADCs, especially NHL followed by KS, in a 70-year-old HIV-infected man who was on antiretroviral therapy and had successful virologic suppression. During HAART, he presented with generalized myalgia and abdominal pain. Multiple liver masses were detected and a biopsy revealed Burkitt's lymphoma. After three cycles of anticancer chemotherapy with a favorable response, he was diagnosed with cytomegalovirus retinitis and the anti-cancer chemotherapy was discontinued. Despite successful virologic suppression with HAART, human herpes virus-8 associated Kaposi's sarcoma was diagnosed in his right thigh. He underwent radiation therapy.\n\n\nCONCLUSIONS\nThese findings suggest that multiple ADCs can occur in PWHA who are receiving HAART and have successful virologic suppression. Healthcare providers caring for PWHA should maintain vigilance for the development of a broad spectrum of cancers.",
"affiliations": "Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469, Korea.;Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469, Korea.;Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469, Korea.;Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469, Korea.;Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469, Korea.;Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469, Korea.;Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469, Korea.;Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea.;Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469, Korea. sijung@chonnam.ac.kr.",
"authors": "Kim|Seong Eun|SE|;Jung|Younggon|Y|http://orcid.org/0000-0002-1577-678X;Oh|Tae Hoon|TH|;Kim|Uh Jin|UJ|;Kang|Seung-Ji|SJ|;Jang|Hee-Chang|HC|;Park|Kyung-Hwa|KH|;Lee|Kyung-Hwa|KH|;Jung|Sook In|SI|",
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"fulltext": "\n==== Front\nBMC CancerBMC CancerBMC Cancer1471-2407BioMed Central London 501910.1186/s12885-018-5019-9Case ReportCase report: dual primary AIDS-defining cancers in an HIV-infected patient receiving antiretroviral therapy: Burkitt’s lymphoma and Kaposi’s sarcoma Kim Seong Eun favorofgod@daum.net 1http://orcid.org/0000-0002-1577-678XJung Younggon hehenayana@naver.com 1Oh Tae Hoon ojj1107@naver.com 1Kim Uh Jin astralio@naver.com 1Kang Seung-Ji sseungi@hanmail.net 1Jang Hee-Chang haroc153@naver.com 1Park Kyung-Hwa iammedkid@naver.com 1Lee Kyung-Hwa mdkaylee@jnu.ac.kr 2Jung Sook In +82.62.220-6502sijung@chonnam.ac.kr 11 0000 0001 0356 9399grid.14005.30Department of Infectious Diseases, Chonnam National University Medical School, 42, Jebong Ro, Donggu, Gwangju, 61469 Korea 2 0000 0001 0356 9399grid.14005.30Department of Pathology, Chonnam National University Medical School, Gwangju, Republic of Korea 8 11 2018 8 11 2018 2018 18 10807 8 2018 31 10 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\nThe incidence of AIDS-defining cancers (ADCs) has decreased markedly in the era of highly active antiretroviral therapy (HAART). The occurrence of two ADCs is rare in people living with HIV or AIDS (PWHA) who are severely immunosuppressed or have incomplete virologic suppression.\n\nCase presentation\nWe report a case of dual primary ADCs, especially NHL followed by KS, in a 70-year-old HIV-infected man who was on antiretroviral therapy and had successful virologic suppression. During HAART, he presented with generalized myalgia and abdominal pain. Multiple liver masses were detected and a biopsy revealed Burkitt’s lymphoma. After three cycles of anticancer chemotherapy with a favorable response, he was diagnosed with cytomegalovirus retinitis and the anti-cancer chemotherapy was discontinued. Despite successful virologic suppression with HAART, human herpes virus-8 associated Kaposi’s sarcoma was diagnosed in his right thigh. He underwent radiation therapy.\n\nConclusion\nThese findings suggest that multiple ADCs can occur in PWHA who are receiving HAART and have successful virologic suppression. Healthcare providers caring for PWHA should maintain vigilance for the development of a broad spectrum of cancers.\n\nKeywords\nHIVBurkitt’s lymphomaKaposi’s sarcomaAntiretroviral therapyissue-copyright-statement© The Author(s) 2018\n==== Body\nBackground\nThe introduction of highly active antiretroviral therapy (HAART) has changed the natural history of opportunistic infections (OIs) and malignancies among people with HIV or AIDS (PWHA). The incidence of AIDS-defining cancers (ADCs), including Kaposi’s sarcoma (KS), non-Hodgkin lymphoma (NHL), and invasive cervical cancer, has decreased significantly [1–3]. Conversely, an increased incidence of non-AIDS related cancers (NADCs) has been reported, especially cancers of the lungs, liver, kidneys, anus, head and neck, and skin, as well as Hodgkin lymphoma [4–7]. ADCs are associated with oncogenic viral infections, including Epstein-Barr virus (EBV), human herpes virus type 8 (HHV-8), cytomegalovirus (CMV), papillomavirus, and possibly other viral agents [3, 8]. The restoration of immune function by HAART may contribute to the decreased incidence of ADCs, which results in fewer AIDS-related deaths.\n\nThe occurrence of dual ADCs is rare in the era of antiretroviral therapy. Here, we describe a case of dual primary ADCs in an HIV-infected patient who was receiving HAART and had successful viral suppression.\n\nCase presentation\nA 70-year-old bisexual man was admitted with generalized myalgia and abdominal pain lasting for 7 days. Three months earlier, he was diagnosed with HIV infection during the evaluation of a fever. The initial HIV RNA level was 36,500 copies/mL, with 114 CD4+ lymphocytes/μL, which were consistent with the definition of AIDS [9] although the exact timing of HIV infection was unknown. At that time, abdominal and chest computed tomography (CT) showed no abnormality and an ophthalmologic examination showed no evidence of ocular disease. In addition, anti-cytomegalovirus (CMV) IgG was positive. For 3 months, he was treated with an integrase strand transfer inhibitor (INSTI)-based regimen (elvitegravir, cobicistat, tenofovir disoproxil fumarate, and emtricitabine) and showed good adherence.\n\nAt the time of the current admission, his vital signs were: blood pressure, 110/80 mmHg; pulse rate, 98/min; body temperature, 38.0 °C; and respiratory rate, 20/min. There was no localized tenderness of the abdomen on physical examination. The laboratory findings showed anemia (hemoglobin, 9.7 g/dL), thrombocytopenia (platelets, 53 × 103/mm3), acute kidney injury (creatinine, 1.8 mg/dL), and an elevated lactate dehydrogenase level (LDH; 6608 U/L). No HIV-RNA was detected (< 20 copies/mL), and there were 256 CD4+ lymphocytes/μL. Abdominal CT revealed multiple liver masses (Fig. 1a), and a core needle biopsy was performed to differentiate between liver abscess and malignancy. An atypical lymphocytic population composed of medium-sized basophilic cells was observed on hematoxylin and eosin staining (Fig. 2a). Immunohistochemistry was positive for the B cell markers CD20 (Fig. 2b) and CD79a (Fig. 2c), and the Ki-67 labelling index approached 90%. The tumor cells were also positive on EBV in situ hybridization (Fig. 2d). The liver lesion was diagnosed as Burkitt’s lymphoma. An additional diffuse hypermetabolic bone marrow lesion was found on positron emission tomography-CT (PET/CT), and he was confirmed to have stage IV Burkitt’s lymphoma by the Lugano classification.Fig. 1 (a) CT of the abdomen revealed 2.5- and 1.5-cm low-attenuated lesions in liver segment 5, with other smaller lesions in both hepatic lobes. (b) Thigh CT showed edematous changes in subcutaneous tissues of the right thigh\n\nFig. 2 (a) Histopathologically, the core biopsy from the liver showed a dense lymphocytic infiltration in the parenchyma (hematoxylin and eosin staining, original magnification × 100). (b-c) The tumor cells were immunopositive for CD20 (b) and CD79a (c) (immunohistochemistry, original magnification × 200). (d) The tumor cells displayed strong positivity on EBV in situ hybridization, consistent with Burkitt’s lymphoma (in situ hybridization, original magnification × 200)\n\n\n\nThree cycles of antineoplastic chemotherapy based on rituximab plus fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (R-hyper-CVAD) were administered, and two cycles of methotrexate were given via an intrathecal route. The HAART was replaced with another INSTI-based regimen (raltegravir, tenofovir disoproxil fumarate, and emtricitabine) after considering potential drug interactions. Interim PET/CT showed a partial response with marked improvement of the lymphomatous involvement in the bone marrow and liver, but hypermetabolic para-aortic, aortocaval lymph nodes remained 3 months after initiating chemotherapy.\n\nJust after the third cycle of R-hyper-CVAD, the patient suddenly complained of decreased visual acuity and an ophthalmologist diagnosed CMV retinitis. At that time, there were 56 CD4+ lymphocytes/μL, but no HIV RNA was detected (< 20 copies/mL). Intravitreal and intravenous ganciclovir were used for induction therapy, and valganciclovir maintenance therapy was continued. Chemotherapy was stopped after the third cycle of R-hyper-CVAD due to intolerance and the CMV retinitis. Four months after discontinuing the chemotherapy, PET/CT showed disease progression in the para-aortic, aortocaval lymph nodes, and newly developed lymphomatous involvement was seen in the paravertebral and cardiophrenic space.\n\nTen months after discontinuing systemic chemotherapy, the patient developed swelling and pain in his right thigh. CT showed edematous changes and skin thickening in this area (Fig. 1b, arrow), but there was no remarkable size increase in the inguinal lymph nodes. There were 129 CD4+ lymphocytes/μL, and HIV RNA was undetectable. A skin punch biopsy was performed because it was unclear whether the manifestation was related to the Burkitt’s lymphoma. The biopsy specimen was composed predominantly of plump spindle cells with intervening vascular spaces (Fig. 3a). Despite the bland cytology of the tumor cells, frequent mitotic figures were seen and the tumor was infiltrating the dermal collagen fibers. The tumor cells were positive for CD31 (Fig. 3b) and HHV-8 latent nuclear antigen-1 (LNA-1) by immunohistochemistry (Fig. 3c). The histology was consistent with KS. Twenty Grays of radiation were given in five fractions without systemic chemotherapy. Two months after radiation therapy, multiorgan (bone, liver, and pericardium) lymphoma aggravation led to his death.Fig. 3 (a) The skin biopsy revealed a highly cellular lesion composed of bland spindle cells and intervening irregular vascular spaces (hematoxylin and eosin staining, original magnification × 100). (b-c) The tumor cells were strongly positive for CD31 (b) and HHV-8 LNA-1 (c), a diagnostic marker of KS (immunohistochemistry, original magnification × 200)\n\n\n\nDiscussion\nTo our knowledge, this is the first described case of dual primary ADCs (NHL, followed by KS) in an HIV-infected patient who was receiving HAART and had successful viral suppression. Before the era of HAART, opportunistic infections and malignancies were major causes of death in PWHA. The introduction of HAART changed the trend in malignancies in PWHA in many countries [10–12]. The decrease in the prevalence of severe immunodeficiency resulted in a rapid reduction of new ADCs, such as KS and NHL [8, 11, 13, 14]. The Swiss HIV cohort study reported that the incidence of KS and NHL declined from 1,375/105 and 952/105 in the pre-HAART era (1985–1996) to 66.9/105 and 98.4/105, respectively, in the late HAART (2002–2006) period [13]. The incidence of ADCs is higher when patients have lower CD4 cell counts, initially present with cancer or revisit after loss to follow-up [15]. Conversely, the risk of ADC is reduced markedly among patients who remain in care and continue HAART [5]. Coexisting or metachronous KS and NHL are rarely reported in PWHA who have severe immunosuppression or incomplete virologic suppression [16–18]. Furthermore, KS developed first, followed by NHL, or these two ADCs developed simultaneously. Interestingly, the reduction in incidence after the introduction of HAART was pronounced for KS compared with NHL [8]. This suggests that patients cease to be at risk of KS once HAART has improved immune function, although patients with a history of severe immunodeficiency continue to be at risk of NHL despite HAART. In this report, NHL was detected first in a patient who was receiving HAART and showed successful viral suppression; KS developed 13 months later, despite discontinuing systemic chemotherapy for NHL. Dual primary malignancies are not uncommon in the general population. However, the relative risk of multiple ADCs in patients with HIV-related immunodeficiency is unknown. Our findings indicate the possibility of multiple ADCs in PWHA who are receiving HAART and show successful virologic suppression.\n\nHIV-related Burkitt’s lymphoma constitutes 24–35% of all HIV-related NHLs [19]. The cure rate was unsatisfactory in patients with HIV-related NHL before HAART, whereas the introduction of HAART increased the treatment options and improved the outcomes for patients with HIV-related Burkitt’s lymphoma [20]. HAART reduces the decline in CD4 counts during chemotherapy, ameliorating the potential for opportunistic infections. Our patient received HAART continuously during cytotoxic chemotherapy. However, in this patient, chemotherapy for Burkitt’s lymphoma could not be continued because of the occurrence of CMV retinitis despite an excellent response to chemotherapy. CMV reactivation during conventional chemotherapy may occur in a high proportion of patient, resulting in CMV-associated diseases [21]. A number of challenges exist in the management of Burkitt’s lymphoma in PWHA. Along with the high risk of tumor lysis syndrome caused by the high tumor burden, physicians should pay attention to the development of infectious or non-infectious complications during cytotoxic chemotherapy.\n\nHHV-8 infection is necessary for the development of KS [22]. KS was the most common ADC in PWHA, especially homosexual men in the early 1980s [23]. After the introduction of HAART, KS decreased dramatically in both the US and Europe [24]. There are three possible mechanisms by which HAART could block KS. They are HAART-induced immune reconstitution against HHV-8 and infected cells [25, 26], reduced circulating levels of HIV-1 Tat protein and inflammatory cytokines [27–29], and direct anti-spindle cell or anti-angiogenic effects of protease inhibitors [30]. In our patient, KS occurred while he was receiving HAART. KS has recently been reported to occur in people with a well-controlled HIV infection and CD4+ T-cell count > 200 cells/mm3. A recent study revealed that imperfect HAART adherence and a latest CD4 count < 350 cells/μL were significantly associated with KS development [31]. CD4 lymphocytes are recovered and resulting plateau about 2–3 years after HAART [32]. More frequent incomplete response (< 500/μL) was seen in patients with low CD4 T lymphocyte counts at baseline or long duration of pre-treatment HIV infection [33]. In this patient, initial CD4+ lymphocyte count at diagnosis was 114 cells/μL. At the time of KS diagnosis, our patient’s CD4+ lymphocyte count was 129 cells/μL although no HIV RNA was detected. The risk for subsequent KS among NHL survivors is relatively high in the general population [34]. Although the risk for the development of KS in HIV-positive NHL survivors is not known, the damaged immune system caused by HIV infection, NHL progression, and cytotoxic chemotherapy might have contributed to the development of KS in this patient.\n\nTests determining the risk of opportunistic infections should be performed for every patient with HIV entering into care as recommended in HIV primary care and opportunitstic infection guidelines [35, 36]. CMV retinitis can be diagnosed through a dilated pupil during an ophthalmoscopic examination by an experienced ophthalmologist. However, blood tests including CMV antigen detection, culture, or PCR are not recommended for diagnosis of CMV end-organ disease because of their poor positive predictive values. Serum antibody to CMV is not diagnostically useful [36]. In addition, use of serologic testing for HHV-8 antibodies is currently not indicated for either diagnostic testing or routine screening for HHV-8-related illnesses due to lack of standardization and poor sensitivity and specificity [37]. Although HIV-infected patients are more likely to have detectable plasma EBV DNA than are HIV-uninfected control subjects, the absolute level of EBV DNA is not predictive of progression to AIDS-related NHL [38]. In this patient, serum IgG antibody to CMV was detected at the time of HIV diagnosis. However, ophthalmologic examination revealed no evidence of CMV retinitis. Chest and abdominal CT showed no abnormality initially. Eventually, dual primary ADCs and CMV retinitis occurred despite viral suppression. Clinicians continue to monitor ADCs and OIs even in the situation of successful viral suppression with ART. Furthermore, development of diagnostic tools to easily predict ADCs and OIs is needed.\n\nConclusion\nIn summary, dual primary ADCs, especially NHL followed by KS, are uncommon in PWHA who are receiving HAART and show successful virologic suppression. Healthcare providers caring for PWHA should maintain high vigilance for the development of a broad spectrum of cancers in all HIV/AIDS patients.\n\nAbbreviations\nADCsAIDS defining cancers\n\nCDCluster of differentiation\n\nCMVCytomegalovirus\n\nCTComputed tomography\n\nEBVEpstein-Barr virus\n\nHAARTHighly active antiretroviral therapy\n\nHHV-8Human herpes virus type 8\n\nINSTIIntegrase strand transfer inhibitor\n\nKSKaposi’s sarcoma\n\nLDHLactate dehydrogenase\n\nLNA-1Latent nuclear antigen-1\n\nNADCNon-AIDS related cancers\n\nNHLNon-Hodgkin’s lymphoma\n\nOIOpportunistic infection\n\nPET-CTPositron emission tomography-computed tomography\n\nPWHAPeople with HIV or AIDS\n\nR-hyper-CVADRituximab plus fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone\n\nAcknowledgements\nNone.\n\nFunding\nNo funding was required for the writing of this case report.\n\nAvailability of data and materials\nNot applicable (no datasets were generated or analyzed during the current study).\n\nAuthors’ contributions\nSEK, SJK, HCJ, SIJ – participated in the clinical care of the patient on the ward. YJ, THO, UJK, HCJ– advised and supervised the laboratory testing, interpretation and reporting. YJ, KHL – perform pathologic diagnosis and report. THO, SJK, UJK, KHP, SIJ – were responsible for the concept for and critical contribution and revision to this manuscript. SEK, KHL, SIJ – wrote the manuscript. All authors critically reviewed the manuscript for publication. All authors read and approved the final manuscript.”\n\nEthics approval and consent to participate\nNot applicable.\n\nConsent for publication\nWritten consent to publish this case report was obtained from the patient (Consent No. 2017-JN24).\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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Robbins HA Shiels MS Pfeiffer RM Engels EA Epidemiologic contributions to recent cancer trends among HIV-infected people in the United States AIDS 2014 28 881 890 10.1097/QAD.0000000000000163 24300545 \n13. Franceschi S Lise M Clifford GM Rickenbach M Levi F Maspoli M Bouchardy C Dehler S Jundt G Ess S Bordoni A Konzelmann I Frick H Dal Maso L Elzi L Furrer H Calmy A Cavassini M Ledergerber B Keiser O Swiss HIV cohort study Changing patterns of cancer incidence in the early- and late-HAART periods: the Swiss HIV cohort study Br J Cancer 2010 103 416 422 10.1038/sj.bjc.6605756 20588274 \n14. 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Manfredi R Calza L Chiodo F Multiple AIDS-related malignancies just in the era of potent antiretroviral therapy. A rare but intriguing finding Infez Med 2003 11 153 156 14985648 \n18. Ascoli V Mastroianni CM Galati V Sirianni MC Fruscalzo A Pistilli A Lo Coco F Primary effusion lymphoma containing human herpesvirus 8 DNA in two AIDS patients with Kaposi's sarcoma Haematologica 1998 83 8 12 9542317 \n19. Hecht JL Aster JC Molecular biology of Burkitt's lymphoma J Clin Oncol 2000 18 3707 3721 10.1200/JCO.2000.18.21.3707 11054444 \n20. Levine AM Challenges in the management of Burkitt's lymphoma Clin Lymphoma 2002 3 Suppl 1 S19 S25 10.3816/CLM.2002.s.011 12521385 \n21. Kuo CP Wu CL Ho HT Chen CG Liu SI Lu YT Detection of cytomegalovirus reactivation in cancer patients receiving chemotherapy Clin Microbiol Infect 2008 14 221 227 10.1111/j.1469-0691.2007.01895.x 18070129 \n22. Chang Y Cesarman E Pessin MS Lee F Culpepper J Knowles DM Moore PS Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi's sarcoma Science 1994 266 1865 1869 10.1126/science.7997879 7997879 \n23. Katz MH Hessol NA Buchbinder SP Hirozawa A O'Malley P Holmberg SD Temporal trends of opportunistic infections and malignancies in homosexual men with AIDS J Infect Dis 1994 170 198 202 10.1093/infdis/170.1.198 8014498 \n24. La Ferla L Pinzone MR Nunnari G Martellotta F Lleshi A Tirelli U De Paoli P Berretta M Cacopardo B Kaposi' s sarcoma in HIV-positive patients: the state of art in the HAART-era Eur Rev Med Pharmacol Sci 2013 17 2354 2365 24065230 \n25. Brander C Suscovich T Lee Y Nguyen PT O'Connor P Seebach J Jones NG van Gorder M Walker BD Scadden DT Impaired CTL recognition of cells latently infected with Kaposi's sarcoma-associated herpes virus J Immunol 2000 165 2077 2083 10.4049/jimmunol.165.4.2077 10925292 \n26. 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Tovo PA Highly active antiretroviral therapy inhibits cytokine production in HIV-uninfected subjects AIDS 2000 14 743 744 10.1097/00002030-200004140-00014 10807198 \n30. Sgadari C Barillari G Toschi E Carlei D Bacigalupo I Baccarini S Palladino C Leone P Bugarini R Malavasi L Cafaro A Falchi M Valdembri D Rezza G Bussolino F Monini P Ensoli B HIV protease inhibitors are potent anti-angiogenic molecules and promote regression of Kaposi sarcoma Nat Med 2002 8 225 232 10.1038/nm0302-225 11875492 \n31. Lupia R Wabuyia PB Otiato P Fang CT Tsai FJ Risk factors for Kaposi's sarcoma in human immunodeficiency virus patients after initiation of antiretroviral therapy: a nested case-control study in Kenya J Microbiol Immunol Infect 2017 50 781 788 10.1016/j.jmii.2015.10.009 26712092 \n32. Kaufmann GR Perrin L Pantaleo G Opravil M Furrer H Telenti A Hirschel B Ledergerber B Vernazza P Bernasconi E Rickenbach M Egger M Battegay M Swiss HIV Cohort Study Group CD4 T-lymphocyte recovery in individuals with advanced HIV-1 infection receiving potent antiretroviral therapy for 4 years: the Swiss HIV cohort study Arch Intern Med 2003 163 2187 2195 10.1001/archinte.163.18.2187 14557216 \n33. Kaufmann GR Furrer H Ledergerber B Perrin L Opravil M Vernazza P Cavassini M Bernasconi E Rickenbach M Hirschel B Battegay M Swiss HIV Cohort Study Characteristics, determinants, and clinical relevance of CD4 T cell recovery to <500 cells/microL in HIV type 1-infected individuals receiving potent antiretroviral therapy Clin Infect Dis 2005 41 361 372 10.1086/431484 16007534 \n34. Dores GM, Cote TR, Travis LB. New malignancies following Hodgkin lymphoma, non-Hodgkin lymphoma, and myeloma. In: Curtis R, Freedman D, Ron E, et al., editors. New Malignancies Among Cancer Survivors: SEER Cancer Registries, 1973–2000. NIH Publ No 05–5302, 2006: p. 397-436. Available at https://seer.cancer.gov/archive/publications/mpmono/MPMonograph_complete.pdf.\n35. Aberg JA Gallant JE Ghanem KG Emmanuel P Zingman BS Horberg MA Infectious Diseases Society of America Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America Clin Infect Dis 2014 58 1 10 10.1093/cid/cit757 24343580 \n36. Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents. 2017. Available at https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-oi-prevention-and-treatment-guidelines/0.\n37. Morrison BJ Labo N Miley WJ Whitby D Serodiagnosis for tumor viruses Semin Oncol 2015 42 191 206 10.1053/j.seminoncol.2014.12.024 25843726 \n38. Van Baarle D Wolthers KC Hovenkamp E Hovenkamp E Niesters HG Osterhaus AD Miedema F Van Oers MH Absolute level of Epstein-Barr virus DNA in human immunodeficiency virus type 1 infection is not predictive of AIDS-related non-Hodgkin lymphoma J Infect Dis 2002 186 405 409 10.1086/341460 12134237\n\n",
"fulltext_license": "CC BY",
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"issue": "18(1)",
"journal": "BMC cancer",
"keywords": "Antiretroviral therapy; Burkitt’s lymphoma; HIV; Kaposi’s sarcoma",
"medline_ta": "BMC Cancer",
"mesh_terms": "D000163:Acquired Immunodeficiency Syndrome; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols; D023241:Antiretroviral Therapy, Highly Active; D015415:Biomarkers; D001706:Biopsy; D002051:Burkitt Lymphoma; D015658:HIV Infections; D006801:Humans; D008297:Male; D000072078:Positron Emission Tomography Computed Tomography; D012514:Sarcoma, Kaposi; D000072339:Sexual and Gender Minorities; D016896:Treatment Outcome",
"nlm_unique_id": "100967800",
"other_id": null,
"pages": "1080",
"pmc": null,
"pmid": "30409111",
"pubdate": "2018-11-08",
"publication_types": "D002363:Case Reports; D016428:Journal Article",
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"title": "Case report: dual primary AIDS-defining cancers in an HIV-infected patient receiving antiretroviral therapy: Burkitt's lymphoma and Kaposi's sarcoma.",
"title_normalized": "case report dual primary aids defining cancers in an hiv infected patient receiving antiretroviral therapy burkitt s lymphoma and kaposi s sarcoma"
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{
"abstract": "The present study was a phase I/II study to determine the maximum tolerated doses (MTDs) and dose-limiting toxicities of the biweekly carboplatin/gemcitabine combination and evaluate its safety and efficacy in patients aged ≥ 70 years with advanced squamous non-small-cell lung cancer (NSCLC).\n\n\n\nPatients aged ≥ 70 years with advanced or metastatic squamous NSCLC received escalated doses of carboplatin (area under the curve [AUC] 2-2.5 intravenously) and gemcitabine (800-1100 mg/m2 intravenously) every 2 weeks (phase I). In the phase II, the drugs were administered at their previously defined MTDs (carboplatin, AUC 2.5; gemcitabine, 1100 mg/m2). The primary endpoint was the overall response rate.\n\n\n\nA total of 69 patients were enrolled (phase I, n = 15). The median age was 76 years (range, 70-84 years); 52 patients had stage IV disease, and 61 and 8 patients had Eastern Cooperative Oncology Group performance status of 0 to 1 and 2, respectively. The MTDs could not be reached at the predefined last dose levels. The dose-limiting toxicities were grade 5 renal toxicity and grade 3 thrombocytopenia. In the phase II study, the overall response rate was 35.8% (95% confidence interval [CI], 23.0%-48.8%). In the intention-to-treat analysis, the median progression-free survival was 6.7 months (95% CI, 4.2-8.8 months), and the median overall survival was 13.3 months (95% CI, 7.1-19.6 months). Grade 3 or 4 neutropenia was observed in 7 patients (12.3%), grade 3 or 4 thrombocytopenia in 4 patients (7.1%), and grade 2 or 3 fatigue in 10 patients (17.5%). One toxic death occurred in the phase I of the study.\n\n\n\nThe biweekly regimen of gemcitabine and carboplatin showed satisfactory efficacy and a favorable toxicity profile in elderly patients with advanced or metastatic squamous cell NSCLC.",
"affiliations": "401 Army General Hospital, Athens, Greece; Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece; Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), Athens, Greece.;Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), Athens, Greece; Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Crete, Greece.;Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), Athens, Greece; Medical Oncology Department, 251 General Air Force Hospital, Athens, Greece.;Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), Athens, Greece; 1st Department of Medicine, Medical School, University of Athens, Laikon General Hospital, Athens, Greece.;Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), Athens, Greece; 1st Department of Pulmonary Disease, Sismanoglion Hospital, Athens, Greece.;Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), Athens, Greece; Unit of Medical Technology and Intelligent Information Systems, Department of Materials Science and Engineering, University of Ioannina, Ioannina, Greece.;401 Army General Hospital, Athens, Greece; Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), Athens, Greece.;Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece; Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), Athens, Greece; Department of Medical Oncology, University General Hospital of Heraklion, Heraklion, Crete, Greece.;Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), Athens, Greece.;Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), Athens, Greece.;Laboratory of Tumor Cell Biology, School of Medicine, University of Crete, Heraklion, Crete, Greece; Lung Cancer Working Group of the Hellenic Oncology Research Group (HORG), Athens, Greece. Electronic address: georgoul@med.uoc.gr.",
"authors": "Karampeazis|Athanasios|A|;Vamvakas|Lambros|L|;Kentepozidis|Nikolaos|N|;Polyzos|Aris|A|;Chandrinos|Vassilis|V|;Rigas|Georgios|G|;Christofyllakis|Charalambos|C|;Kotsakis|Athanasios|A|;Hatzidaki|Dora|D|;Pallis|Athanasios G|AG|;Georgoulias|Vassilis|V|",
"chemical_list": "D003841:Deoxycytidine; C056507:gemcitabine; D016190:Carboplatin",
"country": "United States",
"delete": false,
"doi": "10.1016/j.cllc.2016.05.009",
"fulltext": null,
"fulltext_license": null,
"issn_linking": "1525-7304",
"issue": "17(6)",
"journal": "Clinical lung cancer",
"keywords": "Geriatric assessment; NSCLC; Older; Phase I and II study; Platinum",
"medline_ta": "Clin Lung Cancer",
"mesh_terms": "D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols; D016190:Carboplatin; D002289:Carcinoma, Non-Small-Cell Lung; D002294:Carcinoma, Squamous Cell; D003841:Deoxycytidine; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms; D008297:Male; D020714:Maximum Tolerated Dose; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate",
"nlm_unique_id": "100893225",
"other_id": null,
"pages": "543-549",
"pmc": null,
"pmid": "27397849",
"pubdate": "2016-11",
"publication_types": "D017426:Clinical Trial, Phase I; D017427:Clinical Trial, Phase II; D016428:Journal Article; D016448:Multicenter Study; D013485:Research Support, Non-U.S. Gov't",
"references": null,
"title": "Biweekly Carboplatin Plus Gemcitabine as First-Line Treatment of Elderly Patients With Advanced Squamous Non-Small-cell Lung Cancer: A Multicenter Phase I-II Trial by the Hellenic Oncology Research Group.",
"title_normalized": "biweekly carboplatin plus gemcitabine as first line treatment of elderly patients with advanced squamous non small cell lung cancer a multicenter phase i ii trial by the hellenic oncology research group"
} | [
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"companynumb": "GR-PFIZER INC-2016510212",
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"actiondrug": "6",
"activesubstance": {
"activesubstancename": "GEMCITABINE HYDROCHLORIDE"
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"drugadditional"... |
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